TBD Meeting (3035-24)

Patients with early, triple negative breast cancer (TNBC) and high risk of recurrence after initial therapy had significantly better 3-year overall survival (OS) when given adjuvant avelumab compared with those who were observed without further treatment, in the A-BRAVE trial.

“The 30% reduction in the risk of distant metastasis, and 34% reduction in the risk of death suggests that avelumab may have a role in early triple negative breast cancer patients at high risk of relapse after primary surgery or with invasive residual disease after neoadjuvant chemotherapy,” Pierfranco Conte, MD, from the department of surgery, oncology, and gastroenterology at the University of Padua, Italy, reported at the annual meeting of the American Society of Clinical Oncology.

A-BRAVE is the first randomized phase 3 trial patients with TNBC, treated with adjuvant avelumab, explained Dr. Conte. “Neoadjuvant chemotherapy is recommended for stage cT1c or larger, or cN+ disease. However, in case of invasive residual disease at surgery, prognosis is still very poor.”

TNBC is more immunogenic compared with other breast cancer subtypes, suggesting a role for immune checkpoint inhibitors such as avelumab in this setting, he said.
 

A-BRAVE Methods and Results

The trial enrolled 477 patients, median age 51 years, between June 2016 and October 2020, after their disease had progressed following initial treatment. There were two strata of patients: those who had received upfront surgery and then adjuvant chemotherapy before disease progression (stratum A, 18%); and those who received neoadjuvant chemotherapy, surgery, and then adjuvant chemo, but still had residual disease (stratum B, 82%).

Patients were randomized to either observation (n = 239) or treatment with avelumab (n = 238), at a dose of 10 mg/kg every 2 weeks for one year.

At a median follow-up of 52.1 months, avelumab did not show an advantage for the primary endpoint of 3-year disease-free survival (DFS), with 68.3% of treated patients meeting this endpoint, compared to 63.2% of observed patients (hazard ratio [HR 0.81, P = .172].

However, the treatment did show statistically significant benefits for the secondary 3-year OS endpoint (84.8% vs 76.3%, HR 0.66, P = .035).

“Trying to understand why we did observe a greater benefit with avelumab in overall survival compared to disease-free survival, we also made a post-hoc exploratory analysis on distant disease-free survival,” explained Dr. Conte.

There was a statistically significant 3-year distant disease-free survival (DDFS) benefit for treated patients compared with controls (75.4% vs 67.9%, HR 0.7, P = .0277), translating to a 30% reduction in the risk of distant metastasis, he noted.
 

Findings Are ‘Hypothesis-Generating’

The results are “hypothesis-generating at this point,” Alexandra Thomas, MD, a breast medical oncologist who was not involved in the research, said in an interview. “These results suggest that the story on how to best utilize checkpoint blockade as adjuvant therapy in triple negative breast cancer may not yet be fully written.”

She emphasized the study did not meet its primary endpoint, “though the results for secondary endpoints OS and the exploratory endpoint DDFS are intriguing.

“A-BRAVE is a smaller study, especially relative to Impassion030 (ALEXANDRA), which enrolled over 2,000 patients,” she explained. “It is notable that avelumab has slightly different properties than atezolizumab, which was used in Impassion030.”

“Avelumab is also a weak PD-L2 inhibitor. Could this be important? Notably, today most patients with clinical stage II-III triple negative breast cancer will receive pembrolizumab as per KEYNOTE-522, so the potential for clinical impact is greatly reduced,” added Dr. Thomas, professor and assistant director in the department of internal medicine at Duke Cancer Institute, in Durham, North Carolina.

SWOG1814, which has not been reported yet, “also looks at pembrolizumab in patients with residual disease post neoadjuvant chemotherapy and will provide further important information on in this space,” she said.

Merck KGaA funded the study.

Dr. Conte disclosed consulting or advisory roles with Daiichi Sankyo/Lilly, Gilead Sciences, Reveal Genomics; a HER2Dx patient; and providing expert testimony for AstraZeneca.

Dr. Thomas disclosed research grants from Sanofi and Merck.

Patients with early, triple negative breast cancer (TNBC) and high risk of recurrence after initial therapy had significantly better 3-year overall survival (OS) when given adjuvant avelumab compared with those who were observed without further treatment, in the A-BRAVE trial.

“The 30% reduction in the risk of distant metastasis, and 34% reduction in the risk of death suggests that avelumab may have a role in early triple negative breast cancer patients at high risk of relapse after primary surgery or with invasive residual disease after neoadjuvant chemotherapy,” Pierfranco Conte, MD, from the department of surgery, oncology, and gastroenterology at the University of Padua, Italy, reported at the annual meeting of the American Society of Clinical Oncology.

A-BRAVE is the first randomized phase 3 trial patients with TNBC, treated with adjuvant avelumab, explained Dr. Conte. “Neoadjuvant chemotherapy is recommended for stage cT1c or larger, or cN+ disease. However, in case of invasive residual disease at surgery, prognosis is still very poor.”

TNBC is more immunogenic compared with other breast cancer subtypes, suggesting a role for immune checkpoint inhibitors such as avelumab in this setting, he said.
 

A-BRAVE Methods and Results

The trial enrolled 477 patients, median age 51 years, between June 2016 and October 2020, after their disease had progressed following initial treatment. There were two strata of patients: those who had received upfront surgery and then adjuvant chemotherapy before disease progression (stratum A, 18%); and those who received neoadjuvant chemotherapy, surgery, and then adjuvant chemo, but still had residual disease (stratum B, 82%).

Patients were randomized to either observation (n = 239) or treatment with avelumab (n = 238), at a dose of 10 mg/kg every 2 weeks for one year.

At a median follow-up of 52.1 months, avelumab did not show an advantage for the primary endpoint of 3-year disease-free survival (DFS), with 68.3% of treated patients meeting this endpoint, compared to 63.2% of observed patients (hazard ratio [HR 0.81, P = .172].

However, the treatment did show statistically significant benefits for the secondary 3-year OS endpoint (84.8% vs 76.3%, HR 0.66, P = .035).

“Trying to understand why we did observe a greater benefit with avelumab in overall survival compared to disease-free survival, we also made a post-hoc exploratory analysis on distant disease-free survival,” explained Dr. Conte.

There was a statistically significant 3-year distant disease-free survival (DDFS) benefit for treated patients compared with controls (75.4% vs 67.9%, HR 0.7, P = .0277), translating to a 30% reduction in the risk of distant metastasis, he noted.
 

Findings Are ‘Hypothesis-Generating’

The results are “hypothesis-generating at this point,” Alexandra Thomas, MD, a breast medical oncologist who was not involved in the research, said in an interview. “These results suggest that the story on how to best utilize checkpoint blockade as adjuvant therapy in triple negative breast cancer may not yet be fully written.”

She emphasized the study did not meet its primary endpoint, “though the results for secondary endpoints OS and the exploratory endpoint DDFS are intriguing.

“A-BRAVE is a smaller study, especially relative to Impassion030 (ALEXANDRA), which enrolled over 2,000 patients,” she explained. “It is notable that avelumab has slightly different properties than atezolizumab, which was used in Impassion030.”

“Avelumab is also a weak PD-L2 inhibitor. Could this be important? Notably, today most patients with clinical stage II-III triple negative breast cancer will receive pembrolizumab as per KEYNOTE-522, so the potential for clinical impact is greatly reduced,” added Dr. Thomas, professor and assistant director in the department of internal medicine at Duke Cancer Institute, in Durham, North Carolina.

SWOG1814, which has not been reported yet, “also looks at pembrolizumab in patients with residual disease post neoadjuvant chemotherapy and will provide further important information on in this space,” she said.

Merck KGaA funded the study.

Dr. Conte disclosed consulting or advisory roles with Daiichi Sankyo/Lilly, Gilead Sciences, Reveal Genomics; a HER2Dx patient; and providing expert testimony for AstraZeneca.

Dr. Thomas disclosed research grants from Sanofi and Merck.

Patients with early, triple negative breast cancer (TNBC) and high risk of recurrence after initial therapy had significantly better 3-year overall survival (OS) when given adjuvant avelumab compared with those who were observed without further treatment, in the A-BRAVE trial.

“The 30% reduction in the risk of distant metastasis, and 34% reduction in the risk of death suggests that avelumab may have a role in early triple negative breast cancer patients at high risk of relapse after primary surgery or with invasive residual disease after neoadjuvant chemotherapy,” Pierfranco Conte, MD, from the department of surgery, oncology, and gastroenterology at the University of Padua, Italy, reported at the annual meeting of the American Society of Clinical Oncology.

A-BRAVE is the first randomized phase 3 trial patients with TNBC, treated with adjuvant avelumab, explained Dr. Conte. “Neoadjuvant chemotherapy is recommended for stage cT1c or larger, or cN+ disease. However, in case of invasive residual disease at surgery, prognosis is still very poor.”

TNBC is more immunogenic compared with other breast cancer subtypes, suggesting a role for immune checkpoint inhibitors such as avelumab in this setting, he said.
 

A-BRAVE Methods and Results

The trial enrolled 477 patients, median age 51 years, between June 2016 and October 2020, after their disease had progressed following initial treatment. There were two strata of patients: those who had received upfront surgery and then adjuvant chemotherapy before disease progression (stratum A, 18%); and those who received neoadjuvant chemotherapy, surgery, and then adjuvant chemo, but still had residual disease (stratum B, 82%).

Patients were randomized to either observation (n = 239) or treatment with avelumab (n = 238), at a dose of 10 mg/kg every 2 weeks for one year.

At a median follow-up of 52.1 months, avelumab did not show an advantage for the primary endpoint of 3-year disease-free survival (DFS), with 68.3% of treated patients meeting this endpoint, compared to 63.2% of observed patients (hazard ratio [HR 0.81, P = .172].

However, the treatment did show statistically significant benefits for the secondary 3-year OS endpoint (84.8% vs 76.3%, HR 0.66, P = .035).

“Trying to understand why we did observe a greater benefit with avelumab in overall survival compared to disease-free survival, we also made a post-hoc exploratory analysis on distant disease-free survival,” explained Dr. Conte.

There was a statistically significant 3-year distant disease-free survival (DDFS) benefit for treated patients compared with controls (75.4% vs 67.9%, HR 0.7, P = .0277), translating to a 30% reduction in the risk of distant metastasis, he noted.
 

Findings Are ‘Hypothesis-Generating’

The results are “hypothesis-generating at this point,” Alexandra Thomas, MD, a breast medical oncologist who was not involved in the research, said in an interview. “These results suggest that the story on how to best utilize checkpoint blockade as adjuvant therapy in triple negative breast cancer may not yet be fully written.”

She emphasized the study did not meet its primary endpoint, “though the results for secondary endpoints OS and the exploratory endpoint DDFS are intriguing.

“A-BRAVE is a smaller study, especially relative to Impassion030 (ALEXANDRA), which enrolled over 2,000 patients,” she explained. “It is notable that avelumab has slightly different properties than atezolizumab, which was used in Impassion030.”

“Avelumab is also a weak PD-L2 inhibitor. Could this be important? Notably, today most patients with clinical stage II-III triple negative breast cancer will receive pembrolizumab as per KEYNOTE-522, so the potential for clinical impact is greatly reduced,” added Dr. Thomas, professor and assistant director in the department of internal medicine at Duke Cancer Institute, in Durham, North Carolina.

SWOG1814, which has not been reported yet, “also looks at pembrolizumab in patients with residual disease post neoadjuvant chemotherapy and will provide further important information on in this space,” she said.

Merck KGaA funded the study.

Dr. Conte disclosed consulting or advisory roles with Daiichi Sankyo/Lilly, Gilead Sciences, Reveal Genomics; a HER2Dx patient; and providing expert testimony for AstraZeneca.

Dr. Thomas disclosed research grants from Sanofi and Merck.

CHICAGO — An abbreviated course of azacitidine for 7 days plus venetoclax for 7 days showed similar efficacy to a standard hypomethylating agent plus venetoclax doublets in older and unfit patients with newly diagnosed acute myeloid leukemia (AML) in a multicenter retrospective analysis.

However, the azacitidine plus venetoclax therapy — the “7+7” regimen — was associated with lower platelet transfusion requirements and lower 8-week mortality, suggesting the regimen might be preferable in certain patient populations, Alexandre Bazinet, MD, of the University of Texas MD Anderson Cancer Center, Houston, reported at the American Society of Clinical Oncology (ASCO) annual meeting.

The composite complete remission (CRc) rate, including complete remission with or without complete count recovery, was identical at 72% among 82 patients treated with the 7+7 regimen and 166 treated with standard therapy, and the complete remission (CR) rate was 57% and 55%, respectively, Dr. Bazinet said.

The median number of cycles to first response was one in both groups, but 42% of responders in the 7+7 group required more than one cycle to achieve their first response, compared with just 1% of those in the standard therapy group, he noted, adding that the median number of cycles to achieve best response was two in the 7+7 group and one in the standard therapy group.

The mortality rate at 4 weeks was similar in the groups (2% vs 5% for 7+7 vs standard therapy), but at 8 weeks, the mortality rate was significantly higher in the standard therapy group (6% vs 16%, respectively). Median overall survival (OS) was 11.2 months versus 10.3 months, and median 2-year survival was 27.7% versus 33.6% in the groups, respectively.

Event-free survival was 6.5 versus 7.4 months, and 2-year event-free survival was 24.5% versus 27.0%, respectively.

Of note, fewer patients in the 7+7 group required platelet transfusions during cycle 1 (62% vs 77%) and the cycle 1 rates of neutropenic fever and red cell transfusion requirements were similar in the two treatment groups, Dr. Bazinet said.

Study participants were 82 adults from seven centers in France who received the 7+7 regimen, and 166 adults from MD Anderson who received standard therapy with a hypomethylating agent plus venetoclax doublets given for 21-28 days during induction. Preliminary data on the 7+7 regimen in patients from the French centers were reported previously and “suggested preserved efficacy with potentially less toxicity,” he noted.

“A hypomethylating agent plus venetoclax doublets are standard-of-care in patients with AML who are older or ineligible for chemotherapy due to comorbidities,” Dr. Bazinet explained, adding that although the venetoclax label calls for 28 days of drug per cycle, shorter courses of 14 to 21 days are commonly used.

These findings are limited by the retrospective study design and by small patient numbers in many subgroups, he said.

“In addition, the cohorts were heterogeneous, consisting of patients treated with a variety of different regimens and across multiple centers and countries. The distribution of FLT3-ITD and NRAS/KRAS mutations differed significantly between cohorts,” he explained, also noting that prophylactic azole use differed across the cohort. “Furthermore, analysis of the toxicity results was also limited by likely differing transfusion polices in different centers.”

Overall, however, the findings suggest that reducing the duration of venetoclax is safe and results in similar CRc rates, although responses may be faster with standard dosing, he said, adding that “7+7 is potentially less toxic and is attractive in patients who are more frail or at risk for complications.”

“Our data support further study of shorter venetoclax duration, within emerging triplet regimens in patients with intermediate or low predictive benefit to mitigate toxicity,” he concluded.

Dr. Bazinet reported having no disclosures.

CHICAGO — An abbreviated course of azacitidine for 7 days plus venetoclax for 7 days showed similar efficacy to a standard hypomethylating agent plus venetoclax doublets in older and unfit patients with newly diagnosed acute myeloid leukemia (AML) in a multicenter retrospective analysis.

However, the azacitidine plus venetoclax therapy — the “7+7” regimen — was associated with lower platelet transfusion requirements and lower 8-week mortality, suggesting the regimen might be preferable in certain patient populations, Alexandre Bazinet, MD, of the University of Texas MD Anderson Cancer Center, Houston, reported at the American Society of Clinical Oncology (ASCO) annual meeting.

The composite complete remission (CRc) rate, including complete remission with or without complete count recovery, was identical at 72% among 82 patients treated with the 7+7 regimen and 166 treated with standard therapy, and the complete remission (CR) rate was 57% and 55%, respectively, Dr. Bazinet said.

The median number of cycles to first response was one in both groups, but 42% of responders in the 7+7 group required more than one cycle to achieve their first response, compared with just 1% of those in the standard therapy group, he noted, adding that the median number of cycles to achieve best response was two in the 7+7 group and one in the standard therapy group.

The mortality rate at 4 weeks was similar in the groups (2% vs 5% for 7+7 vs standard therapy), but at 8 weeks, the mortality rate was significantly higher in the standard therapy group (6% vs 16%, respectively). Median overall survival (OS) was 11.2 months versus 10.3 months, and median 2-year survival was 27.7% versus 33.6% in the groups, respectively.

Event-free survival was 6.5 versus 7.4 months, and 2-year event-free survival was 24.5% versus 27.0%, respectively.

Of note, fewer patients in the 7+7 group required platelet transfusions during cycle 1 (62% vs 77%) and the cycle 1 rates of neutropenic fever and red cell transfusion requirements were similar in the two treatment groups, Dr. Bazinet said.

Study participants were 82 adults from seven centers in France who received the 7+7 regimen, and 166 adults from MD Anderson who received standard therapy with a hypomethylating agent plus venetoclax doublets given for 21-28 days during induction. Preliminary data on the 7+7 regimen in patients from the French centers were reported previously and “suggested preserved efficacy with potentially less toxicity,” he noted.

“A hypomethylating agent plus venetoclax doublets are standard-of-care in patients with AML who are older or ineligible for chemotherapy due to comorbidities,” Dr. Bazinet explained, adding that although the venetoclax label calls for 28 days of drug per cycle, shorter courses of 14 to 21 days are commonly used.

These findings are limited by the retrospective study design and by small patient numbers in many subgroups, he said.

“In addition, the cohorts were heterogeneous, consisting of patients treated with a variety of different regimens and across multiple centers and countries. The distribution of FLT3-ITD and NRAS/KRAS mutations differed significantly between cohorts,” he explained, also noting that prophylactic azole use differed across the cohort. “Furthermore, analysis of the toxicity results was also limited by likely differing transfusion polices in different centers.”

Overall, however, the findings suggest that reducing the duration of venetoclax is safe and results in similar CRc rates, although responses may be faster with standard dosing, he said, adding that “7+7 is potentially less toxic and is attractive in patients who are more frail or at risk for complications.”

“Our data support further study of shorter venetoclax duration, within emerging triplet regimens in patients with intermediate or low predictive benefit to mitigate toxicity,” he concluded.

Dr. Bazinet reported having no disclosures.

CHICAGO — An abbreviated course of azacitidine for 7 days plus venetoclax for 7 days showed similar efficacy to a standard hypomethylating agent plus venetoclax doublets in older and unfit patients with newly diagnosed acute myeloid leukemia (AML) in a multicenter retrospective analysis.

However, the azacitidine plus venetoclax therapy — the “7+7” regimen — was associated with lower platelet transfusion requirements and lower 8-week mortality, suggesting the regimen might be preferable in certain patient populations, Alexandre Bazinet, MD, of the University of Texas MD Anderson Cancer Center, Houston, reported at the American Society of Clinical Oncology (ASCO) annual meeting.

The composite complete remission (CRc) rate, including complete remission with or without complete count recovery, was identical at 72% among 82 patients treated with the 7+7 regimen and 166 treated with standard therapy, and the complete remission (CR) rate was 57% and 55%, respectively, Dr. Bazinet said.

The median number of cycles to first response was one in both groups, but 42% of responders in the 7+7 group required more than one cycle to achieve their first response, compared with just 1% of those in the standard therapy group, he noted, adding that the median number of cycles to achieve best response was two in the 7+7 group and one in the standard therapy group.

The mortality rate at 4 weeks was similar in the groups (2% vs 5% for 7+7 vs standard therapy), but at 8 weeks, the mortality rate was significantly higher in the standard therapy group (6% vs 16%, respectively). Median overall survival (OS) was 11.2 months versus 10.3 months, and median 2-year survival was 27.7% versus 33.6% in the groups, respectively.

Event-free survival was 6.5 versus 7.4 months, and 2-year event-free survival was 24.5% versus 27.0%, respectively.

Of note, fewer patients in the 7+7 group required platelet transfusions during cycle 1 (62% vs 77%) and the cycle 1 rates of neutropenic fever and red cell transfusion requirements were similar in the two treatment groups, Dr. Bazinet said.

Study participants were 82 adults from seven centers in France who received the 7+7 regimen, and 166 adults from MD Anderson who received standard therapy with a hypomethylating agent plus venetoclax doublets given for 21-28 days during induction. Preliminary data on the 7+7 regimen in patients from the French centers were reported previously and “suggested preserved efficacy with potentially less toxicity,” he noted.

“A hypomethylating agent plus venetoclax doublets are standard-of-care in patients with AML who are older or ineligible for chemotherapy due to comorbidities,” Dr. Bazinet explained, adding that although the venetoclax label calls for 28 days of drug per cycle, shorter courses of 14 to 21 days are commonly used.

These findings are limited by the retrospective study design and by small patient numbers in many subgroups, he said.

“In addition, the cohorts were heterogeneous, consisting of patients treated with a variety of different regimens and across multiple centers and countries. The distribution of FLT3-ITD and NRAS/KRAS mutations differed significantly between cohorts,” he explained, also noting that prophylactic azole use differed across the cohort. “Furthermore, analysis of the toxicity results was also limited by likely differing transfusion polices in different centers.”

Overall, however, the findings suggest that reducing the duration of venetoclax is safe and results in similar CRc rates, although responses may be faster with standard dosing, he said, adding that “7+7 is potentially less toxic and is attractive in patients who are more frail or at risk for complications.”

“Our data support further study of shorter venetoclax duration, within emerging triplet regimens in patients with intermediate or low predictive benefit to mitigate toxicity,” he concluded.

Dr. Bazinet reported having no disclosures.

The MUC-1 vaccine tecemotide plus standard neoadjuvant systemic therapy was shown to notably improve distant relapse-free survival and overall survival rates in breast cancer patients, in a new study.

“This is the first successful study of a breast cancer vaccine to date,” Christian F. Singer, MD, said during an interview. Dr. Singer, the lead author of the new study, presented the results during a poster session at the 2024 annual meeting of the American Society of Clinical Oncology (ASCO).

Previously known as both liposomal BLP25 and Stimuvax, tecemotide is an antigen-specific immunotherapy that targets the cancer therapy–resistant MUC-1 glycoprotein, which is overexpressed in over 90% of breast cancers. Tecemotide also has been shown to moderately improve overall survival rates in non–small cell lung cancer.

“We are not at all surprised by the results of this study in breast cancer,” Gregory T. Wurz, PhD, senior researcher at RCU Labs in Lincoln, California, said in an interview.

Dr. Wurz is coauthor of several studies on peptide vaccines, including a mouse model study of human MUC-1–expressing mammary tumors showing that tecemotide combined with letrozole had additive antitumor activity. Another paper he coauthored showed that ospemifene enhanced the immune response to tecemotide in both tumor-bearing and non–tumor-bearing mice. These findings, combined with other research, led to the creation of a patented method of combining therapies to enhance the efficacy of immunotherapy in the treatment of cancer and infectious diseases. Dr. Wurz was not involved in the new research that Dr. Singer presented at ASCO.
 

Study Methods and Results

Dr. Singer, head of obstetrics and gynecology at the Medical University of Vienna, Vienna, Austria, and coauthors randomized 400 patients with HER2-negative early breast cancer in a prospective, multicenter, two-arm, phase 2 ABCSG 34 trial to receive preoperative standard of care (SOC) neoadjuvant treatment with or without tecemotide.

Postmenopausal women with luminal A tumors were given 6 months of letrozole as SOC. Postmenopausal patients with triple-negative breast cancer, luminal B tumors, in whom chemotherapy was SOC, as well as all premenopausal study participants, were given four cycles of both epirubicin cyclophosphamide and docetaxel every 3 weeks.

The study’s primary endpoint was the residual cancer burden at the time of surgery.

Long-term outcomes were measured as part of a translational project, while distant relapse-free survival (DRFS) and overall survival (OS) were analyzed with Cox regression models. Long-term outcome data were available for 291 women, of whom 236 had received chemotherapy as SOC.

While tecemotide plus neoadjuvant SOC was not associated with a significant increase in residual cancer burden (RCB) at the time of surgery (36.4% vs 31.5%; P = .42; 40.5% vs 34.8%; P = .37 for the chemotherapy-only cohort), follow-up at 7 years showed 80.8% of patients who had received SOC plus tecemotide were still alive and free from metastasis.

In patients who had received SOC alone, the OS rate at 7 years with no metastasis was 64.7% (hazard ratio [HR] for DRFS, 0.53; 95% CI, 0.34-0.83; P = .005). The OS rate for the study group was 83.0% vs 68.2% in the non-tecemotide cohort (HR for OS, 0.53; 95% CI, 0.33-0.85; P = .008).

The lack of RCB signal at the endpoints, “tells us that pathologic complete response and residual cancer burden simply are not adequate endpoints for cancer vaccination studies and we need to find other predictive/prognostic markers, said Dr. Singer. “We are currently looking into this in exploratory studies.”

The chemotherapy plus tecemotide cohort had a notable outcome with a DRFS of 81.9% vs 65.0% in the SOC group (HR, 0.50; 95% CI, 0.31-0.83; P = .007), and an OS rate of 83.6% vs 67.8% (HR, 0.51; 95% CI, 0.30-0.88; P = .016).

Dr. Singer characterized the HRs as intriguing, saying that they “pave the way for new trials.”
 

Ideas for Further Study of Tecemotide

“What we would like to see next for tecemotide are clinical studies that explore whether immunomodulatory agents can further enhance the response to tecemotide in lung, breast, and potentially other MUC-1–expressing cancers,” Dr. Wurz said.

Future phase 3 studies of MUC-1 cancer vaccines, possibly those using mRNA technology, are yet to come, according to Dr. Singer. “We also need to find out why the vaccine works sometimes and sometimes not.”

Dr. Singer disclosed financial ties to AstraZeneca/MedImmune, Daiichi Sankyo Europe, Novartis, Gilead Sciences, Sanofi/Aventis, Amgen, Myriad Genetics, and Roche. Dr. Wurz had no disclosures, but his research partner and founder of RCU Labs, Michael De Gregorio, is the sole inventor of the patent referenced in the story. That patent has been assigned to the Regents of the University of California.

The MUC-1 vaccine tecemotide plus standard neoadjuvant systemic therapy was shown to notably improve distant relapse-free survival and overall survival rates in breast cancer patients, in a new study.

“This is the first successful study of a breast cancer vaccine to date,” Christian F. Singer, MD, said during an interview. Dr. Singer, the lead author of the new study, presented the results during a poster session at the 2024 annual meeting of the American Society of Clinical Oncology (ASCO).

Previously known as both liposomal BLP25 and Stimuvax, tecemotide is an antigen-specific immunotherapy that targets the cancer therapy–resistant MUC-1 glycoprotein, which is overexpressed in over 90% of breast cancers. Tecemotide also has been shown to moderately improve overall survival rates in non–small cell lung cancer.

“We are not at all surprised by the results of this study in breast cancer,” Gregory T. Wurz, PhD, senior researcher at RCU Labs in Lincoln, California, said in an interview.

Dr. Wurz is coauthor of several studies on peptide vaccines, including a mouse model study of human MUC-1–expressing mammary tumors showing that tecemotide combined with letrozole had additive antitumor activity. Another paper he coauthored showed that ospemifene enhanced the immune response to tecemotide in both tumor-bearing and non–tumor-bearing mice. These findings, combined with other research, led to the creation of a patented method of combining therapies to enhance the efficacy of immunotherapy in the treatment of cancer and infectious diseases. Dr. Wurz was not involved in the new research that Dr. Singer presented at ASCO.
 

Study Methods and Results

Dr. Singer, head of obstetrics and gynecology at the Medical University of Vienna, Vienna, Austria, and coauthors randomized 400 patients with HER2-negative early breast cancer in a prospective, multicenter, two-arm, phase 2 ABCSG 34 trial to receive preoperative standard of care (SOC) neoadjuvant treatment with or without tecemotide.

Postmenopausal women with luminal A tumors were given 6 months of letrozole as SOC. Postmenopausal patients with triple-negative breast cancer, luminal B tumors, in whom chemotherapy was SOC, as well as all premenopausal study participants, were given four cycles of both epirubicin cyclophosphamide and docetaxel every 3 weeks.

The study’s primary endpoint was the residual cancer burden at the time of surgery.

Long-term outcomes were measured as part of a translational project, while distant relapse-free survival (DRFS) and overall survival (OS) were analyzed with Cox regression models. Long-term outcome data were available for 291 women, of whom 236 had received chemotherapy as SOC.

While tecemotide plus neoadjuvant SOC was not associated with a significant increase in residual cancer burden (RCB) at the time of surgery (36.4% vs 31.5%; P = .42; 40.5% vs 34.8%; P = .37 for the chemotherapy-only cohort), follow-up at 7 years showed 80.8% of patients who had received SOC plus tecemotide were still alive and free from metastasis.

In patients who had received SOC alone, the OS rate at 7 years with no metastasis was 64.7% (hazard ratio [HR] for DRFS, 0.53; 95% CI, 0.34-0.83; P = .005). The OS rate for the study group was 83.0% vs 68.2% in the non-tecemotide cohort (HR for OS, 0.53; 95% CI, 0.33-0.85; P = .008).

The lack of RCB signal at the endpoints, “tells us that pathologic complete response and residual cancer burden simply are not adequate endpoints for cancer vaccination studies and we need to find other predictive/prognostic markers, said Dr. Singer. “We are currently looking into this in exploratory studies.”

The chemotherapy plus tecemotide cohort had a notable outcome with a DRFS of 81.9% vs 65.0% in the SOC group (HR, 0.50; 95% CI, 0.31-0.83; P = .007), and an OS rate of 83.6% vs 67.8% (HR, 0.51; 95% CI, 0.30-0.88; P = .016).

Dr. Singer characterized the HRs as intriguing, saying that they “pave the way for new trials.”
 

Ideas for Further Study of Tecemotide

“What we would like to see next for tecemotide are clinical studies that explore whether immunomodulatory agents can further enhance the response to tecemotide in lung, breast, and potentially other MUC-1–expressing cancers,” Dr. Wurz said.

Future phase 3 studies of MUC-1 cancer vaccines, possibly those using mRNA technology, are yet to come, according to Dr. Singer. “We also need to find out why the vaccine works sometimes and sometimes not.”

Dr. Singer disclosed financial ties to AstraZeneca/MedImmune, Daiichi Sankyo Europe, Novartis, Gilead Sciences, Sanofi/Aventis, Amgen, Myriad Genetics, and Roche. Dr. Wurz had no disclosures, but his research partner and founder of RCU Labs, Michael De Gregorio, is the sole inventor of the patent referenced in the story. That patent has been assigned to the Regents of the University of California.

The MUC-1 vaccine tecemotide plus standard neoadjuvant systemic therapy was shown to notably improve distant relapse-free survival and overall survival rates in breast cancer patients, in a new study.

“This is the first successful study of a breast cancer vaccine to date,” Christian F. Singer, MD, said during an interview. Dr. Singer, the lead author of the new study, presented the results during a poster session at the 2024 annual meeting of the American Society of Clinical Oncology (ASCO).

Previously known as both liposomal BLP25 and Stimuvax, tecemotide is an antigen-specific immunotherapy that targets the cancer therapy–resistant MUC-1 glycoprotein, which is overexpressed in over 90% of breast cancers. Tecemotide also has been shown to moderately improve overall survival rates in non–small cell lung cancer.

“We are not at all surprised by the results of this study in breast cancer,” Gregory T. Wurz, PhD, senior researcher at RCU Labs in Lincoln, California, said in an interview.

Dr. Wurz is coauthor of several studies on peptide vaccines, including a mouse model study of human MUC-1–expressing mammary tumors showing that tecemotide combined with letrozole had additive antitumor activity. Another paper he coauthored showed that ospemifene enhanced the immune response to tecemotide in both tumor-bearing and non–tumor-bearing mice. These findings, combined with other research, led to the creation of a patented method of combining therapies to enhance the efficacy of immunotherapy in the treatment of cancer and infectious diseases. Dr. Wurz was not involved in the new research that Dr. Singer presented at ASCO.
 

Study Methods and Results

Dr. Singer, head of obstetrics and gynecology at the Medical University of Vienna, Vienna, Austria, and coauthors randomized 400 patients with HER2-negative early breast cancer in a prospective, multicenter, two-arm, phase 2 ABCSG 34 trial to receive preoperative standard of care (SOC) neoadjuvant treatment with or without tecemotide.

Postmenopausal women with luminal A tumors were given 6 months of letrozole as SOC. Postmenopausal patients with triple-negative breast cancer, luminal B tumors, in whom chemotherapy was SOC, as well as all premenopausal study participants, were given four cycles of both epirubicin cyclophosphamide and docetaxel every 3 weeks.

The study’s primary endpoint was the residual cancer burden at the time of surgery.

Long-term outcomes were measured as part of a translational project, while distant relapse-free survival (DRFS) and overall survival (OS) were analyzed with Cox regression models. Long-term outcome data were available for 291 women, of whom 236 had received chemotherapy as SOC.

While tecemotide plus neoadjuvant SOC was not associated with a significant increase in residual cancer burden (RCB) at the time of surgery (36.4% vs 31.5%; P = .42; 40.5% vs 34.8%; P = .37 for the chemotherapy-only cohort), follow-up at 7 years showed 80.8% of patients who had received SOC plus tecemotide were still alive and free from metastasis.

In patients who had received SOC alone, the OS rate at 7 years with no metastasis was 64.7% (hazard ratio [HR] for DRFS, 0.53; 95% CI, 0.34-0.83; P = .005). The OS rate for the study group was 83.0% vs 68.2% in the non-tecemotide cohort (HR for OS, 0.53; 95% CI, 0.33-0.85; P = .008).

The lack of RCB signal at the endpoints, “tells us that pathologic complete response and residual cancer burden simply are not adequate endpoints for cancer vaccination studies and we need to find other predictive/prognostic markers, said Dr. Singer. “We are currently looking into this in exploratory studies.”

The chemotherapy plus tecemotide cohort had a notable outcome with a DRFS of 81.9% vs 65.0% in the SOC group (HR, 0.50; 95% CI, 0.31-0.83; P = .007), and an OS rate of 83.6% vs 67.8% (HR, 0.51; 95% CI, 0.30-0.88; P = .016).

Dr. Singer characterized the HRs as intriguing, saying that they “pave the way for new trials.”
 

Ideas for Further Study of Tecemotide

“What we would like to see next for tecemotide are clinical studies that explore whether immunomodulatory agents can further enhance the response to tecemotide in lung, breast, and potentially other MUC-1–expressing cancers,” Dr. Wurz said.

Future phase 3 studies of MUC-1 cancer vaccines, possibly those using mRNA technology, are yet to come, according to Dr. Singer. “We also need to find out why the vaccine works sometimes and sometimes not.”

Dr. Singer disclosed financial ties to AstraZeneca/MedImmune, Daiichi Sankyo Europe, Novartis, Gilead Sciences, Sanofi/Aventis, Amgen, Myriad Genetics, and Roche. Dr. Wurz had no disclosures, but his research partner and founder of RCU Labs, Michael De Gregorio, is the sole inventor of the patent referenced in the story. That patent has been assigned to the Regents of the University of California.

CHICAGO — Surgical resection is the standard of care for small colorectal liver metastases, but the results of a phase 3 trial reported at the American Society of Clinical Oncology (ASCO) 2024 annual meeting may prompt a change.

At nearly 30 months of follow-up, European investigators found no difference in overall and progression-free survival with thermal ablation instead of surgery, as well as better local control, fewer adverse events, shorter hospital stays, and no treatment-related deaths.

The benefit of thermal ablation was so substantial that the trial was stopped early with about 300 of the planned 600 patients randomized.

Numerous retrospective studies have compared the two approaches, and some have reported better survival with surgery. As a result, although a large number of lesions are amenable to either approach, “the majority of colorectal liver mets [are] still being” resected, said lead investigator and presenter Martijn R. Meijerink, MD, PhD, an interventional radiologist at the Amsterdam University Medical Center, Amsterdam, the Netherlands.

Dr. Meijerink said many of the previous reviews were unreliable due to selection bias because patients only had ablation if their lesions couldn’t be removed surgically. In contrast, all patients in the COLLISION trial were eligible for resection.

“Thermal ablation in experienced centers seems to be at least as good as surgical resection for small liver tumors.” Patients would benefit if it replaced surgery as the standard of care with no compromise in survival, Dr. Meijerink added.

The 296 COLLISION patients were treated at 14 centers in the Netherlands, Belgium, and Italy. They had no more than 12 liver lesions 3 cm or smaller with a median of two lesions. Participants were split equally between the ablation and surgical arms of the trial.

Almost half of the surgeries were laparoscopic, and nearly 60% of the ablations were percutaneous. Recent technological advances were used in the ablation cases, including software to confirm the complete eradication of targeted metastases.

At 28.8 months, there was no difference in overall survival between treatment arms (hazard ratio [HR], 1.051; P = .813) and no difference in local (HR, 0.817; P = .53) and distant (HR, 1.03; P = .836) progression-free survival. Local control — meaning treated lesions didn’t grow back — favored thermal ablation (HR, 0.092; P = .024).

The results held across number subgroup analyses, including by stage, molecular profile, and number of lesions.

“Interestingly, the majority of ablation site recurrences were somehow retreated, and most of them successfully, [while] the majority of resection plane recurrences were not retreated,” Dr. Meijerink said.

Patients with ablation vs surgery spent a median of 1 day vs 4 days in the hospital. Almost 20% of patients in the surgery group had grade 3/4 treatment-related adverse events vs 6% of those in the ablation group, which isn’t surprising, Dr. Meijerink said, because “the needle is less invasive than a knife.”

Three patients (2.1%) died of surgical complications, but there were no treatment-related deaths with ablation.

Major Kenneth Lee, MD, PhD, a gastrointestinal surgeon at the University of Pennsylvania, Philadelphia, who was the study discussant, emphasized the importance of gathering prospective data to compare the two approaches fairly.

“Ablation appears equivalent to resection for small, ideally located colorectal liver mets,” he said. Still, longer follow-up is needed to ensure that cure rates with ablation match those with surgery.

The study was funded by Medtronic-Covidien, a maker of thermal ablation equipment. Among other industry ties, Dr. Meijerink reported receiving honoraria and research funding from Medtronic and advising the company. Dr. Lee didn’t have any disclosures.

A version of this article appeared on Medscape.com.

CHICAGO — Surgical resection is the standard of care for small colorectal liver metastases, but the results of a phase 3 trial reported at the American Society of Clinical Oncology (ASCO) 2024 annual meeting may prompt a change.

At nearly 30 months of follow-up, European investigators found no difference in overall and progression-free survival with thermal ablation instead of surgery, as well as better local control, fewer adverse events, shorter hospital stays, and no treatment-related deaths.

The benefit of thermal ablation was so substantial that the trial was stopped early with about 300 of the planned 600 patients randomized.

Numerous retrospective studies have compared the two approaches, and some have reported better survival with surgery. As a result, although a large number of lesions are amenable to either approach, “the majority of colorectal liver mets [are] still being” resected, said lead investigator and presenter Martijn R. Meijerink, MD, PhD, an interventional radiologist at the Amsterdam University Medical Center, Amsterdam, the Netherlands.

Dr. Meijerink said many of the previous reviews were unreliable due to selection bias because patients only had ablation if their lesions couldn’t be removed surgically. In contrast, all patients in the COLLISION trial were eligible for resection.

“Thermal ablation in experienced centers seems to be at least as good as surgical resection for small liver tumors.” Patients would benefit if it replaced surgery as the standard of care with no compromise in survival, Dr. Meijerink added.

The 296 COLLISION patients were treated at 14 centers in the Netherlands, Belgium, and Italy. They had no more than 12 liver lesions 3 cm or smaller with a median of two lesions. Participants were split equally between the ablation and surgical arms of the trial.

Almost half of the surgeries were laparoscopic, and nearly 60% of the ablations were percutaneous. Recent technological advances were used in the ablation cases, including software to confirm the complete eradication of targeted metastases.

At 28.8 months, there was no difference in overall survival between treatment arms (hazard ratio [HR], 1.051; P = .813) and no difference in local (HR, 0.817; P = .53) and distant (HR, 1.03; P = .836) progression-free survival. Local control — meaning treated lesions didn’t grow back — favored thermal ablation (HR, 0.092; P = .024).

The results held across number subgroup analyses, including by stage, molecular profile, and number of lesions.

“Interestingly, the majority of ablation site recurrences were somehow retreated, and most of them successfully, [while] the majority of resection plane recurrences were not retreated,” Dr. Meijerink said.

Patients with ablation vs surgery spent a median of 1 day vs 4 days in the hospital. Almost 20% of patients in the surgery group had grade 3/4 treatment-related adverse events vs 6% of those in the ablation group, which isn’t surprising, Dr. Meijerink said, because “the needle is less invasive than a knife.”

Three patients (2.1%) died of surgical complications, but there were no treatment-related deaths with ablation.

Major Kenneth Lee, MD, PhD, a gastrointestinal surgeon at the University of Pennsylvania, Philadelphia, who was the study discussant, emphasized the importance of gathering prospective data to compare the two approaches fairly.

“Ablation appears equivalent to resection for small, ideally located colorectal liver mets,” he said. Still, longer follow-up is needed to ensure that cure rates with ablation match those with surgery.

The study was funded by Medtronic-Covidien, a maker of thermal ablation equipment. Among other industry ties, Dr. Meijerink reported receiving honoraria and research funding from Medtronic and advising the company. Dr. Lee didn’t have any disclosures.

A version of this article appeared on Medscape.com.

CHICAGO — Surgical resection is the standard of care for small colorectal liver metastases, but the results of a phase 3 trial reported at the American Society of Clinical Oncology (ASCO) 2024 annual meeting may prompt a change.

At nearly 30 months of follow-up, European investigators found no difference in overall and progression-free survival with thermal ablation instead of surgery, as well as better local control, fewer adverse events, shorter hospital stays, and no treatment-related deaths.

The benefit of thermal ablation was so substantial that the trial was stopped early with about 300 of the planned 600 patients randomized.

Numerous retrospective studies have compared the two approaches, and some have reported better survival with surgery. As a result, although a large number of lesions are amenable to either approach, “the majority of colorectal liver mets [are] still being” resected, said lead investigator and presenter Martijn R. Meijerink, MD, PhD, an interventional radiologist at the Amsterdam University Medical Center, Amsterdam, the Netherlands.

Dr. Meijerink said many of the previous reviews were unreliable due to selection bias because patients only had ablation if their lesions couldn’t be removed surgically. In contrast, all patients in the COLLISION trial were eligible for resection.

“Thermal ablation in experienced centers seems to be at least as good as surgical resection for small liver tumors.” Patients would benefit if it replaced surgery as the standard of care with no compromise in survival, Dr. Meijerink added.

The 296 COLLISION patients were treated at 14 centers in the Netherlands, Belgium, and Italy. They had no more than 12 liver lesions 3 cm or smaller with a median of two lesions. Participants were split equally between the ablation and surgical arms of the trial.

Almost half of the surgeries were laparoscopic, and nearly 60% of the ablations were percutaneous. Recent technological advances were used in the ablation cases, including software to confirm the complete eradication of targeted metastases.

At 28.8 months, there was no difference in overall survival between treatment arms (hazard ratio [HR], 1.051; P = .813) and no difference in local (HR, 0.817; P = .53) and distant (HR, 1.03; P = .836) progression-free survival. Local control — meaning treated lesions didn’t grow back — favored thermal ablation (HR, 0.092; P = .024).

The results held across number subgroup analyses, including by stage, molecular profile, and number of lesions.

“Interestingly, the majority of ablation site recurrences were somehow retreated, and most of them successfully, [while] the majority of resection plane recurrences were not retreated,” Dr. Meijerink said.

Patients with ablation vs surgery spent a median of 1 day vs 4 days in the hospital. Almost 20% of patients in the surgery group had grade 3/4 treatment-related adverse events vs 6% of those in the ablation group, which isn’t surprising, Dr. Meijerink said, because “the needle is less invasive than a knife.”

Three patients (2.1%) died of surgical complications, but there were no treatment-related deaths with ablation.

Major Kenneth Lee, MD, PhD, a gastrointestinal surgeon at the University of Pennsylvania, Philadelphia, who was the study discussant, emphasized the importance of gathering prospective data to compare the two approaches fairly.

“Ablation appears equivalent to resection for small, ideally located colorectal liver mets,” he said. Still, longer follow-up is needed to ensure that cure rates with ablation match those with surgery.

The study was funded by Medtronic-Covidien, a maker of thermal ablation equipment. Among other industry ties, Dr. Meijerink reported receiving honoraria and research funding from Medtronic and advising the company. Dr. Lee didn’t have any disclosures.

A version of this article appeared on Medscape.com.

A central aim of prostate cancer treatment is to prolong survival, but trials often overlook another key goal: Improving — or at least maintaining — quality of life (QoL).

The recent American Society of Clinical Oncology (ASCO) 2024 annual meeting dedicated a session to QoL outcomes in men with prostate cancer.

The trials explored the effects of treatment suspension or intensification on health-related QoL as well as interventions to manage side effects in different patient populations.

The first presentation focused on a post hoc analysis of the phase 3 EMBARK trial, which looked at the effect of suspending treatment on health-related QoL in men with nonmetastatic disease at a high risk for biochemical recurrence.

Earlier findings from the trial, presented at ESMO in 2023, showed enzalutamide alone or in combination with androgen deprivation therapy (ADT) was associated with a significant improvement in metastasis-free survival vs placebo plus leuprolide.

The initial trial randomized 1068 patients at a high risk for biochemical recurrence to these three treatment groups and suspended therapy at week 37 if prostate-specific antigen (PSA) levels fell below 0.2 ng/mL. Patients, however, were not randomized into the treatment suspension groups. Treatment resumed if PSA levels rose to ≥ 2.0 ng/mL in patients who had undergone radical prostatectomy or ≥ 5.0 ng/mL in those who had not had surgery.

The post hoc analysis, which assessed patient-reported QoL outcomes following treatment suspension at baseline and every 12 weeks until progression, found no meaningful changes in the worst pain in the past 24 hours, as measured by the Brief Pain Inventory–Short Form.

Patients also reported no meaningful changes in total and physical well-being scores on the Functional Assessment of Cancer Therapy–Prostate (FACT-P) and on the European Quality of Life Five-Dimensions (EuroQol-5D) visual analog scale score, as well as no meaningful changes in sexual activity and urinary and bowel symptoms, based on scores from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Prostate 25 (QLQ-PR25).

Hormone treatment-related symptoms on the QLQ-PR25, however, “quickly improved but eventually began to worsen after week 97,” explained lead author Stephen J. Freedland, MD, from Cedars-Sinai Medical Center, Los Angeles, California, who presented the new findings at ASCO.

Dr. Freedland concluded that the EMBARK results show that enzalutamide, with or without ADT, improves metastasis-free survival vs leuprolide alone, without affecting global health-related QoL during treatment or after treatment suspension.

However, Channing J. Paller, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine, Baltimore, Maryland, who was not involved in the research, pointed out that “patient selection is key” when choosing therapies, given that ADT has distinct adverse effects. Comorbidities and adverse effects “must be taken into consideration to help the doctor and patient make more personalized treatment choices.”
 

Treatment Intensification and QoL

Another presentation explored health-related QoL outcomes from the phase 3 PRESTO trial.

The study examined ADT intensification in 504 patients who had high-risk biochemically relapsed nonmetastatic hormone-sensitive prostate cancer and a PSA doubling time of 9 months or less. Patients were randomized to ADT monotherapy with degarelix or leuprolide, ADT plus apalutamide, or ADT plus apalutamide, abiraterone acetate, and prednisone.

In previous data from PRESTO, the combination therapy groups both had significantly longer median PSA progression-free survival than the ADT monotherapy arm.

The latest data looked at the health-related QoL outcomes in the PRESTO population, measured using the Expanded Prostate Cancer Index Composite, the PROMIS Fatigue tool, the Hot Flash Related Daily Interference Scale, and the EuroQol-5D.

Ronald C. Chen, MD, MPH, of the University of Kansas Medical Center, Kansas City, who presented the new findings at ASCO, reported that ADT plus apalutamide improved PSA progression-free survival over ADT alone and did not meaningfully increase common treatment-related symptoms, such as hormonal symptoms, sexual dysfunction, hot flash interference, and fatigue.

However, treatment intensification with triple androgen regimen did not lead to further improvements in PSA progression-free survival but did increase the rate of serious adverse events, the time to testosterone recover, and increased hot flash interference.

PRESTO as well as EMBARK “provide a strong rationale for intensification of androgen blockade in men with high-risk biochemical recurrence after completing primary local therapy” and could even “reduce the need for subsequent treatment,” concluded Dr. Chen.
 

CBT for Managing ADT Side Effects

Up to 80% of men receiving ADT to treat prostate cancer experience night sweats and hot flashes, which are associated with sleep disturbance, anxiety, low mood, and cognitive impairments.

A third trial presented during the session looked at the impact of cognitive-behavioral therapy (CBT) on these side effects of ADT treatment.

Initial findings from the MANCAN study found that CBT delivered by a psychologist reduced the impact of hot flashes and night sweats at 6 weeks.

The MANCAN2 study assessed QoL at 6 months among 162 patients with localized or advanced prostate cancer who underwent at least 6 months of continuous ADT and who experienced more severe hot flashes and night sweats, defined as a score of ≥ 2 on the hot flashes and night sweats problem rating scale.

Study participants were randomized to CBT plus treatment as usual, or treatment as usual alone, with the intervention consisting of two CBT group sessions 4 weeks apart. Between CBT sessions, patients could refer to a booklet and CD, alongside exercises and CBT strategies.

MANCAN2 confirmed that CBT was associated with a significantly greater reduction in hot flash and night sweat scores over standard care alone at 6 weeks. Patients receiving CBT also reported better QoL, sleep, and functional status but those differences did not reach statistical significance.

By 6 months, those in the CBT group still reported better outcomes in each category, but no differences were statistically significant at this time point. Overall, however, 14% of treatment as usual alone patients discontinued ADT at 6 months vs none in the CBT arm.

“Further research is therefore needed to determine whether or not you can make this effect more durable” and to look at “the potential for CBT to support treatment compliance,” said study presenter Simon J. Crabb, PhD, MBBS, from the University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, England.
 

QoL With Radioligand Crossover

Finally, the phase 3 PSMAfore study compared ¹⁷⁷Lu-PSMA-617 with abiraterone or enzalutamide in 468 taxane-naive patients with metastatic castration-resistant prostate cancer who had progressed on a previous androgen receptor pathway inhibitor.

In earlier analyses, Karim Fizazi, MD, PhD, Institut Gustave Roussy, Université Paris-Saclay, Paris, France, reported that ¹⁷⁷Lu-PSMA-617 improved radiographic progression-free survival by 59% over androgen receptor pathway inhibitor therapy but did not lead to significant differences in overall survival.

In a new interim analysis, Dr. Fizazi and colleagues explored outcomes in patients eligible to cross over to ¹⁷⁷Lu-PSMA-617 following androgen receptor pathway inhibitor therapy. Assessments of health-related QoL revealed that ¹⁷⁷Lu-PSMA-617 led to about a 40% improvement in scores on two QoL tools — 41% with FACT-P and 39% with EuroQol-5D.

On subscales of FACT-P, Dr. Fizazi reported that ¹⁷⁷Lu-PSMA-617 was also associated with a significantly longer time to worsening in physical, functional, and emotional well-being over standard therapy. A pain inventory score indicated that ¹⁷⁷Lu-PSMA-617 led to a 31% improvement in the time to worsening pain intensity, as well as a 33% increase in the time to worsening pain interference.

With the treatment having a “favorable safety profile,” Dr. Fizazi said the results suggest ¹⁷⁷Lu-PSMA-617 is a “treatment option” for patients with metastatic castration-resistant prostate cancer who have undergone androgen receptor pathway inhibitor treatment.

MANCAN2 was funded by the UK National Institute for Health and Care Research. EMBARK was funded by Astellas Pharma and Pfizer, the codevelopers of enzalutamide. PRESTO was funded by Alliance Foundation Trials and Johnson & Johnson. PSMAfore was funded by Novartis. Dr. Freedland declared relationships with Pfizer and Astellas Pharma, among others. Paller declared relationships with AstraZeneca, Dendreon, Exelixis, Janssen Oncology, Omnitura, Lilly, and Bayer. Dr. Chen declared relationships with Astellas Pharma, Pfizer, and others. Dr. Crabb declared relationships with AstraZeneca, Bristol-Myers Squibb, Ipsen, Merck, Amgen, Amphista Therapeutics, Bayer, Janssen, MSD, Pfizer, Astex Pharmaceuticals, Clovis Oncology, and Roche. Dr. Fizazi reported relationships with Novartis, AstraZeneca, and a dozen other companies.

A version of this article first appeared on Medscape.com.

A central aim of prostate cancer treatment is to prolong survival, but trials often overlook another key goal: Improving — or at least maintaining — quality of life (QoL).

The recent American Society of Clinical Oncology (ASCO) 2024 annual meeting dedicated a session to QoL outcomes in men with prostate cancer.

The trials explored the effects of treatment suspension or intensification on health-related QoL as well as interventions to manage side effects in different patient populations.

The first presentation focused on a post hoc analysis of the phase 3 EMBARK trial, which looked at the effect of suspending treatment on health-related QoL in men with nonmetastatic disease at a high risk for biochemical recurrence.

Earlier findings from the trial, presented at ESMO in 2023, showed enzalutamide alone or in combination with androgen deprivation therapy (ADT) was associated with a significant improvement in metastasis-free survival vs placebo plus leuprolide.

The initial trial randomized 1068 patients at a high risk for biochemical recurrence to these three treatment groups and suspended therapy at week 37 if prostate-specific antigen (PSA) levels fell below 0.2 ng/mL. Patients, however, were not randomized into the treatment suspension groups. Treatment resumed if PSA levels rose to ≥ 2.0 ng/mL in patients who had undergone radical prostatectomy or ≥ 5.0 ng/mL in those who had not had surgery.

The post hoc analysis, which assessed patient-reported QoL outcomes following treatment suspension at baseline and every 12 weeks until progression, found no meaningful changes in the worst pain in the past 24 hours, as measured by the Brief Pain Inventory–Short Form.

Patients also reported no meaningful changes in total and physical well-being scores on the Functional Assessment of Cancer Therapy–Prostate (FACT-P) and on the European Quality of Life Five-Dimensions (EuroQol-5D) visual analog scale score, as well as no meaningful changes in sexual activity and urinary and bowel symptoms, based on scores from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Prostate 25 (QLQ-PR25).

Hormone treatment-related symptoms on the QLQ-PR25, however, “quickly improved but eventually began to worsen after week 97,” explained lead author Stephen J. Freedland, MD, from Cedars-Sinai Medical Center, Los Angeles, California, who presented the new findings at ASCO.

Dr. Freedland concluded that the EMBARK results show that enzalutamide, with or without ADT, improves metastasis-free survival vs leuprolide alone, without affecting global health-related QoL during treatment or after treatment suspension.

However, Channing J. Paller, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine, Baltimore, Maryland, who was not involved in the research, pointed out that “patient selection is key” when choosing therapies, given that ADT has distinct adverse effects. Comorbidities and adverse effects “must be taken into consideration to help the doctor and patient make more personalized treatment choices.”
 

Treatment Intensification and QoL

Another presentation explored health-related QoL outcomes from the phase 3 PRESTO trial.

The study examined ADT intensification in 504 patients who had high-risk biochemically relapsed nonmetastatic hormone-sensitive prostate cancer and a PSA doubling time of 9 months or less. Patients were randomized to ADT monotherapy with degarelix or leuprolide, ADT plus apalutamide, or ADT plus apalutamide, abiraterone acetate, and prednisone.

In previous data from PRESTO, the combination therapy groups both had significantly longer median PSA progression-free survival than the ADT monotherapy arm.

The latest data looked at the health-related QoL outcomes in the PRESTO population, measured using the Expanded Prostate Cancer Index Composite, the PROMIS Fatigue tool, the Hot Flash Related Daily Interference Scale, and the EuroQol-5D.

Ronald C. Chen, MD, MPH, of the University of Kansas Medical Center, Kansas City, who presented the new findings at ASCO, reported that ADT plus apalutamide improved PSA progression-free survival over ADT alone and did not meaningfully increase common treatment-related symptoms, such as hormonal symptoms, sexual dysfunction, hot flash interference, and fatigue.

However, treatment intensification with triple androgen regimen did not lead to further improvements in PSA progression-free survival but did increase the rate of serious adverse events, the time to testosterone recover, and increased hot flash interference.

PRESTO as well as EMBARK “provide a strong rationale for intensification of androgen blockade in men with high-risk biochemical recurrence after completing primary local therapy” and could even “reduce the need for subsequent treatment,” concluded Dr. Chen.
 

CBT for Managing ADT Side Effects

Up to 80% of men receiving ADT to treat prostate cancer experience night sweats and hot flashes, which are associated with sleep disturbance, anxiety, low mood, and cognitive impairments.

A third trial presented during the session looked at the impact of cognitive-behavioral therapy (CBT) on these side effects of ADT treatment.

Initial findings from the MANCAN study found that CBT delivered by a psychologist reduced the impact of hot flashes and night sweats at 6 weeks.

The MANCAN2 study assessed QoL at 6 months among 162 patients with localized or advanced prostate cancer who underwent at least 6 months of continuous ADT and who experienced more severe hot flashes and night sweats, defined as a score of ≥ 2 on the hot flashes and night sweats problem rating scale.

Study participants were randomized to CBT plus treatment as usual, or treatment as usual alone, with the intervention consisting of two CBT group sessions 4 weeks apart. Between CBT sessions, patients could refer to a booklet and CD, alongside exercises and CBT strategies.

MANCAN2 confirmed that CBT was associated with a significantly greater reduction in hot flash and night sweat scores over standard care alone at 6 weeks. Patients receiving CBT also reported better QoL, sleep, and functional status but those differences did not reach statistical significance.

By 6 months, those in the CBT group still reported better outcomes in each category, but no differences were statistically significant at this time point. Overall, however, 14% of treatment as usual alone patients discontinued ADT at 6 months vs none in the CBT arm.

“Further research is therefore needed to determine whether or not you can make this effect more durable” and to look at “the potential for CBT to support treatment compliance,” said study presenter Simon J. Crabb, PhD, MBBS, from the University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, England.
 

QoL With Radioligand Crossover

Finally, the phase 3 PSMAfore study compared ¹⁷⁷Lu-PSMA-617 with abiraterone or enzalutamide in 468 taxane-naive patients with metastatic castration-resistant prostate cancer who had progressed on a previous androgen receptor pathway inhibitor.

In earlier analyses, Karim Fizazi, MD, PhD, Institut Gustave Roussy, Université Paris-Saclay, Paris, France, reported that ¹⁷⁷Lu-PSMA-617 improved radiographic progression-free survival by 59% over androgen receptor pathway inhibitor therapy but did not lead to significant differences in overall survival.

In a new interim analysis, Dr. Fizazi and colleagues explored outcomes in patients eligible to cross over to ¹⁷⁷Lu-PSMA-617 following androgen receptor pathway inhibitor therapy. Assessments of health-related QoL revealed that ¹⁷⁷Lu-PSMA-617 led to about a 40% improvement in scores on two QoL tools — 41% with FACT-P and 39% with EuroQol-5D.

On subscales of FACT-P, Dr. Fizazi reported that ¹⁷⁷Lu-PSMA-617 was also associated with a significantly longer time to worsening in physical, functional, and emotional well-being over standard therapy. A pain inventory score indicated that ¹⁷⁷Lu-PSMA-617 led to a 31% improvement in the time to worsening pain intensity, as well as a 33% increase in the time to worsening pain interference.

With the treatment having a “favorable safety profile,” Dr. Fizazi said the results suggest ¹⁷⁷Lu-PSMA-617 is a “treatment option” for patients with metastatic castration-resistant prostate cancer who have undergone androgen receptor pathway inhibitor treatment.

MANCAN2 was funded by the UK National Institute for Health and Care Research. EMBARK was funded by Astellas Pharma and Pfizer, the codevelopers of enzalutamide. PRESTO was funded by Alliance Foundation Trials and Johnson & Johnson. PSMAfore was funded by Novartis. Dr. Freedland declared relationships with Pfizer and Astellas Pharma, among others. Paller declared relationships with AstraZeneca, Dendreon, Exelixis, Janssen Oncology, Omnitura, Lilly, and Bayer. Dr. Chen declared relationships with Astellas Pharma, Pfizer, and others. Dr. Crabb declared relationships with AstraZeneca, Bristol-Myers Squibb, Ipsen, Merck, Amgen, Amphista Therapeutics, Bayer, Janssen, MSD, Pfizer, Astex Pharmaceuticals, Clovis Oncology, and Roche. Dr. Fizazi reported relationships with Novartis, AstraZeneca, and a dozen other companies.

A version of this article first appeared on Medscape.com.

A central aim of prostate cancer treatment is to prolong survival, but trials often overlook another key goal: Improving — or at least maintaining — quality of life (QoL).

The recent American Society of Clinical Oncology (ASCO) 2024 annual meeting dedicated a session to QoL outcomes in men with prostate cancer.

The trials explored the effects of treatment suspension or intensification on health-related QoL as well as interventions to manage side effects in different patient populations.

The first presentation focused on a post hoc analysis of the phase 3 EMBARK trial, which looked at the effect of suspending treatment on health-related QoL in men with nonmetastatic disease at a high risk for biochemical recurrence.

Earlier findings from the trial, presented at ESMO in 2023, showed enzalutamide alone or in combination with androgen deprivation therapy (ADT) was associated with a significant improvement in metastasis-free survival vs placebo plus leuprolide.

The initial trial randomized 1068 patients at a high risk for biochemical recurrence to these three treatment groups and suspended therapy at week 37 if prostate-specific antigen (PSA) levels fell below 0.2 ng/mL. Patients, however, were not randomized into the treatment suspension groups. Treatment resumed if PSA levels rose to ≥ 2.0 ng/mL in patients who had undergone radical prostatectomy or ≥ 5.0 ng/mL in those who had not had surgery.

The post hoc analysis, which assessed patient-reported QoL outcomes following treatment suspension at baseline and every 12 weeks until progression, found no meaningful changes in the worst pain in the past 24 hours, as measured by the Brief Pain Inventory–Short Form.

Patients also reported no meaningful changes in total and physical well-being scores on the Functional Assessment of Cancer Therapy–Prostate (FACT-P) and on the European Quality of Life Five-Dimensions (EuroQol-5D) visual analog scale score, as well as no meaningful changes in sexual activity and urinary and bowel symptoms, based on scores from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Prostate 25 (QLQ-PR25).

Hormone treatment-related symptoms on the QLQ-PR25, however, “quickly improved but eventually began to worsen after week 97,” explained lead author Stephen J. Freedland, MD, from Cedars-Sinai Medical Center, Los Angeles, California, who presented the new findings at ASCO.

Dr. Freedland concluded that the EMBARK results show that enzalutamide, with or without ADT, improves metastasis-free survival vs leuprolide alone, without affecting global health-related QoL during treatment or after treatment suspension.

However, Channing J. Paller, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine, Baltimore, Maryland, who was not involved in the research, pointed out that “patient selection is key” when choosing therapies, given that ADT has distinct adverse effects. Comorbidities and adverse effects “must be taken into consideration to help the doctor and patient make more personalized treatment choices.”
 

Treatment Intensification and QoL

Another presentation explored health-related QoL outcomes from the phase 3 PRESTO trial.

The study examined ADT intensification in 504 patients who had high-risk biochemically relapsed nonmetastatic hormone-sensitive prostate cancer and a PSA doubling time of 9 months or less. Patients were randomized to ADT monotherapy with degarelix or leuprolide, ADT plus apalutamide, or ADT plus apalutamide, abiraterone acetate, and prednisone.

In previous data from PRESTO, the combination therapy groups both had significantly longer median PSA progression-free survival than the ADT monotherapy arm.

The latest data looked at the health-related QoL outcomes in the PRESTO population, measured using the Expanded Prostate Cancer Index Composite, the PROMIS Fatigue tool, the Hot Flash Related Daily Interference Scale, and the EuroQol-5D.

Ronald C. Chen, MD, MPH, of the University of Kansas Medical Center, Kansas City, who presented the new findings at ASCO, reported that ADT plus apalutamide improved PSA progression-free survival over ADT alone and did not meaningfully increase common treatment-related symptoms, such as hormonal symptoms, sexual dysfunction, hot flash interference, and fatigue.

However, treatment intensification with triple androgen regimen did not lead to further improvements in PSA progression-free survival but did increase the rate of serious adverse events, the time to testosterone recover, and increased hot flash interference.

PRESTO as well as EMBARK “provide a strong rationale for intensification of androgen blockade in men with high-risk biochemical recurrence after completing primary local therapy” and could even “reduce the need for subsequent treatment,” concluded Dr. Chen.
 

CBT for Managing ADT Side Effects

Up to 80% of men receiving ADT to treat prostate cancer experience night sweats and hot flashes, which are associated with sleep disturbance, anxiety, low mood, and cognitive impairments.

A third trial presented during the session looked at the impact of cognitive-behavioral therapy (CBT) on these side effects of ADT treatment.

Initial findings from the MANCAN study found that CBT delivered by a psychologist reduced the impact of hot flashes and night sweats at 6 weeks.

The MANCAN2 study assessed QoL at 6 months among 162 patients with localized or advanced prostate cancer who underwent at least 6 months of continuous ADT and who experienced more severe hot flashes and night sweats, defined as a score of ≥ 2 on the hot flashes and night sweats problem rating scale.

Study participants were randomized to CBT plus treatment as usual, or treatment as usual alone, with the intervention consisting of two CBT group sessions 4 weeks apart. Between CBT sessions, patients could refer to a booklet and CD, alongside exercises and CBT strategies.

MANCAN2 confirmed that CBT was associated with a significantly greater reduction in hot flash and night sweat scores over standard care alone at 6 weeks. Patients receiving CBT also reported better QoL, sleep, and functional status but those differences did not reach statistical significance.

By 6 months, those in the CBT group still reported better outcomes in each category, but no differences were statistically significant at this time point. Overall, however, 14% of treatment as usual alone patients discontinued ADT at 6 months vs none in the CBT arm.

“Further research is therefore needed to determine whether or not you can make this effect more durable” and to look at “the potential for CBT to support treatment compliance,” said study presenter Simon J. Crabb, PhD, MBBS, from the University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, England.
 

QoL With Radioligand Crossover

Finally, the phase 3 PSMAfore study compared ¹⁷⁷Lu-PSMA-617 with abiraterone or enzalutamide in 468 taxane-naive patients with metastatic castration-resistant prostate cancer who had progressed on a previous androgen receptor pathway inhibitor.

In earlier analyses, Karim Fizazi, MD, PhD, Institut Gustave Roussy, Université Paris-Saclay, Paris, France, reported that ¹⁷⁷Lu-PSMA-617 improved radiographic progression-free survival by 59% over androgen receptor pathway inhibitor therapy but did not lead to significant differences in overall survival.

In a new interim analysis, Dr. Fizazi and colleagues explored outcomes in patients eligible to cross over to ¹⁷⁷Lu-PSMA-617 following androgen receptor pathway inhibitor therapy. Assessments of health-related QoL revealed that ¹⁷⁷Lu-PSMA-617 led to about a 40% improvement in scores on two QoL tools — 41% with FACT-P and 39% with EuroQol-5D.

On subscales of FACT-P, Dr. Fizazi reported that ¹⁷⁷Lu-PSMA-617 was also associated with a significantly longer time to worsening in physical, functional, and emotional well-being over standard therapy. A pain inventory score indicated that ¹⁷⁷Lu-PSMA-617 led to a 31% improvement in the time to worsening pain intensity, as well as a 33% increase in the time to worsening pain interference.

With the treatment having a “favorable safety profile,” Dr. Fizazi said the results suggest ¹⁷⁷Lu-PSMA-617 is a “treatment option” for patients with metastatic castration-resistant prostate cancer who have undergone androgen receptor pathway inhibitor treatment.

MANCAN2 was funded by the UK National Institute for Health and Care Research. EMBARK was funded by Astellas Pharma and Pfizer, the codevelopers of enzalutamide. PRESTO was funded by Alliance Foundation Trials and Johnson & Johnson. PSMAfore was funded by Novartis. Dr. Freedland declared relationships with Pfizer and Astellas Pharma, among others. Paller declared relationships with AstraZeneca, Dendreon, Exelixis, Janssen Oncology, Omnitura, Lilly, and Bayer. Dr. Chen declared relationships with Astellas Pharma, Pfizer, and others. Dr. Crabb declared relationships with AstraZeneca, Bristol-Myers Squibb, Ipsen, Merck, Amgen, Amphista Therapeutics, Bayer, Janssen, MSD, Pfizer, Astex Pharmaceuticals, Clovis Oncology, and Roche. Dr. Fizazi reported relationships with Novartis, AstraZeneca, and a dozen other companies.

A version of this article first appeared on Medscape.com.

Findings from the phase 3 ESOPEC trial demonstrate an overall survival advantage with a perioperative chemotherapy regimen known as FLOT, compared with a neoadjuvant chemoradiation approach, called CROSS, in patients with resectable, locally advanced esophageal adenocarcinoma.

The study results, presented as a late-breaking abstract at the annual meeting of the American Society of Clinical Oncology (ASCO), help settle a long-standing debate about whether chemotherapy with FLOT — 5-florouracil, leucovorin, oxaliplatin, and docetaxel — before and after surgery, or neoadjuvant radiation plus CROSS — carboplatin and paclitaxel — followed by surgery is the best approach.

There has been “considerable disagreement as to whether giving all adjuvant therapy upfront versus ‘sandwich’ adjuvant therapy before and after surgery is the better standard of care for locally advanced resectable esophageal cancer,” Jennifer Tseng, MD, of Boston Medical Center, Boston, said in an ASCO press release. This randomized clinical trial shows the sandwich approach “provides better outcomes.”

The practice-changing ESOPEC findings will have an important effect on the management of patients with resectable esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma, but local and distant failures remain a challenge in this population, explained invited discussant Karyn A. Goodman, MD.

Advances since the initiation of ESOPEC — such as immunotherapy options and personalized strategies — suggest the esophageal adenocarcinoma story is still evolving, said Dr. Goodman, professor and vice chair of research and quality in the Department of Radiation Oncology at Icahn School of Medicine at Mount Sinai, New York. 
 

The ESOPEC trial

Both the FLOT and CROSS regimens are established standards of care in resectable esophageal adenocarcinoma, and the choice of treatment has largely varied based on geographical location.

The current randomized, prospective, open-label ESOPEC trial, however, demonstrated that FLOT can prolong overall survival, first author Jens Hoeppner, MD, from the University of Bielefeld in Detmold, Germany, reported.

Overall, 438 patients with locally advanced, resectable esophageal adenocarcinoma recruited between February 2016 and April 2020 from 25 sites in Germany and randomized to either FLOT (n = 221) or CROSS (n = 217). The median age was 63 years, and most (89.3%) were men. Patients were followed until November 2023, and median follow-up was 55 months.

Patients in the FLOT arm received four cycles — one every 2 weeks for 8 weeks — followed by surgery 4-6 weeks later. FLOT cycles were reinitiated 4-6 weeks after surgery and given every 2 weeks for 8 weeks.

Those in the CROSS arm received one cycle per week of radiation therapy for 5 weeks plus carboplatin and paclitaxel followed by surgery 4-6 weeks after the last cycle.

Overall, 86% received both neoadjuvant therapy and surgery in the FLOT arm versus 82.9% in the CROSS group. Among these patients, 16.8% in the FLOT group achieved a pathological complete remission versus 10.0% in the CROSS arm.

In the intention-to-treat population, median overall survival was almost twice as long in the FLOT group — 66 months versus 37 months. At 3 years, those who received FLOT had a 30% lower risk of dying (hazard ratio [HR], 0.70), with 57.4% of patients alive at that point, compared with 50.7% patients in the CROSS arm.

The 5-year overall survival was 50.6% in the FLOT group versus 38.7% in the CROSS group.

Patients receiving FLOT also demonstrated improved progression-free survival (PFS), with a median PFS of 38 months versus 16 months. The 3-year PFS was 51.6% with FLOT versus 35.0% with CROSS (HR, 0.66). The exploratory subgroup analyses for sex, age, ECOG status, and clinical T and N stages also favored FLOT.

The 30-day postoperative mortality was 1.0% in the FLOT group and 1.7% in the CROSS group, and the 90-day postoperative mortality rate was 3.2% and 5.6%, respectively.

Based on these findings, perioperative chemotherapy with FLOT should be preferred over neoadjuvant chemoradiation with CROSS, Dr. Hoeppner concluded.

Dr. Goodman agreed, noting that, in the wake of ESOPEC, FLOT will likely be adopted as a more standard approach in the United States for patients who are fit. And, for patients who are not candidates for FLOT, CROSS is a reasonable option, she said.

But, she asked, does it really have to be an either/or situation?

Multiple studies, including Dr. Goodman’s 2021 Alliance/CALGB 80803 study, have demonstrated promising outcomes with combined modalities and adapting therapy based on treatment response. Several trials, for instance, are evaluating combining FLOT and CROSS, with some showing the approach is feasible and comes with manageable toxicity.

It’s also important to look outside of FLOT and CROSS. During ESOPEC, new approaches entered the treatment landscape, including the use of adjuvant immunotherapy following neoadjuvant chemoradiation and surgery for noncomplete response.

Take the CheckMate 577 study, which found that adjuvant nivolumab immunotherapy after preoperative CROSS and surgery significantly reduced metastatic recurrence and doubled disease-free survival in patients who did not achieve a complete response. This approach is now a standard of care for those patients.

FLOT plus neoadjuvant nivolumab may also be a viable option, Dr. Goodman noted, but we haven’t yet seen “any benefit in survival with the combo of chemotherapy and immunotherapy for resectable esophago-gastric cancer.”

Further studies are needed to evaluate the synergy of immunotherapy and radiotherapy. The next chapter of the esophageal adenocarcinoma story may feature a “best-of-both-worlds” approach that combines induction chemotherapy, followed by personalized chemoradiation, surgery, and potentially adjuvant immunotherapy, Dr. Goodman explained.

While the ESOPEC findings are impressive, the 5-year overall survival of only 50% is still suboptimal, she noted. “Given the poor prognosis with this disease, we need to continue to develop clinical trials to identify better targets, novel treatment combinations, and select patients that will respond best to specific treatment.”

ESOPEC was funded by the Deutsche Forschungsgemeinschaft (German Research Foundation). Dr. Hoeppner reported receiving travel, accommodations, and expenses from Intuitive Surgical. Dr. Goodman reported a relationship with the National Cancer Institute and consulting or advisory roles for Novartis, Philips Healthcare, RenovoRX, and Roche/Genentech.

A version of this article first appeared on Medscape.com.

Findings from the phase 3 ESOPEC trial demonstrate an overall survival advantage with a perioperative chemotherapy regimen known as FLOT, compared with a neoadjuvant chemoradiation approach, called CROSS, in patients with resectable, locally advanced esophageal adenocarcinoma.

The study results, presented as a late-breaking abstract at the annual meeting of the American Society of Clinical Oncology (ASCO), help settle a long-standing debate about whether chemotherapy with FLOT — 5-florouracil, leucovorin, oxaliplatin, and docetaxel — before and after surgery, or neoadjuvant radiation plus CROSS — carboplatin and paclitaxel — followed by surgery is the best approach.

There has been “considerable disagreement as to whether giving all adjuvant therapy upfront versus ‘sandwich’ adjuvant therapy before and after surgery is the better standard of care for locally advanced resectable esophageal cancer,” Jennifer Tseng, MD, of Boston Medical Center, Boston, said in an ASCO press release. This randomized clinical trial shows the sandwich approach “provides better outcomes.”

The practice-changing ESOPEC findings will have an important effect on the management of patients with resectable esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma, but local and distant failures remain a challenge in this population, explained invited discussant Karyn A. Goodman, MD.

Advances since the initiation of ESOPEC — such as immunotherapy options and personalized strategies — suggest the esophageal adenocarcinoma story is still evolving, said Dr. Goodman, professor and vice chair of research and quality in the Department of Radiation Oncology at Icahn School of Medicine at Mount Sinai, New York. 
 

The ESOPEC trial

Both the FLOT and CROSS regimens are established standards of care in resectable esophageal adenocarcinoma, and the choice of treatment has largely varied based on geographical location.

The current randomized, prospective, open-label ESOPEC trial, however, demonstrated that FLOT can prolong overall survival, first author Jens Hoeppner, MD, from the University of Bielefeld in Detmold, Germany, reported.

Overall, 438 patients with locally advanced, resectable esophageal adenocarcinoma recruited between February 2016 and April 2020 from 25 sites in Germany and randomized to either FLOT (n = 221) or CROSS (n = 217). The median age was 63 years, and most (89.3%) were men. Patients were followed until November 2023, and median follow-up was 55 months.

Patients in the FLOT arm received four cycles — one every 2 weeks for 8 weeks — followed by surgery 4-6 weeks later. FLOT cycles were reinitiated 4-6 weeks after surgery and given every 2 weeks for 8 weeks.

Those in the CROSS arm received one cycle per week of radiation therapy for 5 weeks plus carboplatin and paclitaxel followed by surgery 4-6 weeks after the last cycle.

Overall, 86% received both neoadjuvant therapy and surgery in the FLOT arm versus 82.9% in the CROSS group. Among these patients, 16.8% in the FLOT group achieved a pathological complete remission versus 10.0% in the CROSS arm.

In the intention-to-treat population, median overall survival was almost twice as long in the FLOT group — 66 months versus 37 months. At 3 years, those who received FLOT had a 30% lower risk of dying (hazard ratio [HR], 0.70), with 57.4% of patients alive at that point, compared with 50.7% patients in the CROSS arm.

The 5-year overall survival was 50.6% in the FLOT group versus 38.7% in the CROSS group.

Patients receiving FLOT also demonstrated improved progression-free survival (PFS), with a median PFS of 38 months versus 16 months. The 3-year PFS was 51.6% with FLOT versus 35.0% with CROSS (HR, 0.66). The exploratory subgroup analyses for sex, age, ECOG status, and clinical T and N stages also favored FLOT.

The 30-day postoperative mortality was 1.0% in the FLOT group and 1.7% in the CROSS group, and the 90-day postoperative mortality rate was 3.2% and 5.6%, respectively.

Based on these findings, perioperative chemotherapy with FLOT should be preferred over neoadjuvant chemoradiation with CROSS, Dr. Hoeppner concluded.

Dr. Goodman agreed, noting that, in the wake of ESOPEC, FLOT will likely be adopted as a more standard approach in the United States for patients who are fit. And, for patients who are not candidates for FLOT, CROSS is a reasonable option, she said.

But, she asked, does it really have to be an either/or situation?

Multiple studies, including Dr. Goodman’s 2021 Alliance/CALGB 80803 study, have demonstrated promising outcomes with combined modalities and adapting therapy based on treatment response. Several trials, for instance, are evaluating combining FLOT and CROSS, with some showing the approach is feasible and comes with manageable toxicity.

It’s also important to look outside of FLOT and CROSS. During ESOPEC, new approaches entered the treatment landscape, including the use of adjuvant immunotherapy following neoadjuvant chemoradiation and surgery for noncomplete response.

Take the CheckMate 577 study, which found that adjuvant nivolumab immunotherapy after preoperative CROSS and surgery significantly reduced metastatic recurrence and doubled disease-free survival in patients who did not achieve a complete response. This approach is now a standard of care for those patients.

FLOT plus neoadjuvant nivolumab may also be a viable option, Dr. Goodman noted, but we haven’t yet seen “any benefit in survival with the combo of chemotherapy and immunotherapy for resectable esophago-gastric cancer.”

Further studies are needed to evaluate the synergy of immunotherapy and radiotherapy. The next chapter of the esophageal adenocarcinoma story may feature a “best-of-both-worlds” approach that combines induction chemotherapy, followed by personalized chemoradiation, surgery, and potentially adjuvant immunotherapy, Dr. Goodman explained.

While the ESOPEC findings are impressive, the 5-year overall survival of only 50% is still suboptimal, she noted. “Given the poor prognosis with this disease, we need to continue to develop clinical trials to identify better targets, novel treatment combinations, and select patients that will respond best to specific treatment.”

ESOPEC was funded by the Deutsche Forschungsgemeinschaft (German Research Foundation). Dr. Hoeppner reported receiving travel, accommodations, and expenses from Intuitive Surgical. Dr. Goodman reported a relationship with the National Cancer Institute and consulting or advisory roles for Novartis, Philips Healthcare, RenovoRX, and Roche/Genentech.

A version of this article first appeared on Medscape.com.

Findings from the phase 3 ESOPEC trial demonstrate an overall survival advantage with a perioperative chemotherapy regimen known as FLOT, compared with a neoadjuvant chemoradiation approach, called CROSS, in patients with resectable, locally advanced esophageal adenocarcinoma.

The study results, presented as a late-breaking abstract at the annual meeting of the American Society of Clinical Oncology (ASCO), help settle a long-standing debate about whether chemotherapy with FLOT — 5-florouracil, leucovorin, oxaliplatin, and docetaxel — before and after surgery, or neoadjuvant radiation plus CROSS — carboplatin and paclitaxel — followed by surgery is the best approach.

There has been “considerable disagreement as to whether giving all adjuvant therapy upfront versus ‘sandwich’ adjuvant therapy before and after surgery is the better standard of care for locally advanced resectable esophageal cancer,” Jennifer Tseng, MD, of Boston Medical Center, Boston, said in an ASCO press release. This randomized clinical trial shows the sandwich approach “provides better outcomes.”

The practice-changing ESOPEC findings will have an important effect on the management of patients with resectable esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma, but local and distant failures remain a challenge in this population, explained invited discussant Karyn A. Goodman, MD.

Advances since the initiation of ESOPEC — such as immunotherapy options and personalized strategies — suggest the esophageal adenocarcinoma story is still evolving, said Dr. Goodman, professor and vice chair of research and quality in the Department of Radiation Oncology at Icahn School of Medicine at Mount Sinai, New York. 
 

The ESOPEC trial

Both the FLOT and CROSS regimens are established standards of care in resectable esophageal adenocarcinoma, and the choice of treatment has largely varied based on geographical location.

The current randomized, prospective, open-label ESOPEC trial, however, demonstrated that FLOT can prolong overall survival, first author Jens Hoeppner, MD, from the University of Bielefeld in Detmold, Germany, reported.

Overall, 438 patients with locally advanced, resectable esophageal adenocarcinoma recruited between February 2016 and April 2020 from 25 sites in Germany and randomized to either FLOT (n = 221) or CROSS (n = 217). The median age was 63 years, and most (89.3%) were men. Patients were followed until November 2023, and median follow-up was 55 months.

Patients in the FLOT arm received four cycles — one every 2 weeks for 8 weeks — followed by surgery 4-6 weeks later. FLOT cycles were reinitiated 4-6 weeks after surgery and given every 2 weeks for 8 weeks.

Those in the CROSS arm received one cycle per week of radiation therapy for 5 weeks plus carboplatin and paclitaxel followed by surgery 4-6 weeks after the last cycle.

Overall, 86% received both neoadjuvant therapy and surgery in the FLOT arm versus 82.9% in the CROSS group. Among these patients, 16.8% in the FLOT group achieved a pathological complete remission versus 10.0% in the CROSS arm.

In the intention-to-treat population, median overall survival was almost twice as long in the FLOT group — 66 months versus 37 months. At 3 years, those who received FLOT had a 30% lower risk of dying (hazard ratio [HR], 0.70), with 57.4% of patients alive at that point, compared with 50.7% patients in the CROSS arm.

The 5-year overall survival was 50.6% in the FLOT group versus 38.7% in the CROSS group.

Patients receiving FLOT also demonstrated improved progression-free survival (PFS), with a median PFS of 38 months versus 16 months. The 3-year PFS was 51.6% with FLOT versus 35.0% with CROSS (HR, 0.66). The exploratory subgroup analyses for sex, age, ECOG status, and clinical T and N stages also favored FLOT.

The 30-day postoperative mortality was 1.0% in the FLOT group and 1.7% in the CROSS group, and the 90-day postoperative mortality rate was 3.2% and 5.6%, respectively.

Based on these findings, perioperative chemotherapy with FLOT should be preferred over neoadjuvant chemoradiation with CROSS, Dr. Hoeppner concluded.

Dr. Goodman agreed, noting that, in the wake of ESOPEC, FLOT will likely be adopted as a more standard approach in the United States for patients who are fit. And, for patients who are not candidates for FLOT, CROSS is a reasonable option, she said.

But, she asked, does it really have to be an either/or situation?

Multiple studies, including Dr. Goodman’s 2021 Alliance/CALGB 80803 study, have demonstrated promising outcomes with combined modalities and adapting therapy based on treatment response. Several trials, for instance, are evaluating combining FLOT and CROSS, with some showing the approach is feasible and comes with manageable toxicity.

It’s also important to look outside of FLOT and CROSS. During ESOPEC, new approaches entered the treatment landscape, including the use of adjuvant immunotherapy following neoadjuvant chemoradiation and surgery for noncomplete response.

Take the CheckMate 577 study, which found that adjuvant nivolumab immunotherapy after preoperative CROSS and surgery significantly reduced metastatic recurrence and doubled disease-free survival in patients who did not achieve a complete response. This approach is now a standard of care for those patients.

FLOT plus neoadjuvant nivolumab may also be a viable option, Dr. Goodman noted, but we haven’t yet seen “any benefit in survival with the combo of chemotherapy and immunotherapy for resectable esophago-gastric cancer.”

Further studies are needed to evaluate the synergy of immunotherapy and radiotherapy. The next chapter of the esophageal adenocarcinoma story may feature a “best-of-both-worlds” approach that combines induction chemotherapy, followed by personalized chemoradiation, surgery, and potentially adjuvant immunotherapy, Dr. Goodman explained.

While the ESOPEC findings are impressive, the 5-year overall survival of only 50% is still suboptimal, she noted. “Given the poor prognosis with this disease, we need to continue to develop clinical trials to identify better targets, novel treatment combinations, and select patients that will respond best to specific treatment.”

ESOPEC was funded by the Deutsche Forschungsgemeinschaft (German Research Foundation). Dr. Hoeppner reported receiving travel, accommodations, and expenses from Intuitive Surgical. Dr. Goodman reported a relationship with the National Cancer Institute and consulting or advisory roles for Novartis, Philips Healthcare, RenovoRX, and Roche/Genentech.

A version of this article first appeared on Medscape.com.

CHICAGO — Adding carboplatin to standard anthracycline/taxane treatment for early-stage triple-negative breast cancer (TNBC) improves event-free and overall survival in the neoadjuvant and adjuvant setting, according to a phase 3 trial presented at the annual meeting of the American Society of Clinical Oncology (ASCO).

The outcomes of the South Korean study, dubbed PEARLY, provide strong evidence for incorporating carboplatin into both the neoadjuvant and adjuvant settings in patients with early-stage TNBC, said lead investigator and presenter Joohyuk Sohn, MD, PhD, a medical oncologist at Yonsei University, Seoul, South Korea.

In early-stage TNBC, carboplatin is already being incorporated into the neoadjuvant setting on the basis of trial results from KEYNOTE-522 that demonstrated improved pathologic complete response rates and event-free survival with the platinum alongside pembrolizumab.

However, the overall survival benefit of carboplatin in this setting remains unclear, as does the benefit of platinum add-on in the adjuvant setting, Dr. Sohn explained.

Dr. Sohn and colleagues randomized 868 patients evenly to either standard treatment — doxorubicin, anthracycline, and cyclophosphamide followed by a taxane — or an experimental arm that added carboplatin to the taxane phase of treatment.

About 30% of women were treated in the adjuvant setting, the rest in the neoadjuvant setting. The two arms of the study were generally well balanced — about 80% of patients had stage II disease, half were node negative, and 11% had deleterious germline mutations.

The primary endpoint, event-free survival, was broadly defined. Events included disease progression, local or distant recurrence, occurrence of a second primary cancer, inoperable status after neoadjuvant therapy, or death from any cause.

Adding carboplatin increased 5-year event-free survival rates from 75.1% to 82.3% (hazard ratio [HR], 0.67; P = .012) with the benefit holding across various subgroup analyses and particularly strong for adjuvant carboplatin (HR, 0.26).

Five-year overall survival was also better in the carboplatin arm — 90.7% vs 87% in the control arm (HR, 0.65; 95% CI, 0.42-1.02) — but that benefit did not reach statistical significance (P = .057)

Invasive disease-free survival (HR, 0.73) and distant recurrence-free survival (HR, 0.77) favored carboplatin, but the results also weren’t statistically significant.

Overall, 46% of patients had a pathologic complete response with carboplatin vs nearly 40% in the control arm. The pathologic complete response benefit from carboplatin add-on was consistent with past reports.

As expected, adding carboplatin to treatment increased hematologic toxicity and other adverse events, with three-quarters of patients experiencing grade 3 or worse adverse events vs 56.7% of control participants. There was one death in the carboplatin arm from pneumonia and two in the control arm — one from septic shock and the other from suicide.

Dr. Sohn and colleagues, however, did not observe a quality of life difference between the two groups.

“The PEARLY trial provides compelling evidence for including carboplatin in the treatment of early-stage TNBC,” Dr. Sohn concluded, adding that the results underscore the benefit in the neoadjuvant setting and suggest “potential applicability in the adjuvant setting post surgery.”

Study discussant Javier Cortes, MD, PhD, believes that the PEARLY provides a strong signal for adding carboplatin in the adjuvant setting.

“That’s something I would do in my clinical practice,” said Dr. Cortes, head of the International Breast Cancer Center in Barcelona, Spain. “After ASCO this year, I would offer taxanes plus carboplatin following anthracyclines.”

An audience member, William Sikov, MD, a breast cancer specialist at Brown University in Providence, Rhode Island, said he hopes “we’ve reached the end of a road that started many years ago in terms of incorporating carboplatin as part of neoadjuvant and adjuvant therapy for triple-negative breast cancer, where we finally [reach] consensus that this is necessary in our triple-negative patients.”

The work was funded by the government of South Korea and others. Dr. Sohn reported stock in Daiichi Sankyo and research funding from Daiichi and other companies. Dr. Cortes disclosed numerous industry ties, including honoraria, research funding, and/or travel expenses from AstraZeneca, Daiichi, and others.

A version of this article first appeared on Medscape.com.

CHICAGO — Adding carboplatin to standard anthracycline/taxane treatment for early-stage triple-negative breast cancer (TNBC) improves event-free and overall survival in the neoadjuvant and adjuvant setting, according to a phase 3 trial presented at the annual meeting of the American Society of Clinical Oncology (ASCO).

The outcomes of the South Korean study, dubbed PEARLY, provide strong evidence for incorporating carboplatin into both the neoadjuvant and adjuvant settings in patients with early-stage TNBC, said lead investigator and presenter Joohyuk Sohn, MD, PhD, a medical oncologist at Yonsei University, Seoul, South Korea.

In early-stage TNBC, carboplatin is already being incorporated into the neoadjuvant setting on the basis of trial results from KEYNOTE-522 that demonstrated improved pathologic complete response rates and event-free survival with the platinum alongside pembrolizumab.

However, the overall survival benefit of carboplatin in this setting remains unclear, as does the benefit of platinum add-on in the adjuvant setting, Dr. Sohn explained.

Dr. Sohn and colleagues randomized 868 patients evenly to either standard treatment — doxorubicin, anthracycline, and cyclophosphamide followed by a taxane — or an experimental arm that added carboplatin to the taxane phase of treatment.

About 30% of women were treated in the adjuvant setting, the rest in the neoadjuvant setting. The two arms of the study were generally well balanced — about 80% of patients had stage II disease, half were node negative, and 11% had deleterious germline mutations.

The primary endpoint, event-free survival, was broadly defined. Events included disease progression, local or distant recurrence, occurrence of a second primary cancer, inoperable status after neoadjuvant therapy, or death from any cause.

Adding carboplatin increased 5-year event-free survival rates from 75.1% to 82.3% (hazard ratio [HR], 0.67; P = .012) with the benefit holding across various subgroup analyses and particularly strong for adjuvant carboplatin (HR, 0.26).

Five-year overall survival was also better in the carboplatin arm — 90.7% vs 87% in the control arm (HR, 0.65; 95% CI, 0.42-1.02) — but that benefit did not reach statistical significance (P = .057)

Invasive disease-free survival (HR, 0.73) and distant recurrence-free survival (HR, 0.77) favored carboplatin, but the results also weren’t statistically significant.

Overall, 46% of patients had a pathologic complete response with carboplatin vs nearly 40% in the control arm. The pathologic complete response benefit from carboplatin add-on was consistent with past reports.

As expected, adding carboplatin to treatment increased hematologic toxicity and other adverse events, with three-quarters of patients experiencing grade 3 or worse adverse events vs 56.7% of control participants. There was one death in the carboplatin arm from pneumonia and two in the control arm — one from septic shock and the other from suicide.

Dr. Sohn and colleagues, however, did not observe a quality of life difference between the two groups.

“The PEARLY trial provides compelling evidence for including carboplatin in the treatment of early-stage TNBC,” Dr. Sohn concluded, adding that the results underscore the benefit in the neoadjuvant setting and suggest “potential applicability in the adjuvant setting post surgery.”

Study discussant Javier Cortes, MD, PhD, believes that the PEARLY provides a strong signal for adding carboplatin in the adjuvant setting.

“That’s something I would do in my clinical practice,” said Dr. Cortes, head of the International Breast Cancer Center in Barcelona, Spain. “After ASCO this year, I would offer taxanes plus carboplatin following anthracyclines.”

An audience member, William Sikov, MD, a breast cancer specialist at Brown University in Providence, Rhode Island, said he hopes “we’ve reached the end of a road that started many years ago in terms of incorporating carboplatin as part of neoadjuvant and adjuvant therapy for triple-negative breast cancer, where we finally [reach] consensus that this is necessary in our triple-negative patients.”

The work was funded by the government of South Korea and others. Dr. Sohn reported stock in Daiichi Sankyo and research funding from Daiichi and other companies. Dr. Cortes disclosed numerous industry ties, including honoraria, research funding, and/or travel expenses from AstraZeneca, Daiichi, and others.

A version of this article first appeared on Medscape.com.

CHICAGO — Adding carboplatin to standard anthracycline/taxane treatment for early-stage triple-negative breast cancer (TNBC) improves event-free and overall survival in the neoadjuvant and adjuvant setting, according to a phase 3 trial presented at the annual meeting of the American Society of Clinical Oncology (ASCO).

The outcomes of the South Korean study, dubbed PEARLY, provide strong evidence for incorporating carboplatin into both the neoadjuvant and adjuvant settings in patients with early-stage TNBC, said lead investigator and presenter Joohyuk Sohn, MD, PhD, a medical oncologist at Yonsei University, Seoul, South Korea.

In early-stage TNBC, carboplatin is already being incorporated into the neoadjuvant setting on the basis of trial results from KEYNOTE-522 that demonstrated improved pathologic complete response rates and event-free survival with the platinum alongside pembrolizumab.

However, the overall survival benefit of carboplatin in this setting remains unclear, as does the benefit of platinum add-on in the adjuvant setting, Dr. Sohn explained.

Dr. Sohn and colleagues randomized 868 patients evenly to either standard treatment — doxorubicin, anthracycline, and cyclophosphamide followed by a taxane — or an experimental arm that added carboplatin to the taxane phase of treatment.

About 30% of women were treated in the adjuvant setting, the rest in the neoadjuvant setting. The two arms of the study were generally well balanced — about 80% of patients had stage II disease, half were node negative, and 11% had deleterious germline mutations.

The primary endpoint, event-free survival, was broadly defined. Events included disease progression, local or distant recurrence, occurrence of a second primary cancer, inoperable status after neoadjuvant therapy, or death from any cause.

Adding carboplatin increased 5-year event-free survival rates from 75.1% to 82.3% (hazard ratio [HR], 0.67; P = .012) with the benefit holding across various subgroup analyses and particularly strong for adjuvant carboplatin (HR, 0.26).

Five-year overall survival was also better in the carboplatin arm — 90.7% vs 87% in the control arm (HR, 0.65; 95% CI, 0.42-1.02) — but that benefit did not reach statistical significance (P = .057)

Invasive disease-free survival (HR, 0.73) and distant recurrence-free survival (HR, 0.77) favored carboplatin, but the results also weren’t statistically significant.

Overall, 46% of patients had a pathologic complete response with carboplatin vs nearly 40% in the control arm. The pathologic complete response benefit from carboplatin add-on was consistent with past reports.

As expected, adding carboplatin to treatment increased hematologic toxicity and other adverse events, with three-quarters of patients experiencing grade 3 or worse adverse events vs 56.7% of control participants. There was one death in the carboplatin arm from pneumonia and two in the control arm — one from septic shock and the other from suicide.

Dr. Sohn and colleagues, however, did not observe a quality of life difference between the two groups.

“The PEARLY trial provides compelling evidence for including carboplatin in the treatment of early-stage TNBC,” Dr. Sohn concluded, adding that the results underscore the benefit in the neoadjuvant setting and suggest “potential applicability in the adjuvant setting post surgery.”

Study discussant Javier Cortes, MD, PhD, believes that the PEARLY provides a strong signal for adding carboplatin in the adjuvant setting.

“That’s something I would do in my clinical practice,” said Dr. Cortes, head of the International Breast Cancer Center in Barcelona, Spain. “After ASCO this year, I would offer taxanes plus carboplatin following anthracyclines.”

An audience member, William Sikov, MD, a breast cancer specialist at Brown University in Providence, Rhode Island, said he hopes “we’ve reached the end of a road that started many years ago in terms of incorporating carboplatin as part of neoadjuvant and adjuvant therapy for triple-negative breast cancer, where we finally [reach] consensus that this is necessary in our triple-negative patients.”

The work was funded by the government of South Korea and others. Dr. Sohn reported stock in Daiichi Sankyo and research funding from Daiichi and other companies. Dr. Cortes disclosed numerous industry ties, including honoraria, research funding, and/or travel expenses from AstraZeneca, Daiichi, and others.

A version of this article first appeared on Medscape.com.

CHICAGO – Circulating tumor DNA (ctDNA), or DNA shed from tumors that is detected in the bloodstream, has shown increasing promise as a prognostic tool in gastrointestinal cancers, allowing investigators to make real-time assessments of treatment response and the likelihood of recurrence.

Depending on the type of assay and analysis used, ctDNA can provide a wealth of information about cancer genetic variants. ctDNA assays can be used for primary screening, to track tumor burden, or to detect minimal residual disease (MRD) after cancer surgery.

However, ctDNA’s role in guiding clinical decisions is still being defined. Australian investigators presented research showing that a negative ctDNA finding can be used to avoid unnecessary chemotherapy in postoperative stage II colon cancer patients without affecting survival outcomes, at the annual meeting of the American Society of Clinical Oncology (ASCO), in Chicago.

The same group also presented exploratory findings showing that positive ctDNA is a significant predictor of recurrence in people with early-stage pancreatic cancer following surgery. However, the investigators concluded, ctDNA status should not be used to inform treatment decisions concerning duration of adjuvant chemotherapy in these patients.
 

DYNAMIC Trial Results

Jeanne Tie, MD, of the Peter MacCallum Cancer Centre in Melbourne, presented 5-year survival results at ASCO from the DYNAMIC randomized controlled trial, whose 2-year findings had already shown ctDNA to be helpful in stratifying stage II colon cancer patients for adjuvant chemotherapy or no treatment.

Because surgery is curative in 80% of these patients, it is important to identify the minority that will need chemotherapy, Dr. Tie said.

At 5 years’ follow-up, Dr. Tie reported, patients randomized to a ctDNA-guided approach (negative ctDNA post surgery resulted in no treatment, and positive ctDNA led to adjuvant chemotherapy) did not see differences in overall survival compared with conventionally managed patients, who received chemotherapy at the clinician’s discretion.

Among ctDNA-guided patients in the study (n = 302), 5-year overall survival was 93.8%. For conventionally managed patients (n = 153), overall survival was 93.3% at 5 years (hazard ratio [HR], 1.05; 95% CI, 0.47-2.37; P = .887).

Further, the researchers found that a high ctDNA clearance rate was achieved with adjuvant chemotherapy in postoperative patients who were ctDNA positive. And 5-year recurrence rates were markedly lower in patients who achieved ctDNA clearance, compared with those who did not: 85.2% vs 20% (HR, 15.4; 95% CI, 3.91-61.0; P < .001).

“This approach of only treating patients with a positive ctDNA achieved excellent survival outcomes, including in patients with T4 disease. A high ctDNA clearance rate can be achieved with adjuvant chemotherapy, and this in turn was associated with favorable outcomes,” Dr. Tie said during the meeting. “And finally, the precision of the ctDNA approach may be further refined by increasing [the number of genetic variants] tracked and by incorporating ctDNA molecular burden. However, these findings will require further validation.”
 

DYNAMIC-Pancreas Study Results

In a separate presentation during the same session, Belinda Lee, MD, also of the Peter MacCallum Cancer Centre, showed results from the DYNAMIC-Pancreas study, which looked at ctDNA testing a median 5 weeks after surgery in 102 people with early-stage (Eastern Cooperative Oncology Group 0-1) pancreatic cancer. Patients who were ctDNA positive received 6 months of adjuvant chemotherapy of the physician’s choice (FOLFIRINOX or gemcitabine/capecitabine) while those who were ctDNA negative after surgery had the option to de-escalate to 3 months of chemotherapy treatment at the physician’s discretion.

At a median 3 years’ follow-up, Dr. Lee and colleagues found that the median recurrence-free survival was 13 months for patients who were ctDNA positive after surgery and 22 months for those who were ctDNA negative (HR, 0.52; P = .003), showing that positive ctDNA is prognostic of earlier recurrence independent of other factors.

Dr. Lee said that, given the high recurrence risk also seen in ctDNA-negative patients, reducing duration of chemotherapy was not recommended based on ctDNA-negative status.

In an interview, Stacey Cohen, MD, of Fred Hutch Cancer Center in Seattle, Washington, the discussant on the two presentations at ASCO, said that, until these results are further validated in stage II colon cancer patients,t it is unlikely that they will change clinical practice guidelines.

“They did an amazing job,” Dr. Cohen said of the researchers. “They’re at the forefront of the field of actually doing prospective analysis. And yet there are still some gaps that are missing in our understanding.”

The assays used in both studies, Dr. Cohen noted, are used only in research and are not available commercially in the United States. That, plus the fact that physicians were allowed to choose between chemotherapy regimens, made it harder to parse the results.

“Provider choice increases bias,” Dr. Cohen said. “And I think that’s the problem of having two chemo regimens to choose from, or in the case of the colon cancer trial, not selecting whether patients got a single chemotherapy agent or a doublet. These are pretty big differences.”

But the field is moving quickly, “and it is an exciting time to improve patient selection for chemotherapy treatment,” she continued.

Allowing physicians to choose chemotherapy regimens reflected real-world clinical practice, “especially given that this study is designed to test a strategy rather than a specific treatment, said Dr. Tie in an interview. “More work will need to be done to specifically address the question of which chemotherapy regimen is more effective to treat ctDNA-positive disease.”

Dr. Cohen noted that, while evidence is mounting to support the value of ctDNA in colon cancer, there is far less evidence for pancreatic cancer.

Dr. Lee and colleagues’ study “adds to the literature, and I think what it teaches us is that ctDNA remains a prognostic risk factor,” she said. “But we saw that even patients who are negative have a high recurrence risk. So we’re not ready to act on it yet. As with the colon cancer study, different chemotherapy regimens were used, and for different time lengths.”

Whether in colon cancer or pancreatic cancer, ctDNA results, “are highly tied to which assay you’re using and which scenario you’re testing them in,” Dr. Cohen said.

Dr. Tie and colleagues’ study was sponsored by her institution, with additional funding received from the Australian government, the National Institutes of Health, and other foundations. She disclosed speaking and/or consulting fees from Haystack Oncology, Amgen, Novartis, Bristol-Myers Squibb, Merck, AstraZeneca, and others. Dr. Lee’s study was sponsored by the Marcus Foundation. She disclosed receiving honoraria from Roche. Dr. Cohen reported no conflicts of interest.

CHICAGO – Circulating tumor DNA (ctDNA), or DNA shed from tumors that is detected in the bloodstream, has shown increasing promise as a prognostic tool in gastrointestinal cancers, allowing investigators to make real-time assessments of treatment response and the likelihood of recurrence.

Depending on the type of assay and analysis used, ctDNA can provide a wealth of information about cancer genetic variants. ctDNA assays can be used for primary screening, to track tumor burden, or to detect minimal residual disease (MRD) after cancer surgery.

However, ctDNA’s role in guiding clinical decisions is still being defined. Australian investigators presented research showing that a negative ctDNA finding can be used to avoid unnecessary chemotherapy in postoperative stage II colon cancer patients without affecting survival outcomes, at the annual meeting of the American Society of Clinical Oncology (ASCO), in Chicago.

The same group also presented exploratory findings showing that positive ctDNA is a significant predictor of recurrence in people with early-stage pancreatic cancer following surgery. However, the investigators concluded, ctDNA status should not be used to inform treatment decisions concerning duration of adjuvant chemotherapy in these patients.
 

DYNAMIC Trial Results

Jeanne Tie, MD, of the Peter MacCallum Cancer Centre in Melbourne, presented 5-year survival results at ASCO from the DYNAMIC randomized controlled trial, whose 2-year findings had already shown ctDNA to be helpful in stratifying stage II colon cancer patients for adjuvant chemotherapy or no treatment.

Because surgery is curative in 80% of these patients, it is important to identify the minority that will need chemotherapy, Dr. Tie said.

At 5 years’ follow-up, Dr. Tie reported, patients randomized to a ctDNA-guided approach (negative ctDNA post surgery resulted in no treatment, and positive ctDNA led to adjuvant chemotherapy) did not see differences in overall survival compared with conventionally managed patients, who received chemotherapy at the clinician’s discretion.

Among ctDNA-guided patients in the study (n = 302), 5-year overall survival was 93.8%. For conventionally managed patients (n = 153), overall survival was 93.3% at 5 years (hazard ratio [HR], 1.05; 95% CI, 0.47-2.37; P = .887).

Further, the researchers found that a high ctDNA clearance rate was achieved with adjuvant chemotherapy in postoperative patients who were ctDNA positive. And 5-year recurrence rates were markedly lower in patients who achieved ctDNA clearance, compared with those who did not: 85.2% vs 20% (HR, 15.4; 95% CI, 3.91-61.0; P < .001).

“This approach of only treating patients with a positive ctDNA achieved excellent survival outcomes, including in patients with T4 disease. A high ctDNA clearance rate can be achieved with adjuvant chemotherapy, and this in turn was associated with favorable outcomes,” Dr. Tie said during the meeting. “And finally, the precision of the ctDNA approach may be further refined by increasing [the number of genetic variants] tracked and by incorporating ctDNA molecular burden. However, these findings will require further validation.”
 

DYNAMIC-Pancreas Study Results

In a separate presentation during the same session, Belinda Lee, MD, also of the Peter MacCallum Cancer Centre, showed results from the DYNAMIC-Pancreas study, which looked at ctDNA testing a median 5 weeks after surgery in 102 people with early-stage (Eastern Cooperative Oncology Group 0-1) pancreatic cancer. Patients who were ctDNA positive received 6 months of adjuvant chemotherapy of the physician’s choice (FOLFIRINOX or gemcitabine/capecitabine) while those who were ctDNA negative after surgery had the option to de-escalate to 3 months of chemotherapy treatment at the physician’s discretion.

At a median 3 years’ follow-up, Dr. Lee and colleagues found that the median recurrence-free survival was 13 months for patients who were ctDNA positive after surgery and 22 months for those who were ctDNA negative (HR, 0.52; P = .003), showing that positive ctDNA is prognostic of earlier recurrence independent of other factors.

Dr. Lee said that, given the high recurrence risk also seen in ctDNA-negative patients, reducing duration of chemotherapy was not recommended based on ctDNA-negative status.

In an interview, Stacey Cohen, MD, of Fred Hutch Cancer Center in Seattle, Washington, the discussant on the two presentations at ASCO, said that, until these results are further validated in stage II colon cancer patients,t it is unlikely that they will change clinical practice guidelines.

“They did an amazing job,” Dr. Cohen said of the researchers. “They’re at the forefront of the field of actually doing prospective analysis. And yet there are still some gaps that are missing in our understanding.”

The assays used in both studies, Dr. Cohen noted, are used only in research and are not available commercially in the United States. That, plus the fact that physicians were allowed to choose between chemotherapy regimens, made it harder to parse the results.

“Provider choice increases bias,” Dr. Cohen said. “And I think that’s the problem of having two chemo regimens to choose from, or in the case of the colon cancer trial, not selecting whether patients got a single chemotherapy agent or a doublet. These are pretty big differences.”

But the field is moving quickly, “and it is an exciting time to improve patient selection for chemotherapy treatment,” she continued.

Allowing physicians to choose chemotherapy regimens reflected real-world clinical practice, “especially given that this study is designed to test a strategy rather than a specific treatment, said Dr. Tie in an interview. “More work will need to be done to specifically address the question of which chemotherapy regimen is more effective to treat ctDNA-positive disease.”

Dr. Cohen noted that, while evidence is mounting to support the value of ctDNA in colon cancer, there is far less evidence for pancreatic cancer.

Dr. Lee and colleagues’ study “adds to the literature, and I think what it teaches us is that ctDNA remains a prognostic risk factor,” she said. “But we saw that even patients who are negative have a high recurrence risk. So we’re not ready to act on it yet. As with the colon cancer study, different chemotherapy regimens were used, and for different time lengths.”

Whether in colon cancer or pancreatic cancer, ctDNA results, “are highly tied to which assay you’re using and which scenario you’re testing them in,” Dr. Cohen said.

Dr. Tie and colleagues’ study was sponsored by her institution, with additional funding received from the Australian government, the National Institutes of Health, and other foundations. She disclosed speaking and/or consulting fees from Haystack Oncology, Amgen, Novartis, Bristol-Myers Squibb, Merck, AstraZeneca, and others. Dr. Lee’s study was sponsored by the Marcus Foundation. She disclosed receiving honoraria from Roche. Dr. Cohen reported no conflicts of interest.

CHICAGO – Circulating tumor DNA (ctDNA), or DNA shed from tumors that is detected in the bloodstream, has shown increasing promise as a prognostic tool in gastrointestinal cancers, allowing investigators to make real-time assessments of treatment response and the likelihood of recurrence.

Depending on the type of assay and analysis used, ctDNA can provide a wealth of information about cancer genetic variants. ctDNA assays can be used for primary screening, to track tumor burden, or to detect minimal residual disease (MRD) after cancer surgery.

However, ctDNA’s role in guiding clinical decisions is still being defined. Australian investigators presented research showing that a negative ctDNA finding can be used to avoid unnecessary chemotherapy in postoperative stage II colon cancer patients without affecting survival outcomes, at the annual meeting of the American Society of Clinical Oncology (ASCO), in Chicago.

The same group also presented exploratory findings showing that positive ctDNA is a significant predictor of recurrence in people with early-stage pancreatic cancer following surgery. However, the investigators concluded, ctDNA status should not be used to inform treatment decisions concerning duration of adjuvant chemotherapy in these patients.
 

DYNAMIC Trial Results

Jeanne Tie, MD, of the Peter MacCallum Cancer Centre in Melbourne, presented 5-year survival results at ASCO from the DYNAMIC randomized controlled trial, whose 2-year findings had already shown ctDNA to be helpful in stratifying stage II colon cancer patients for adjuvant chemotherapy or no treatment.

Because surgery is curative in 80% of these patients, it is important to identify the minority that will need chemotherapy, Dr. Tie said.

At 5 years’ follow-up, Dr. Tie reported, patients randomized to a ctDNA-guided approach (negative ctDNA post surgery resulted in no treatment, and positive ctDNA led to adjuvant chemotherapy) did not see differences in overall survival compared with conventionally managed patients, who received chemotherapy at the clinician’s discretion.

Among ctDNA-guided patients in the study (n = 302), 5-year overall survival was 93.8%. For conventionally managed patients (n = 153), overall survival was 93.3% at 5 years (hazard ratio [HR], 1.05; 95% CI, 0.47-2.37; P = .887).

Further, the researchers found that a high ctDNA clearance rate was achieved with adjuvant chemotherapy in postoperative patients who were ctDNA positive. And 5-year recurrence rates were markedly lower in patients who achieved ctDNA clearance, compared with those who did not: 85.2% vs 20% (HR, 15.4; 95% CI, 3.91-61.0; P < .001).

“This approach of only treating patients with a positive ctDNA achieved excellent survival outcomes, including in patients with T4 disease. A high ctDNA clearance rate can be achieved with adjuvant chemotherapy, and this in turn was associated with favorable outcomes,” Dr. Tie said during the meeting. “And finally, the precision of the ctDNA approach may be further refined by increasing [the number of genetic variants] tracked and by incorporating ctDNA molecular burden. However, these findings will require further validation.”
 

DYNAMIC-Pancreas Study Results

In a separate presentation during the same session, Belinda Lee, MD, also of the Peter MacCallum Cancer Centre, showed results from the DYNAMIC-Pancreas study, which looked at ctDNA testing a median 5 weeks after surgery in 102 people with early-stage (Eastern Cooperative Oncology Group 0-1) pancreatic cancer. Patients who were ctDNA positive received 6 months of adjuvant chemotherapy of the physician’s choice (FOLFIRINOX or gemcitabine/capecitabine) while those who were ctDNA negative after surgery had the option to de-escalate to 3 months of chemotherapy treatment at the physician’s discretion.

At a median 3 years’ follow-up, Dr. Lee and colleagues found that the median recurrence-free survival was 13 months for patients who were ctDNA positive after surgery and 22 months for those who were ctDNA negative (HR, 0.52; P = .003), showing that positive ctDNA is prognostic of earlier recurrence independent of other factors.

Dr. Lee said that, given the high recurrence risk also seen in ctDNA-negative patients, reducing duration of chemotherapy was not recommended based on ctDNA-negative status.

In an interview, Stacey Cohen, MD, of Fred Hutch Cancer Center in Seattle, Washington, the discussant on the two presentations at ASCO, said that, until these results are further validated in stage II colon cancer patients,t it is unlikely that they will change clinical practice guidelines.

“They did an amazing job,” Dr. Cohen said of the researchers. “They’re at the forefront of the field of actually doing prospective analysis. And yet there are still some gaps that are missing in our understanding.”

The assays used in both studies, Dr. Cohen noted, are used only in research and are not available commercially in the United States. That, plus the fact that physicians were allowed to choose between chemotherapy regimens, made it harder to parse the results.

“Provider choice increases bias,” Dr. Cohen said. “And I think that’s the problem of having two chemo regimens to choose from, or in the case of the colon cancer trial, not selecting whether patients got a single chemotherapy agent or a doublet. These are pretty big differences.”

But the field is moving quickly, “and it is an exciting time to improve patient selection for chemotherapy treatment,” she continued.

Allowing physicians to choose chemotherapy regimens reflected real-world clinical practice, “especially given that this study is designed to test a strategy rather than a specific treatment, said Dr. Tie in an interview. “More work will need to be done to specifically address the question of which chemotherapy regimen is more effective to treat ctDNA-positive disease.”

Dr. Cohen noted that, while evidence is mounting to support the value of ctDNA in colon cancer, there is far less evidence for pancreatic cancer.

Dr. Lee and colleagues’ study “adds to the literature, and I think what it teaches us is that ctDNA remains a prognostic risk factor,” she said. “But we saw that even patients who are negative have a high recurrence risk. So we’re not ready to act on it yet. As with the colon cancer study, different chemotherapy regimens were used, and for different time lengths.”

Whether in colon cancer or pancreatic cancer, ctDNA results, “are highly tied to which assay you’re using and which scenario you’re testing them in,” Dr. Cohen said.

Dr. Tie and colleagues’ study was sponsored by her institution, with additional funding received from the Australian government, the National Institutes of Health, and other foundations. She disclosed speaking and/or consulting fees from Haystack Oncology, Amgen, Novartis, Bristol-Myers Squibb, Merck, AstraZeneca, and others. Dr. Lee’s study was sponsored by the Marcus Foundation. She disclosed receiving honoraria from Roche. Dr. Cohen reported no conflicts of interest.

CHICAGO — Prominent Chinese oncologist Tony Shu-Kam Mok, MD, who presented as first author of a phase 3 non–small cell lung cancer study at ASCO 2024, made a dramatic swerve in his career path at age 36.

After 20 years in Canada — 7 spent practicing community oncology near Toronto — Dr. Mok was visiting family in his native Hong Kong back in 1996 when a job offer there enabled him to revive his early dream of doing academic research. Dr. Mok and his family moved back home just before the former British colony was returned to China in 1997.

courtesy of Dr. Tony Mok

That leap of faith helped Dr. Mok play a role in the global paradigm shift on treating lung cancer. He chairs the department of clinical oncology at the Chinese University of Hong Kong. A leader in ushering in targeted therapies and personalized medicine in China and globally, he has helped advance the goal of transforming lung cancer from a death sentence to a chronic disease.

Among Dr. Mok’s other accomplishments, he has published eight books and more than 200 journal articles. Since 2006, he has been writing a twice-weekly column in the Hong Kong Economic Times. At the annual meeting of the American Society of Clinical Oncology (ASCO), Dr. Mok sat down with this news organization to discuss his latest findings, his career path, and China’s ever-growing presence in multinational clinical trials, pharmaceuticals, and cancer research in general.
 

Question: At ASCO 2024 in Chicago, you presented as first author of the KRYSTAL-12 study. Can you give a short “elevator speech” summarizing those findings?

Dr. Mok: KRYSTAL-12 is a randomized phase 3 study comparing adagrasib with docetaxel in patients with previously treated advanced/metastatic non–small cell lung cancer harboring a KRAS G12C-mutation. And the findings are positive, with a median progression free survival of 5.5 months vs 3.8 months, with a significant hazard ratio [of 0.58]. And then there are also differences in their response rates of 32% versus 9%, and that gives you an [odds] ratio of 4.86. So yes, it’s significant.

Question: Now that you’ve given this presentation and perhaps taken some good, meaningful questions about it, are there any further points you’d like to make — anything you’d like to add?

Dr. Mok: You have to understand that whatever I said has been scrutinized by the pharmaceutical company, but now I can say whatever I like. I think the key point is that we actually have made the first so-called achievement in the KRAS G12C space. But this is only the beginning.

I want to note that the median progression-free survival is different, but not the best. The median 5.5 months result is good, but not good enough. So, we still have to work hard to answer the question: How can we best deliver care to patients with KRAS G12C?
 

Question: Speaking more generally about the challenges of targeting KRAS, what issues arise in terms of biomarker testing for KRAS mutations in the clinic? Dr. Mok: In colorectal cancer, there has been testing for KRAS [mutations] for a long, long time. So, most of the laboratories, as long as they are well equipped, will be able to test for KRAS. Usually, the cheaper way is to buy PCR [polymerase chain reaction]. However, these days it’s getting trendier to use NGS [next-generation sequencing]. So, one way or another, specificity is very high. I don’t think we have too much of a problem. The only difference between colorectal cancer and lung cancer is that the tissue sample may not be as good for lung cancer with a small biopsy, but otherwise testing is not an issue.

Question: What clinical trials should oncologist be watching to come into this space?Dr. Mok: There are a lot. Right now, there is the so-called first-line study that’s coming up. So, I can cite you some examples for the KRYSTAL-7 trial, which is the combination of pembrolizumab together with adagrasib in the PD-L1 Tumor Proportion Score ≥ 50%.

That’s one example. And then there is the CodeBreaK 202 trial, which is actually the combination of chemotherapy with sotorasib versus chemotherapy and I-O [immune-oncology]. That is also an ongoing study.
 

Question: I also want to ask you some background questions about yourself. Back in the day, you lived in Canada and were a community oncologist. Then you made a very big change in your life and moved back home to Hong Kong in 1996, on the eve of its return to China the following year.

Dr. Mok: Well, I was born and raised in Hong Kong, but I left for Canada for education when I was 16 and kind of stayed there and got medical school oncology training and then started my practice. At that time, I never imagined myself going back. But 1996 was a big year. Incidentally, I went back to Hong Kong then to visit my friends and was offered a job at the Chinese University of Hong Kong. Then 1997 was coming. I found it very exciting that we could work with China. So that’s why I decided to return. And this was probably one of my best decisions I ever made in my life.

Question: And you went from being a community oncologist to academic research?

Dr. Mok: Here’s a personal thing that I can share with you: When I finished my oncology training at Princess Margaret Hospital in Toronto, I thought of going into research and becoming an academic. However, my son was born. Household costs went up, and I didn’t want to be a low-income, poor PhD student, so I decided that I may as well go into private practice. Returning to Hong Kong [in 1996] gave me a second chance. I went from being a community oncologist for seven years in Canada to a totally new environment in Hong Kong, where I started my academic work at age 36. It has been a good journey.

Question: Why do you say that was the best decision you ever made?Dr. Mok: At that time, it took me about 2 weeks to make this important decision. Basically: I had to give up my big house and my big car in Canada and move back to a small apartment in Hong Kong. That was a tough decision to make. However, it was a matter of certainty versus uncertainty.

In Canada, I actually had a very stable situation. I had a big practice in the Scarborough area [of Toronto], with a lot of Chinese patients, so I had a better, more comfortable life. It was predictable. But then I asked myself what I would be like in 10 years if I stayed in Canada versus Hong Kong. My answer is that I had no idea what would happen to me 10 years later in Hong Kong. In certain parts of life, you have to decide between certainty and uncertainty. And this time, uncertainty brought me great adventure. I definitely would not have done the things I’ve done if I’d stayed in Canada.



Question: At this ASCO, you’ve spoken primarily about your latest research on non–small cell lung cancer with KRAS G12C mutation.Dr. Mok: Actually, my research has been mostly on targeted therapy. My first break was on the EGFR [epidermal growth factor receptor] mutation. I was one of the first to help define personalized medicine according to the EGFR mutation in the IPASS study [2009]. That’s how I started my academic career.



Question: I read some quotes from your writing some years back about “living with imperfection,” and where you wrote about the whole continuum of cancer research. Years ago, you noted that lung cancer was moving from being a death sentence to becoming a chronic condition.

Dr. Mok: The objective is this: A lot of cancer patients, especially lung cancer patients, had a very short survival, but now we are able to identify a subgroup of patients with a driver oncogene.

And with that, we can use a tyrosine kinase inhibitor — which although it has toxicity, it’s manageable toxicity — such that you can take one pill a day and continue to live a normal life. So that would be not so different from diabetes or hypertension: You live with the disease. So that’s what we like to see: the conversion of a fatal disease into a chronic disease.
 

Question: So many countries now, including the United States and many others, are facing the challenges of cancer care in rural versus urban areas. Is this a topic you’d be willing to address? Dr. Mok: Well, in Hong Kong we don’t have rural areas! But in China, this is a major problem. There most of the cancer care is focused on the so-called three major cities [Shanghai, Beijing, Guangzhou]. And after that, there are second-tier cities that also have reasonably good care. But when you filter down to the third and fourth layer, the oncology care actually deteriorates. So that’s why we end up with a lot of people from the more rural areas moving and going to the city looking for care and consultation. So yes, the disparity is significant.

But China is a growing country. It takes time to change. Right now, we can see at ASCO this year, there are a lot of investigators from China sharing their new findings, which is a major development, compared to 10 years ago. Therefore, I think that when you have this type of proliferative development, eventually the good care, the high-quality care will filter down to more rural areas. So, at this moment, I think there is still a lot of work to do.
 

Question: You’ve talked about how oncologists from China are coming up in the field, and this year they have an even greater presence at ASCO, as well as oncologists from elsewhere in Asia, including South Korea, Japan, and Vietnam. You’ve been coming to ASCO for many years. Can you talk about the factors behind China’s increasing presence? Dr. Mok: I think it’s a combination of factors. First of all, I had the honor of working with lung cancer researchers from China from way back, 25 years ago. At that time, we all had nothing. Then with the development of multitargeted therapies, they managed to build up a very good infrastructure for clinical trials. And then, based on that good infrastructure, they were able to do international collaborative studies and provide a supply of patient resources and high-quality data. So, they’ve learned the trick, done a good job, but they cannot have so-called independence until there is a development of pharmaceuticals in China.

And then over the past 10 years, there’s been a proliferation — actually an explosion I would even say — of high-quality pharmaceutical companies in China. First, they’ve got the resources to build the companies. Second, they’ve got the talent resources returning from the United States. So, putting all that together, these were able to go from start-ups to full-fledged functional companies in a very short time.

And with that, they actually sponsored a lot of trials within China. And you can see that putting all the components together: you’ve got high-quality researchers, you’ve got the infrastructure, and now you’ve got your drugs and the money to do the trials. As a result, you’ve got a lot of good data coming from China.
 

Question: There’s also a population with these mutations.Dr. Mok: That for one, but most have multitargeted therapies, but they also have immunotherapies that have nothing to do with the high incidence. But I think in a sense, in the beginning, they were doing `me-too’ compounds, but now I think they are starting to do ‘me-better’ compounds.

Question: Is there anything you want to say about some of the other presentations that have your name on them at ASCO this year?Dr. Mok: I think the most important one I was engaged in is the CROWN study. The CROWN study is actually a phase 3 study that compares lorlatinib versus crizotinib in patients with advanced, ALK-positive non–small cell lung cancer.

This is a 5-year follow-up, and we were actually able to report an outrageously encouraging 5-year progression-free rate at 60%, meaning that the patient is walking in the door 5 years later when they are on the drug, and 60% of them actually do not have progression, not death, just not progression, just staying on the same pill—which is quite outrageously good for lung cancer.

CHICAGO — Prominent Chinese oncologist Tony Shu-Kam Mok, MD, who presented as first author of a phase 3 non–small cell lung cancer study at ASCO 2024, made a dramatic swerve in his career path at age 36.

After 20 years in Canada — 7 spent practicing community oncology near Toronto — Dr. Mok was visiting family in his native Hong Kong back in 1996 when a job offer there enabled him to revive his early dream of doing academic research. Dr. Mok and his family moved back home just before the former British colony was returned to China in 1997.

courtesy of Dr. Tony Mok

That leap of faith helped Dr. Mok play a role in the global paradigm shift on treating lung cancer. He chairs the department of clinical oncology at the Chinese University of Hong Kong. A leader in ushering in targeted therapies and personalized medicine in China and globally, he has helped advance the goal of transforming lung cancer from a death sentence to a chronic disease.

Among Dr. Mok’s other accomplishments, he has published eight books and more than 200 journal articles. Since 2006, he has been writing a twice-weekly column in the Hong Kong Economic Times. At the annual meeting of the American Society of Clinical Oncology (ASCO), Dr. Mok sat down with this news organization to discuss his latest findings, his career path, and China’s ever-growing presence in multinational clinical trials, pharmaceuticals, and cancer research in general.
 

Question: At ASCO 2024 in Chicago, you presented as first author of the KRYSTAL-12 study. Can you give a short “elevator speech” summarizing those findings?

Dr. Mok: KRYSTAL-12 is a randomized phase 3 study comparing adagrasib with docetaxel in patients with previously treated advanced/metastatic non–small cell lung cancer harboring a KRAS G12C-mutation. And the findings are positive, with a median progression free survival of 5.5 months vs 3.8 months, with a significant hazard ratio [of 0.58]. And then there are also differences in their response rates of 32% versus 9%, and that gives you an [odds] ratio of 4.86. So yes, it’s significant.

Question: Now that you’ve given this presentation and perhaps taken some good, meaningful questions about it, are there any further points you’d like to make — anything you’d like to add?

Dr. Mok: You have to understand that whatever I said has been scrutinized by the pharmaceutical company, but now I can say whatever I like. I think the key point is that we actually have made the first so-called achievement in the KRAS G12C space. But this is only the beginning.

I want to note that the median progression-free survival is different, but not the best. The median 5.5 months result is good, but not good enough. So, we still have to work hard to answer the question: How can we best deliver care to patients with KRAS G12C?
 

Question: Speaking more generally about the challenges of targeting KRAS, what issues arise in terms of biomarker testing for KRAS mutations in the clinic? Dr. Mok: In colorectal cancer, there has been testing for KRAS [mutations] for a long, long time. So, most of the laboratories, as long as they are well equipped, will be able to test for KRAS. Usually, the cheaper way is to buy PCR [polymerase chain reaction]. However, these days it’s getting trendier to use NGS [next-generation sequencing]. So, one way or another, specificity is very high. I don’t think we have too much of a problem. The only difference between colorectal cancer and lung cancer is that the tissue sample may not be as good for lung cancer with a small biopsy, but otherwise testing is not an issue.

Question: What clinical trials should oncologist be watching to come into this space?Dr. Mok: There are a lot. Right now, there is the so-called first-line study that’s coming up. So, I can cite you some examples for the KRYSTAL-7 trial, which is the combination of pembrolizumab together with adagrasib in the PD-L1 Tumor Proportion Score ≥ 50%.

That’s one example. And then there is the CodeBreaK 202 trial, which is actually the combination of chemotherapy with sotorasib versus chemotherapy and I-O [immune-oncology]. That is also an ongoing study.
 

Question: I also want to ask you some background questions about yourself. Back in the day, you lived in Canada and were a community oncologist. Then you made a very big change in your life and moved back home to Hong Kong in 1996, on the eve of its return to China the following year.

Dr. Mok: Well, I was born and raised in Hong Kong, but I left for Canada for education when I was 16 and kind of stayed there and got medical school oncology training and then started my practice. At that time, I never imagined myself going back. But 1996 was a big year. Incidentally, I went back to Hong Kong then to visit my friends and was offered a job at the Chinese University of Hong Kong. Then 1997 was coming. I found it very exciting that we could work with China. So that’s why I decided to return. And this was probably one of my best decisions I ever made in my life.

Question: And you went from being a community oncologist to academic research?

Dr. Mok: Here’s a personal thing that I can share with you: When I finished my oncology training at Princess Margaret Hospital in Toronto, I thought of going into research and becoming an academic. However, my son was born. Household costs went up, and I didn’t want to be a low-income, poor PhD student, so I decided that I may as well go into private practice. Returning to Hong Kong [in 1996] gave me a second chance. I went from being a community oncologist for seven years in Canada to a totally new environment in Hong Kong, where I started my academic work at age 36. It has been a good journey.

Question: Why do you say that was the best decision you ever made?Dr. Mok: At that time, it took me about 2 weeks to make this important decision. Basically: I had to give up my big house and my big car in Canada and move back to a small apartment in Hong Kong. That was a tough decision to make. However, it was a matter of certainty versus uncertainty.

In Canada, I actually had a very stable situation. I had a big practice in the Scarborough area [of Toronto], with a lot of Chinese patients, so I had a better, more comfortable life. It was predictable. But then I asked myself what I would be like in 10 years if I stayed in Canada versus Hong Kong. My answer is that I had no idea what would happen to me 10 years later in Hong Kong. In certain parts of life, you have to decide between certainty and uncertainty. And this time, uncertainty brought me great adventure. I definitely would not have done the things I’ve done if I’d stayed in Canada.



Question: At this ASCO, you’ve spoken primarily about your latest research on non–small cell lung cancer with KRAS G12C mutation.Dr. Mok: Actually, my research has been mostly on targeted therapy. My first break was on the EGFR [epidermal growth factor receptor] mutation. I was one of the first to help define personalized medicine according to the EGFR mutation in the IPASS study [2009]. That’s how I started my academic career.



Question: I read some quotes from your writing some years back about “living with imperfection,” and where you wrote about the whole continuum of cancer research. Years ago, you noted that lung cancer was moving from being a death sentence to becoming a chronic condition.

Dr. Mok: The objective is this: A lot of cancer patients, especially lung cancer patients, had a very short survival, but now we are able to identify a subgroup of patients with a driver oncogene.

And with that, we can use a tyrosine kinase inhibitor — which although it has toxicity, it’s manageable toxicity — such that you can take one pill a day and continue to live a normal life. So that would be not so different from diabetes or hypertension: You live with the disease. So that’s what we like to see: the conversion of a fatal disease into a chronic disease.
 

Question: So many countries now, including the United States and many others, are facing the challenges of cancer care in rural versus urban areas. Is this a topic you’d be willing to address? Dr. Mok: Well, in Hong Kong we don’t have rural areas! But in China, this is a major problem. There most of the cancer care is focused on the so-called three major cities [Shanghai, Beijing, Guangzhou]. And after that, there are second-tier cities that also have reasonably good care. But when you filter down to the third and fourth layer, the oncology care actually deteriorates. So that’s why we end up with a lot of people from the more rural areas moving and going to the city looking for care and consultation. So yes, the disparity is significant.

But China is a growing country. It takes time to change. Right now, we can see at ASCO this year, there are a lot of investigators from China sharing their new findings, which is a major development, compared to 10 years ago. Therefore, I think that when you have this type of proliferative development, eventually the good care, the high-quality care will filter down to more rural areas. So, at this moment, I think there is still a lot of work to do.
 

Question: You’ve talked about how oncologists from China are coming up in the field, and this year they have an even greater presence at ASCO, as well as oncologists from elsewhere in Asia, including South Korea, Japan, and Vietnam. You’ve been coming to ASCO for many years. Can you talk about the factors behind China’s increasing presence? Dr. Mok: I think it’s a combination of factors. First of all, I had the honor of working with lung cancer researchers from China from way back, 25 years ago. At that time, we all had nothing. Then with the development of multitargeted therapies, they managed to build up a very good infrastructure for clinical trials. And then, based on that good infrastructure, they were able to do international collaborative studies and provide a supply of patient resources and high-quality data. So, they’ve learned the trick, done a good job, but they cannot have so-called independence until there is a development of pharmaceuticals in China.

And then over the past 10 years, there’s been a proliferation — actually an explosion I would even say — of high-quality pharmaceutical companies in China. First, they’ve got the resources to build the companies. Second, they’ve got the talent resources returning from the United States. So, putting all that together, these were able to go from start-ups to full-fledged functional companies in a very short time.

And with that, they actually sponsored a lot of trials within China. And you can see that putting all the components together: you’ve got high-quality researchers, you’ve got the infrastructure, and now you’ve got your drugs and the money to do the trials. As a result, you’ve got a lot of good data coming from China.
 

Question: There’s also a population with these mutations.Dr. Mok: That for one, but most have multitargeted therapies, but they also have immunotherapies that have nothing to do with the high incidence. But I think in a sense, in the beginning, they were doing `me-too’ compounds, but now I think they are starting to do ‘me-better’ compounds.

Question: Is there anything you want to say about some of the other presentations that have your name on them at ASCO this year?Dr. Mok: I think the most important one I was engaged in is the CROWN study. The CROWN study is actually a phase 3 study that compares lorlatinib versus crizotinib in patients with advanced, ALK-positive non–small cell lung cancer.

This is a 5-year follow-up, and we were actually able to report an outrageously encouraging 5-year progression-free rate at 60%, meaning that the patient is walking in the door 5 years later when they are on the drug, and 60% of them actually do not have progression, not death, just not progression, just staying on the same pill—which is quite outrageously good for lung cancer.

CHICAGO — Prominent Chinese oncologist Tony Shu-Kam Mok, MD, who presented as first author of a phase 3 non–small cell lung cancer study at ASCO 2024, made a dramatic swerve in his career path at age 36.

After 20 years in Canada — 7 spent practicing community oncology near Toronto — Dr. Mok was visiting family in his native Hong Kong back in 1996 when a job offer there enabled him to revive his early dream of doing academic research. Dr. Mok and his family moved back home just before the former British colony was returned to China in 1997.

courtesy of Dr. Tony Mok

That leap of faith helped Dr. Mok play a role in the global paradigm shift on treating lung cancer. He chairs the department of clinical oncology at the Chinese University of Hong Kong. A leader in ushering in targeted therapies and personalized medicine in China and globally, he has helped advance the goal of transforming lung cancer from a death sentence to a chronic disease.

Among Dr. Mok’s other accomplishments, he has published eight books and more than 200 journal articles. Since 2006, he has been writing a twice-weekly column in the Hong Kong Economic Times. At the annual meeting of the American Society of Clinical Oncology (ASCO), Dr. Mok sat down with this news organization to discuss his latest findings, his career path, and China’s ever-growing presence in multinational clinical trials, pharmaceuticals, and cancer research in general.
 

Question: At ASCO 2024 in Chicago, you presented as first author of the KRYSTAL-12 study. Can you give a short “elevator speech” summarizing those findings?

Dr. Mok: KRYSTAL-12 is a randomized phase 3 study comparing adagrasib with docetaxel in patients with previously treated advanced/metastatic non–small cell lung cancer harboring a KRAS G12C-mutation. And the findings are positive, with a median progression free survival of 5.5 months vs 3.8 months, with a significant hazard ratio [of 0.58]. And then there are also differences in their response rates of 32% versus 9%, and that gives you an [odds] ratio of 4.86. So yes, it’s significant.

Question: Now that you’ve given this presentation and perhaps taken some good, meaningful questions about it, are there any further points you’d like to make — anything you’d like to add?

Dr. Mok: You have to understand that whatever I said has been scrutinized by the pharmaceutical company, but now I can say whatever I like. I think the key point is that we actually have made the first so-called achievement in the KRAS G12C space. But this is only the beginning.

I want to note that the median progression-free survival is different, but not the best. The median 5.5 months result is good, but not good enough. So, we still have to work hard to answer the question: How can we best deliver care to patients with KRAS G12C?
 

Question: Speaking more generally about the challenges of targeting KRAS, what issues arise in terms of biomarker testing for KRAS mutations in the clinic? Dr. Mok: In colorectal cancer, there has been testing for KRAS [mutations] for a long, long time. So, most of the laboratories, as long as they are well equipped, will be able to test for KRAS. Usually, the cheaper way is to buy PCR [polymerase chain reaction]. However, these days it’s getting trendier to use NGS [next-generation sequencing]. So, one way or another, specificity is very high. I don’t think we have too much of a problem. The only difference between colorectal cancer and lung cancer is that the tissue sample may not be as good for lung cancer with a small biopsy, but otherwise testing is not an issue.

Question: What clinical trials should oncologist be watching to come into this space?Dr. Mok: There are a lot. Right now, there is the so-called first-line study that’s coming up. So, I can cite you some examples for the KRYSTAL-7 trial, which is the combination of pembrolizumab together with adagrasib in the PD-L1 Tumor Proportion Score ≥ 50%.

That’s one example. And then there is the CodeBreaK 202 trial, which is actually the combination of chemotherapy with sotorasib versus chemotherapy and I-O [immune-oncology]. That is also an ongoing study.
 

Question: I also want to ask you some background questions about yourself. Back in the day, you lived in Canada and were a community oncologist. Then you made a very big change in your life and moved back home to Hong Kong in 1996, on the eve of its return to China the following year.

Dr. Mok: Well, I was born and raised in Hong Kong, but I left for Canada for education when I was 16 and kind of stayed there and got medical school oncology training and then started my practice. At that time, I never imagined myself going back. But 1996 was a big year. Incidentally, I went back to Hong Kong then to visit my friends and was offered a job at the Chinese University of Hong Kong. Then 1997 was coming. I found it very exciting that we could work with China. So that’s why I decided to return. And this was probably one of my best decisions I ever made in my life.

Question: And you went from being a community oncologist to academic research?

Dr. Mok: Here’s a personal thing that I can share with you: When I finished my oncology training at Princess Margaret Hospital in Toronto, I thought of going into research and becoming an academic. However, my son was born. Household costs went up, and I didn’t want to be a low-income, poor PhD student, so I decided that I may as well go into private practice. Returning to Hong Kong [in 1996] gave me a second chance. I went from being a community oncologist for seven years in Canada to a totally new environment in Hong Kong, where I started my academic work at age 36. It has been a good journey.

Question: Why do you say that was the best decision you ever made?Dr. Mok: At that time, it took me about 2 weeks to make this important decision. Basically: I had to give up my big house and my big car in Canada and move back to a small apartment in Hong Kong. That was a tough decision to make. However, it was a matter of certainty versus uncertainty.

In Canada, I actually had a very stable situation. I had a big practice in the Scarborough area [of Toronto], with a lot of Chinese patients, so I had a better, more comfortable life. It was predictable. But then I asked myself what I would be like in 10 years if I stayed in Canada versus Hong Kong. My answer is that I had no idea what would happen to me 10 years later in Hong Kong. In certain parts of life, you have to decide between certainty and uncertainty. And this time, uncertainty brought me great adventure. I definitely would not have done the things I’ve done if I’d stayed in Canada.



Question: At this ASCO, you’ve spoken primarily about your latest research on non–small cell lung cancer with KRAS G12C mutation.Dr. Mok: Actually, my research has been mostly on targeted therapy. My first break was on the EGFR [epidermal growth factor receptor] mutation. I was one of the first to help define personalized medicine according to the EGFR mutation in the IPASS study [2009]. That’s how I started my academic career.



Question: I read some quotes from your writing some years back about “living with imperfection,” and where you wrote about the whole continuum of cancer research. Years ago, you noted that lung cancer was moving from being a death sentence to becoming a chronic condition.

Dr. Mok: The objective is this: A lot of cancer patients, especially lung cancer patients, had a very short survival, but now we are able to identify a subgroup of patients with a driver oncogene.

And with that, we can use a tyrosine kinase inhibitor — which although it has toxicity, it’s manageable toxicity — such that you can take one pill a day and continue to live a normal life. So that would be not so different from diabetes or hypertension: You live with the disease. So that’s what we like to see: the conversion of a fatal disease into a chronic disease.
 

Question: So many countries now, including the United States and many others, are facing the challenges of cancer care in rural versus urban areas. Is this a topic you’d be willing to address? Dr. Mok: Well, in Hong Kong we don’t have rural areas! But in China, this is a major problem. There most of the cancer care is focused on the so-called three major cities [Shanghai, Beijing, Guangzhou]. And after that, there are second-tier cities that also have reasonably good care. But when you filter down to the third and fourth layer, the oncology care actually deteriorates. So that’s why we end up with a lot of people from the more rural areas moving and going to the city looking for care and consultation. So yes, the disparity is significant.

But China is a growing country. It takes time to change. Right now, we can see at ASCO this year, there are a lot of investigators from China sharing their new findings, which is a major development, compared to 10 years ago. Therefore, I think that when you have this type of proliferative development, eventually the good care, the high-quality care will filter down to more rural areas. So, at this moment, I think there is still a lot of work to do.
 

Question: You’ve talked about how oncologists from China are coming up in the field, and this year they have an even greater presence at ASCO, as well as oncologists from elsewhere in Asia, including South Korea, Japan, and Vietnam. You’ve been coming to ASCO for many years. Can you talk about the factors behind China’s increasing presence? Dr. Mok: I think it’s a combination of factors. First of all, I had the honor of working with lung cancer researchers from China from way back, 25 years ago. At that time, we all had nothing. Then with the development of multitargeted therapies, they managed to build up a very good infrastructure for clinical trials. And then, based on that good infrastructure, they were able to do international collaborative studies and provide a supply of patient resources and high-quality data. So, they’ve learned the trick, done a good job, but they cannot have so-called independence until there is a development of pharmaceuticals in China.

And then over the past 10 years, there’s been a proliferation — actually an explosion I would even say — of high-quality pharmaceutical companies in China. First, they’ve got the resources to build the companies. Second, they’ve got the talent resources returning from the United States. So, putting all that together, these were able to go from start-ups to full-fledged functional companies in a very short time.

And with that, they actually sponsored a lot of trials within China. And you can see that putting all the components together: you’ve got high-quality researchers, you’ve got the infrastructure, and now you’ve got your drugs and the money to do the trials. As a result, you’ve got a lot of good data coming from China.
 

Question: There’s also a population with these mutations.Dr. Mok: That for one, but most have multitargeted therapies, but they also have immunotherapies that have nothing to do with the high incidence. But I think in a sense, in the beginning, they were doing `me-too’ compounds, but now I think they are starting to do ‘me-better’ compounds.

Question: Is there anything you want to say about some of the other presentations that have your name on them at ASCO this year?Dr. Mok: I think the most important one I was engaged in is the CROWN study. The CROWN study is actually a phase 3 study that compares lorlatinib versus crizotinib in patients with advanced, ALK-positive non–small cell lung cancer.

This is a 5-year follow-up, and we were actually able to report an outrageously encouraging 5-year progression-free rate at 60%, meaning that the patient is walking in the door 5 years later when they are on the drug, and 60% of them actually do not have progression, not death, just not progression, just staying on the same pill—which is quite outrageously good for lung cancer.

The experimental drug inavolisib showed sustained benefit combined with standard treatment in advanced, PIK3CA-mutated, hormone receptor–positive, human epidermal growth factor receptor 2–negative (HR+/HER2-) locally advanced metastatic breast cancer (LA/mBC), the INAVO120 trial.

The U.S. Food and Drug Administration (FDA) recently granted Breakthrough Therapy Designation for inavolisib in combination with palbociclib and fulvestrant based on initial results of the study presented at a December 2023 meeting. The phase 3 results showed the inavolisib-based regimen more than doubled progression-free survival (PFS) compared with the two other drugs alone as first-line treatment, researchers reported.

The expanded analysis of the trial, which was presented at the annual meeting of the American Society of Clinical Oncology, looked at additional endpoints, including PFS2 (defined as time from randomization to end of next-line treatment), time to first chemotherapy, key adverse events (AEs) and patient-reported outcomes (PROs).

“Triple combination of inavolisib, a novel PI3K inhibitor, with palbociclib and fulvestrant, resulted in significant and clinically meaningful improvement in PFS (15.0 vs 7.3 months, hazard ratio [HR] 0.43, P less than .0001),” lead investigator Dejan Juric, MD, reported at the meeting, referring to the initial results.

In additional endpoints, the inavolisib-based triplet also “sustained benefit beyond disease progression, delay in chemotherapy initiation, a manageable safety profile, prolonged time to deterioration in pain severity, and maintained quality of life, supporting the overall conclusion that this triple combination is a promising new treatment option for patients with PIK3CA-mutated HR-positive, HER2-negative metastatic breast cancer,” said the oncologist, of Massachusetts General Hospital Cancer Center and assistant professor at Harvard Medical School in Boston.
 

Methods and Results

The trial enrolled 325 patients whose disease had progressed during or within 12 months of adjuvant endocrine therapy (ET) with an aromatase inhibitor or tamoxifen and who had not received prior systemic therapy for recurrent LA/mBC. Patients were enrolled from December 2019 to September 2023 and randomized to either the triplet combination of inavolisib with palbociclib and fulvestrant (n = 161) or the doublet therapy of placebo with palbociclib and fulvestrant (n = 164) until discontinuation due to progressive disease or toxicity.

At the analysis cutoff date at the end of September, 57.8% of patients in the experimental triple therapy arm and 70.1% in the doublet arm had discontinued treatment. In addition, “7.5% versus 11.6% of patients died without subsequent therapy,” said Dr. Juric, and 40.4% of those in the triplet arm, and 50% in the doublet arm received subsequent therapy.

In the expanded analysis, at a median follow-up of 21.3 months, the triplet combination was associated with a PFS2 benefit of 8.9 months over the doublet – meaning patients had 24 months versus 15.1 months from randomization to end of next-line treatment (HR = 0.54). There was a similar benefit in time to first chemotherapy.

Hyperglycemia, diarrhea, rash, and mucosal effects are a known toxicity of PI3K inhibition and were experienced more frequently in the inavolisib arm compared with the placebo arm: (59% vs 9%; 48% vs 16%; 25% vs 17%; and 51% vs 27% respectively). However, “in the vast majority of patients these AEs were experienced in a grade 1 or grade 2 level,” and had resolved by the cutoff date, said Dr. Juric.

There was a 6.2% rate of inavolisib discontinuation due to AEs, but most AEs could be managed with “common approaches” such as metformin for hyperglycemia, loperamide for diarrhea, topical hydrocortisone for rash, and steroid mouthwash for stomatitis/mucosal inflammation, he added.

Patients in the triple treatment arm experienced a longer interval before pain worsened, a median of 30.9 versus 18.1 months, and patient-reported outcomes and health-related quality of life measures showed no decrease with the addition of inavolisib, Dr. Juric reported.
 

Rationale for Using PFS2 as Endpoint

The PFS2 endpoint has emerged with studies of targeted cancer therapies, Kevin Kalinsky, MD, director of the Glenn Family Breast Center at Winship Cancer Institute of Emory University, in Atlanta, said in an interview.

“Presenting PFS2 is not a new thing — we’ve been doing this in other breast cancer studies (of CDK4/6 inhibitors),” said Dr. Kalinsky, a coauthor of the study. “The concern is that you give a drug, and then, after that, things grow so rapidly that then you’re actually not benefiting the patient.

“If you’re giving a targeted agent in the first-line, then the biology changes after that first-line, are you really even making a difference? Or is the drug so toxic that they’re not able to tolerate a next line of treatment?” Dr. Kalinsky continued. “So that’s really the intent of PFS2. The PFS2 included the next line of treatment, so it’s really a first, and second-line representation of treatment. The study presented at ASCO was really about toxicity.”

The study was funded by F. Hoffmann-La Roche Ltd. Dr. Juric disclosed having stock and other ownership interests in PIC Therapeutics, Relay Therapeutics, and Vibliome Therapeutics; consulting or advisory roles with AstraZeneca, Eisai, Genentech, Lilly, MapKure, Novartis, Pfizer, PIC Therapeutics, Relay Therapeutics, and Vibliome Therapeutics; and research funding from Amgen, Arvinas, AstraZeneca, Blueprint Medicines, Eisai, Genentech, Infinity Pharmaceuticals, InventisBio, Novartis, Pfizer, Ribon Therapeutics, Scorpion Therapeutics, Syros Pharmaceuticals, and Takeda.

The experimental drug inavolisib showed sustained benefit combined with standard treatment in advanced, PIK3CA-mutated, hormone receptor–positive, human epidermal growth factor receptor 2–negative (HR+/HER2-) locally advanced metastatic breast cancer (LA/mBC), the INAVO120 trial.

The U.S. Food and Drug Administration (FDA) recently granted Breakthrough Therapy Designation for inavolisib in combination with palbociclib and fulvestrant based on initial results of the study presented at a December 2023 meeting. The phase 3 results showed the inavolisib-based regimen more than doubled progression-free survival (PFS) compared with the two other drugs alone as first-line treatment, researchers reported.

The expanded analysis of the trial, which was presented at the annual meeting of the American Society of Clinical Oncology, looked at additional endpoints, including PFS2 (defined as time from randomization to end of next-line treatment), time to first chemotherapy, key adverse events (AEs) and patient-reported outcomes (PROs).

“Triple combination of inavolisib, a novel PI3K inhibitor, with palbociclib and fulvestrant, resulted in significant and clinically meaningful improvement in PFS (15.0 vs 7.3 months, hazard ratio [HR] 0.43, P less than .0001),” lead investigator Dejan Juric, MD, reported at the meeting, referring to the initial results.

In additional endpoints, the inavolisib-based triplet also “sustained benefit beyond disease progression, delay in chemotherapy initiation, a manageable safety profile, prolonged time to deterioration in pain severity, and maintained quality of life, supporting the overall conclusion that this triple combination is a promising new treatment option for patients with PIK3CA-mutated HR-positive, HER2-negative metastatic breast cancer,” said the oncologist, of Massachusetts General Hospital Cancer Center and assistant professor at Harvard Medical School in Boston.
 

Methods and Results

The trial enrolled 325 patients whose disease had progressed during or within 12 months of adjuvant endocrine therapy (ET) with an aromatase inhibitor or tamoxifen and who had not received prior systemic therapy for recurrent LA/mBC. Patients were enrolled from December 2019 to September 2023 and randomized to either the triplet combination of inavolisib with palbociclib and fulvestrant (n = 161) or the doublet therapy of placebo with palbociclib and fulvestrant (n = 164) until discontinuation due to progressive disease or toxicity.

At the analysis cutoff date at the end of September, 57.8% of patients in the experimental triple therapy arm and 70.1% in the doublet arm had discontinued treatment. In addition, “7.5% versus 11.6% of patients died without subsequent therapy,” said Dr. Juric, and 40.4% of those in the triplet arm, and 50% in the doublet arm received subsequent therapy.

In the expanded analysis, at a median follow-up of 21.3 months, the triplet combination was associated with a PFS2 benefit of 8.9 months over the doublet – meaning patients had 24 months versus 15.1 months from randomization to end of next-line treatment (HR = 0.54). There was a similar benefit in time to first chemotherapy.

Hyperglycemia, diarrhea, rash, and mucosal effects are a known toxicity of PI3K inhibition and were experienced more frequently in the inavolisib arm compared with the placebo arm: (59% vs 9%; 48% vs 16%; 25% vs 17%; and 51% vs 27% respectively). However, “in the vast majority of patients these AEs were experienced in a grade 1 or grade 2 level,” and had resolved by the cutoff date, said Dr. Juric.

There was a 6.2% rate of inavolisib discontinuation due to AEs, but most AEs could be managed with “common approaches” such as metformin for hyperglycemia, loperamide for diarrhea, topical hydrocortisone for rash, and steroid mouthwash for stomatitis/mucosal inflammation, he added.

Patients in the triple treatment arm experienced a longer interval before pain worsened, a median of 30.9 versus 18.1 months, and patient-reported outcomes and health-related quality of life measures showed no decrease with the addition of inavolisib, Dr. Juric reported.
 

Rationale for Using PFS2 as Endpoint

The PFS2 endpoint has emerged with studies of targeted cancer therapies, Kevin Kalinsky, MD, director of the Glenn Family Breast Center at Winship Cancer Institute of Emory University, in Atlanta, said in an interview.

“Presenting PFS2 is not a new thing — we’ve been doing this in other breast cancer studies (of CDK4/6 inhibitors),” said Dr. Kalinsky, a coauthor of the study. “The concern is that you give a drug, and then, after that, things grow so rapidly that then you’re actually not benefiting the patient.

“If you’re giving a targeted agent in the first-line, then the biology changes after that first-line, are you really even making a difference? Or is the drug so toxic that they’re not able to tolerate a next line of treatment?” Dr. Kalinsky continued. “So that’s really the intent of PFS2. The PFS2 included the next line of treatment, so it’s really a first, and second-line representation of treatment. The study presented at ASCO was really about toxicity.”

The study was funded by F. Hoffmann-La Roche Ltd. Dr. Juric disclosed having stock and other ownership interests in PIC Therapeutics, Relay Therapeutics, and Vibliome Therapeutics; consulting or advisory roles with AstraZeneca, Eisai, Genentech, Lilly, MapKure, Novartis, Pfizer, PIC Therapeutics, Relay Therapeutics, and Vibliome Therapeutics; and research funding from Amgen, Arvinas, AstraZeneca, Blueprint Medicines, Eisai, Genentech, Infinity Pharmaceuticals, InventisBio, Novartis, Pfizer, Ribon Therapeutics, Scorpion Therapeutics, Syros Pharmaceuticals, and Takeda.

The experimental drug inavolisib showed sustained benefit combined with standard treatment in advanced, PIK3CA-mutated, hormone receptor–positive, human epidermal growth factor receptor 2–negative (HR+/HER2-) locally advanced metastatic breast cancer (LA/mBC), the INAVO120 trial.

The U.S. Food and Drug Administration (FDA) recently granted Breakthrough Therapy Designation for inavolisib in combination with palbociclib and fulvestrant based on initial results of the study presented at a December 2023 meeting. The phase 3 results showed the inavolisib-based regimen more than doubled progression-free survival (PFS) compared with the two other drugs alone as first-line treatment, researchers reported.

The expanded analysis of the trial, which was presented at the annual meeting of the American Society of Clinical Oncology, looked at additional endpoints, including PFS2 (defined as time from randomization to end of next-line treatment), time to first chemotherapy, key adverse events (AEs) and patient-reported outcomes (PROs).

“Triple combination of inavolisib, a novel PI3K inhibitor, with palbociclib and fulvestrant, resulted in significant and clinically meaningful improvement in PFS (15.0 vs 7.3 months, hazard ratio [HR] 0.43, P less than .0001),” lead investigator Dejan Juric, MD, reported at the meeting, referring to the initial results.

In additional endpoints, the inavolisib-based triplet also “sustained benefit beyond disease progression, delay in chemotherapy initiation, a manageable safety profile, prolonged time to deterioration in pain severity, and maintained quality of life, supporting the overall conclusion that this triple combination is a promising new treatment option for patients with PIK3CA-mutated HR-positive, HER2-negative metastatic breast cancer,” said the oncologist, of Massachusetts General Hospital Cancer Center and assistant professor at Harvard Medical School in Boston.
 

Methods and Results

The trial enrolled 325 patients whose disease had progressed during or within 12 months of adjuvant endocrine therapy (ET) with an aromatase inhibitor or tamoxifen and who had not received prior systemic therapy for recurrent LA/mBC. Patients were enrolled from December 2019 to September 2023 and randomized to either the triplet combination of inavolisib with palbociclib and fulvestrant (n = 161) or the doublet therapy of placebo with palbociclib and fulvestrant (n = 164) until discontinuation due to progressive disease or toxicity.

At the analysis cutoff date at the end of September, 57.8% of patients in the experimental triple therapy arm and 70.1% in the doublet arm had discontinued treatment. In addition, “7.5% versus 11.6% of patients died without subsequent therapy,” said Dr. Juric, and 40.4% of those in the triplet arm, and 50% in the doublet arm received subsequent therapy.

In the expanded analysis, at a median follow-up of 21.3 months, the triplet combination was associated with a PFS2 benefit of 8.9 months over the doublet – meaning patients had 24 months versus 15.1 months from randomization to end of next-line treatment (HR = 0.54). There was a similar benefit in time to first chemotherapy.

Hyperglycemia, diarrhea, rash, and mucosal effects are a known toxicity of PI3K inhibition and were experienced more frequently in the inavolisib arm compared with the placebo arm: (59% vs 9%; 48% vs 16%; 25% vs 17%; and 51% vs 27% respectively). However, “in the vast majority of patients these AEs were experienced in a grade 1 or grade 2 level,” and had resolved by the cutoff date, said Dr. Juric.

There was a 6.2% rate of inavolisib discontinuation due to AEs, but most AEs could be managed with “common approaches” such as metformin for hyperglycemia, loperamide for diarrhea, topical hydrocortisone for rash, and steroid mouthwash for stomatitis/mucosal inflammation, he added.

Patients in the triple treatment arm experienced a longer interval before pain worsened, a median of 30.9 versus 18.1 months, and patient-reported outcomes and health-related quality of life measures showed no decrease with the addition of inavolisib, Dr. Juric reported.
 

Rationale for Using PFS2 as Endpoint

The PFS2 endpoint has emerged with studies of targeted cancer therapies, Kevin Kalinsky, MD, director of the Glenn Family Breast Center at Winship Cancer Institute of Emory University, in Atlanta, said in an interview.

“Presenting PFS2 is not a new thing — we’ve been doing this in other breast cancer studies (of CDK4/6 inhibitors),” said Dr. Kalinsky, a coauthor of the study. “The concern is that you give a drug, and then, after that, things grow so rapidly that then you’re actually not benefiting the patient.

“If you’re giving a targeted agent in the first-line, then the biology changes after that first-line, are you really even making a difference? Or is the drug so toxic that they’re not able to tolerate a next line of treatment?” Dr. Kalinsky continued. “So that’s really the intent of PFS2. The PFS2 included the next line of treatment, so it’s really a first, and second-line representation of treatment. The study presented at ASCO was really about toxicity.”

The study was funded by F. Hoffmann-La Roche Ltd. Dr. Juric disclosed having stock and other ownership interests in PIC Therapeutics, Relay Therapeutics, and Vibliome Therapeutics; consulting or advisory roles with AstraZeneca, Eisai, Genentech, Lilly, MapKure, Novartis, Pfizer, PIC Therapeutics, Relay Therapeutics, and Vibliome Therapeutics; and research funding from Amgen, Arvinas, AstraZeneca, Blueprint Medicines, Eisai, Genentech, Infinity Pharmaceuticals, InventisBio, Novartis, Pfizer, Ribon Therapeutics, Scorpion Therapeutics, Syros Pharmaceuticals, and Takeda.