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‘Promising’ durvalumab results spark phase 3 trial in mesothelioma
Adding durvalumab to first-line pemetrexed and cisplatin improved survival in patients with unresectable malignant pleural mesothelioma (MPM) in a phase 2 trial, compared with historical controls who received only pemetrexed and cisplatin.
The median overall survival was 20.4 months in patients who received durvalumab plus pemetrexed-cisplatin. This is significantly longer than the median overall survival of 12.1 months (P = .0014) observed with pemetrexed-cisplatin in a prior phase 3 study (J Clin Oncol. 2003 Jul 15;21[14]:2636-44).
The new phase 2 results are “promising,” said lead investigator Patrick Forde, MBBCh, director of the thoracic cancer clinical research program at Johns Hopkins University in Baltimore.
He presented the results as part of the American Society of Clinical Oncology virtual scientific program.
Dr. Forde noted that a phase 3 trial directly comparing pemetrexed-cisplatin plus durvalumab to pemetrexed-cisplatin will begin recruiting this year. The trial is a collaboration between U.S. investigators and Australian researchers who reported their own phase 2 results with durvalumab plus pemetrexed-cisplatin in 2018 (J Thorac Oncol. 2018 Oct;13[10]:S338-339).
Study details
Dr. Forde’s phase 2 study enrolled 55 patients with treatment-naive, unresectable MPM. Their median age was 68 years (range, 35-83 years), and 45 (82%) were men. All had an Eastern Cooperative Oncology Group performance status of 0-1.
Epithelioid mesothelioma was the histologic subtype in three-quarters of patients. “It was a fairly typical mesothelioma population,” Dr. Forde said.
The patients received durvalumab at 1,120 mg plus pemetrexed at 500 mg/m2 and cisplatin at 75 mg/m2 every 3 weeks for up to six cycles. Carboplatin was substituted when cisplatin was contraindicated or patients developed toxicities.
All but one patient had stable or responding disease on radiography and went on to durvalumab maintenance, also given at 1,120 mg every 3 weeks, for up to 1 year from study entry.
Results
Dr. Forde said this study had 90% power to detect a 58% improvement in median overall survival, from the 12.1 months seen in historical controls to 19 months, which was the goal of this study.
It was a positive study, he said, as the median overall survival was 20.4 months (P = .0014).
The overall survival rate was 87.2% at 6 months, 70.4% at 12 months, and 44.2% at 24 months. The progression-free survival rate was 69.1% at 6 months, 16.4% at 12 months, and 10.9% at 24 months.
The overall response rate was 56.4%, which comprised 31 partial responses. Forty percent of patients (n = 22) had stable disease. One patient had progressive disease, and one was not evaluable (1.8% each).
To help with future patient selection, the researchers looked for baseline biomarkers that predicted response. Tumor PD-L1 expression, tumor mutation burden, and other potential candidates haven’t worked out so far, but the work continues, Dr. Forde said.
He noted that many of the adverse events in this trial are those typically seen with platinum-based chemotherapy.
Grade 3/4 treatment-emergent adverse events included anemia (n = 14), fatigue (n = 4), decreased appetite (n = 1), and hypomagnesemia (n = 1).
The most common grade 1/2 adverse events of special interest were hypothyroidism (n = 7), rash (n = 5), pruritus (n = 3), AST elevation (n = 3), and hyperthyroidism (n = 3).
Putting the results in context
Given the role of inflammation in MPM, durvalumab is among several immunotherapies under investigation for the disease.
A phase 3 French trial showed MPM patients had a median overall survival of 18.8 months with pemetrexed-cisplatin plus bevacizumab versus 16.1 months with pemetrexed-cisplatin only (Lancet. 2016 Apr 2;387[10026]:1405-1414).
The higher overall survival in the French study’s pemetrexed-cisplatin arm, compared with the 2003 trial results, is likely due to the use of modern second-line options, said Marjorie Zauderer, MD, codirector of the mesothelioma program at Memorial Sloan Kettering Cancer Center in New York, who was the discussant for Dr. Forde’s presentation.
“I think the improvement in overall survival presented by Dr. Forde is potentially clinically meaningful,” she said, but it was “well within the 95% confidence interval” of the bevacizumab trial. Even so, “I look forward” to the phase 3 results, she said.
Dr. Zauderer also pointed out an April press release from Bristol Myers Squibb that reported improved survival over pemetrexed-cisplatin with two of the company’s immunotherapies, nivolumab and ipilimumab, not as additions but as replacement first-line therapy. However, the randomized trial data haven’t been released yet. “We are all eager to evaluate this option further,” she said.
AstraZeneca, maker of durvalumab, funded the current study. Dr. Forde is an adviser for the company and reported research funding. Dr. Zauderer reported a relationship with Roche, which markets bevacizumab through its subsidiary, Genentech. She also disclosed research funding from Bristol Myers Squibb.
SOURCE: Forde PM et al. ASCO 2020, Abstract 9003.
Adding durvalumab to first-line pemetrexed and cisplatin improved survival in patients with unresectable malignant pleural mesothelioma (MPM) in a phase 2 trial, compared with historical controls who received only pemetrexed and cisplatin.
The median overall survival was 20.4 months in patients who received durvalumab plus pemetrexed-cisplatin. This is significantly longer than the median overall survival of 12.1 months (P = .0014) observed with pemetrexed-cisplatin in a prior phase 3 study (J Clin Oncol. 2003 Jul 15;21[14]:2636-44).
The new phase 2 results are “promising,” said lead investigator Patrick Forde, MBBCh, director of the thoracic cancer clinical research program at Johns Hopkins University in Baltimore.
He presented the results as part of the American Society of Clinical Oncology virtual scientific program.
Dr. Forde noted that a phase 3 trial directly comparing pemetrexed-cisplatin plus durvalumab to pemetrexed-cisplatin will begin recruiting this year. The trial is a collaboration between U.S. investigators and Australian researchers who reported their own phase 2 results with durvalumab plus pemetrexed-cisplatin in 2018 (J Thorac Oncol. 2018 Oct;13[10]:S338-339).
Study details
Dr. Forde’s phase 2 study enrolled 55 patients with treatment-naive, unresectable MPM. Their median age was 68 years (range, 35-83 years), and 45 (82%) were men. All had an Eastern Cooperative Oncology Group performance status of 0-1.
Epithelioid mesothelioma was the histologic subtype in three-quarters of patients. “It was a fairly typical mesothelioma population,” Dr. Forde said.
The patients received durvalumab at 1,120 mg plus pemetrexed at 500 mg/m2 and cisplatin at 75 mg/m2 every 3 weeks for up to six cycles. Carboplatin was substituted when cisplatin was contraindicated or patients developed toxicities.
All but one patient had stable or responding disease on radiography and went on to durvalumab maintenance, also given at 1,120 mg every 3 weeks, for up to 1 year from study entry.
Results
Dr. Forde said this study had 90% power to detect a 58% improvement in median overall survival, from the 12.1 months seen in historical controls to 19 months, which was the goal of this study.
It was a positive study, he said, as the median overall survival was 20.4 months (P = .0014).
The overall survival rate was 87.2% at 6 months, 70.4% at 12 months, and 44.2% at 24 months. The progression-free survival rate was 69.1% at 6 months, 16.4% at 12 months, and 10.9% at 24 months.
The overall response rate was 56.4%, which comprised 31 partial responses. Forty percent of patients (n = 22) had stable disease. One patient had progressive disease, and one was not evaluable (1.8% each).
To help with future patient selection, the researchers looked for baseline biomarkers that predicted response. Tumor PD-L1 expression, tumor mutation burden, and other potential candidates haven’t worked out so far, but the work continues, Dr. Forde said.
He noted that many of the adverse events in this trial are those typically seen with platinum-based chemotherapy.
Grade 3/4 treatment-emergent adverse events included anemia (n = 14), fatigue (n = 4), decreased appetite (n = 1), and hypomagnesemia (n = 1).
The most common grade 1/2 adverse events of special interest were hypothyroidism (n = 7), rash (n = 5), pruritus (n = 3), AST elevation (n = 3), and hyperthyroidism (n = 3).
Putting the results in context
Given the role of inflammation in MPM, durvalumab is among several immunotherapies under investigation for the disease.
A phase 3 French trial showed MPM patients had a median overall survival of 18.8 months with pemetrexed-cisplatin plus bevacizumab versus 16.1 months with pemetrexed-cisplatin only (Lancet. 2016 Apr 2;387[10026]:1405-1414).
The higher overall survival in the French study’s pemetrexed-cisplatin arm, compared with the 2003 trial results, is likely due to the use of modern second-line options, said Marjorie Zauderer, MD, codirector of the mesothelioma program at Memorial Sloan Kettering Cancer Center in New York, who was the discussant for Dr. Forde’s presentation.
“I think the improvement in overall survival presented by Dr. Forde is potentially clinically meaningful,” she said, but it was “well within the 95% confidence interval” of the bevacizumab trial. Even so, “I look forward” to the phase 3 results, she said.
Dr. Zauderer also pointed out an April press release from Bristol Myers Squibb that reported improved survival over pemetrexed-cisplatin with two of the company’s immunotherapies, nivolumab and ipilimumab, not as additions but as replacement first-line therapy. However, the randomized trial data haven’t been released yet. “We are all eager to evaluate this option further,” she said.
AstraZeneca, maker of durvalumab, funded the current study. Dr. Forde is an adviser for the company and reported research funding. Dr. Zauderer reported a relationship with Roche, which markets bevacizumab through its subsidiary, Genentech. She also disclosed research funding from Bristol Myers Squibb.
SOURCE: Forde PM et al. ASCO 2020, Abstract 9003.
Adding durvalumab to first-line pemetrexed and cisplatin improved survival in patients with unresectable malignant pleural mesothelioma (MPM) in a phase 2 trial, compared with historical controls who received only pemetrexed and cisplatin.
The median overall survival was 20.4 months in patients who received durvalumab plus pemetrexed-cisplatin. This is significantly longer than the median overall survival of 12.1 months (P = .0014) observed with pemetrexed-cisplatin in a prior phase 3 study (J Clin Oncol. 2003 Jul 15;21[14]:2636-44).
The new phase 2 results are “promising,” said lead investigator Patrick Forde, MBBCh, director of the thoracic cancer clinical research program at Johns Hopkins University in Baltimore.
He presented the results as part of the American Society of Clinical Oncology virtual scientific program.
Dr. Forde noted that a phase 3 trial directly comparing pemetrexed-cisplatin plus durvalumab to pemetrexed-cisplatin will begin recruiting this year. The trial is a collaboration between U.S. investigators and Australian researchers who reported their own phase 2 results with durvalumab plus pemetrexed-cisplatin in 2018 (J Thorac Oncol. 2018 Oct;13[10]:S338-339).
Study details
Dr. Forde’s phase 2 study enrolled 55 patients with treatment-naive, unresectable MPM. Their median age was 68 years (range, 35-83 years), and 45 (82%) were men. All had an Eastern Cooperative Oncology Group performance status of 0-1.
Epithelioid mesothelioma was the histologic subtype in three-quarters of patients. “It was a fairly typical mesothelioma population,” Dr. Forde said.
The patients received durvalumab at 1,120 mg plus pemetrexed at 500 mg/m2 and cisplatin at 75 mg/m2 every 3 weeks for up to six cycles. Carboplatin was substituted when cisplatin was contraindicated or patients developed toxicities.
All but one patient had stable or responding disease on radiography and went on to durvalumab maintenance, also given at 1,120 mg every 3 weeks, for up to 1 year from study entry.
Results
Dr. Forde said this study had 90% power to detect a 58% improvement in median overall survival, from the 12.1 months seen in historical controls to 19 months, which was the goal of this study.
It was a positive study, he said, as the median overall survival was 20.4 months (P = .0014).
The overall survival rate was 87.2% at 6 months, 70.4% at 12 months, and 44.2% at 24 months. The progression-free survival rate was 69.1% at 6 months, 16.4% at 12 months, and 10.9% at 24 months.
The overall response rate was 56.4%, which comprised 31 partial responses. Forty percent of patients (n = 22) had stable disease. One patient had progressive disease, and one was not evaluable (1.8% each).
To help with future patient selection, the researchers looked for baseline biomarkers that predicted response. Tumor PD-L1 expression, tumor mutation burden, and other potential candidates haven’t worked out so far, but the work continues, Dr. Forde said.
He noted that many of the adverse events in this trial are those typically seen with platinum-based chemotherapy.
Grade 3/4 treatment-emergent adverse events included anemia (n = 14), fatigue (n = 4), decreased appetite (n = 1), and hypomagnesemia (n = 1).
The most common grade 1/2 adverse events of special interest were hypothyroidism (n = 7), rash (n = 5), pruritus (n = 3), AST elevation (n = 3), and hyperthyroidism (n = 3).
Putting the results in context
Given the role of inflammation in MPM, durvalumab is among several immunotherapies under investigation for the disease.
A phase 3 French trial showed MPM patients had a median overall survival of 18.8 months with pemetrexed-cisplatin plus bevacizumab versus 16.1 months with pemetrexed-cisplatin only (Lancet. 2016 Apr 2;387[10026]:1405-1414).
The higher overall survival in the French study’s pemetrexed-cisplatin arm, compared with the 2003 trial results, is likely due to the use of modern second-line options, said Marjorie Zauderer, MD, codirector of the mesothelioma program at Memorial Sloan Kettering Cancer Center in New York, who was the discussant for Dr. Forde’s presentation.
“I think the improvement in overall survival presented by Dr. Forde is potentially clinically meaningful,” she said, but it was “well within the 95% confidence interval” of the bevacizumab trial. Even so, “I look forward” to the phase 3 results, she said.
Dr. Zauderer also pointed out an April press release from Bristol Myers Squibb that reported improved survival over pemetrexed-cisplatin with two of the company’s immunotherapies, nivolumab and ipilimumab, not as additions but as replacement first-line therapy. However, the randomized trial data haven’t been released yet. “We are all eager to evaluate this option further,” she said.
AstraZeneca, maker of durvalumab, funded the current study. Dr. Forde is an adviser for the company and reported research funding. Dr. Zauderer reported a relationship with Roche, which markets bevacizumab through its subsidiary, Genentech. She also disclosed research funding from Bristol Myers Squibb.
SOURCE: Forde PM et al. ASCO 2020, Abstract 9003.
FROM ASCO 2020
Celecoxib ‘should not be used’ as adjuvant therapy for stage III colon cancer
results of the phase 3 CALGB/SWOG 80702 trial showed.
The trial included 2,526 patients randomized to either 6 or 12 cycles of adjuvant FOLFOX with either celecoxib or placebo. The 3-year disease-free survival (DFS) rate was 76.3% for patients on celecoxib and 73.4% for those on placebo. The 5-year overall survival (OS) was 84% and 81.8%, respectively.
“The addition of celecoxib to FOLFOX adjuvant therapy in stage III colon cancer did not significantly improve disease-free or overall survival,” Jeffrey A. Meyerhardt, MD, of the Dana-Farber Cancer Institute in Boston, said while presenting the results as part of the American Society of Clinical Oncology virtual scientific program.
“We did not detect a significant interaction between celecoxib and duration of FOLFOX therapy for disease-free survival. Similarly, we did not detect a significant interaction between celecoxib and duration of FOLFOX therapy for overall survival,” Dr. Meyerhardt said.
“Simply put, celecoxib should not be used for the secondary prevention of colon cancer,” said invited discussant Christopher Lieu, MD, of the University of Colorado Cancer Center, Aurora.
Trial details
The 80702 trial was designed to test whether the COX-2 inhibitor celecoxib could help further reduce the risk of recurrence when added to adjuvant chemotherapy with 3 or 6 months of FOLFOX. Data on the FOLFOX portion of the trial were previously reported as part of the International Duration Evaluation of Adjuvant Therapy collaboration (N Engl J Med. 2018;378:1177-88).
The trial enrolled 2,526 patients with resected stage III colon cancer. They were randomized to receive 3 or 6 months (6 or 12 cycles) of FOLFOX with either concurrent celecoxib at 400 mg daily (n = 1,265) or placebo (n = 1,261) for 3 years from the start of the trial.
The primary endpoint of 3-year DFS did not differ between the groups (hazard ratio, 0.90; P = .16). Likewise, 5-year OS rates did not differ significantly (HR, 0.89; P = .22).
As Dr. Meyerhardt said, there were no significant interactions detected among any subgroups for DFS or OS, including by age, N or T stage, risk group, concurrent low-dose aspirin use, sex, race/ethnicity, baseline performance status, FOLFOX duration, body mass index, or tumor location.
Rates of toxicities were similar between the groups, except for a higher incidence of hypertension of any grade with celecoxib during FOLFOX therapy (14.6% vs. 10.9%, P = .01) and a grade 2 or greater creatinine increase with celecoxib after FOLFOX (1.7% vs. 0.5%, P = .01).
About 40% of patients completed all 3 years of celecoxib or placebo. Reasons for discontinuation included recurrent disease, adverse events, patient withdrawal from the study, physician decision, or other complicating disease.
Why didn’t it work?
Previous studies have indicated that aspirin and cyclooxygenase (COX)-2 inhibitors are associated with a reduced risk of colorectal polyps and cancer, Dr. Lieu said. So why didn’t celecoxib improve survival in the current trial?
“There are obviously COX-1 and COX-independent targets that aspirin hit that celecoxib does not, and its survival impact of affecting these targets is still largely unclear,” Dr. Lieu said.
He added that ongoing trials – including the Add-Aspirin and ASCOLT studies – should provide more insight.
The current trial was sponsored by the Alliance for Clinical Trials in Oncology in collaboration with the National Cancer Institute. Pfizer provided the celecoxib and placebo. Dr. Meyerhardt disclosed relationships with Cota Healthcare, Taiho Pharmaceutical, and Array BioPharma. Dr. Lieu disclosed relationships with Foundation Medicine, Ipsen, Merck, and Immune Design.
SOURCE: Meyerhardt JA et al. ASCO 2020, Abstract 4003.
results of the phase 3 CALGB/SWOG 80702 trial showed.
The trial included 2,526 patients randomized to either 6 or 12 cycles of adjuvant FOLFOX with either celecoxib or placebo. The 3-year disease-free survival (DFS) rate was 76.3% for patients on celecoxib and 73.4% for those on placebo. The 5-year overall survival (OS) was 84% and 81.8%, respectively.
“The addition of celecoxib to FOLFOX adjuvant therapy in stage III colon cancer did not significantly improve disease-free or overall survival,” Jeffrey A. Meyerhardt, MD, of the Dana-Farber Cancer Institute in Boston, said while presenting the results as part of the American Society of Clinical Oncology virtual scientific program.
“We did not detect a significant interaction between celecoxib and duration of FOLFOX therapy for disease-free survival. Similarly, we did not detect a significant interaction between celecoxib and duration of FOLFOX therapy for overall survival,” Dr. Meyerhardt said.
“Simply put, celecoxib should not be used for the secondary prevention of colon cancer,” said invited discussant Christopher Lieu, MD, of the University of Colorado Cancer Center, Aurora.
Trial details
The 80702 trial was designed to test whether the COX-2 inhibitor celecoxib could help further reduce the risk of recurrence when added to adjuvant chemotherapy with 3 or 6 months of FOLFOX. Data on the FOLFOX portion of the trial were previously reported as part of the International Duration Evaluation of Adjuvant Therapy collaboration (N Engl J Med. 2018;378:1177-88).
The trial enrolled 2,526 patients with resected stage III colon cancer. They were randomized to receive 3 or 6 months (6 or 12 cycles) of FOLFOX with either concurrent celecoxib at 400 mg daily (n = 1,265) or placebo (n = 1,261) for 3 years from the start of the trial.
The primary endpoint of 3-year DFS did not differ between the groups (hazard ratio, 0.90; P = .16). Likewise, 5-year OS rates did not differ significantly (HR, 0.89; P = .22).
As Dr. Meyerhardt said, there were no significant interactions detected among any subgroups for DFS or OS, including by age, N or T stage, risk group, concurrent low-dose aspirin use, sex, race/ethnicity, baseline performance status, FOLFOX duration, body mass index, or tumor location.
Rates of toxicities were similar between the groups, except for a higher incidence of hypertension of any grade with celecoxib during FOLFOX therapy (14.6% vs. 10.9%, P = .01) and a grade 2 or greater creatinine increase with celecoxib after FOLFOX (1.7% vs. 0.5%, P = .01).
About 40% of patients completed all 3 years of celecoxib or placebo. Reasons for discontinuation included recurrent disease, adverse events, patient withdrawal from the study, physician decision, or other complicating disease.
Why didn’t it work?
Previous studies have indicated that aspirin and cyclooxygenase (COX)-2 inhibitors are associated with a reduced risk of colorectal polyps and cancer, Dr. Lieu said. So why didn’t celecoxib improve survival in the current trial?
“There are obviously COX-1 and COX-independent targets that aspirin hit that celecoxib does not, and its survival impact of affecting these targets is still largely unclear,” Dr. Lieu said.
He added that ongoing trials – including the Add-Aspirin and ASCOLT studies – should provide more insight.
The current trial was sponsored by the Alliance for Clinical Trials in Oncology in collaboration with the National Cancer Institute. Pfizer provided the celecoxib and placebo. Dr. Meyerhardt disclosed relationships with Cota Healthcare, Taiho Pharmaceutical, and Array BioPharma. Dr. Lieu disclosed relationships with Foundation Medicine, Ipsen, Merck, and Immune Design.
SOURCE: Meyerhardt JA et al. ASCO 2020, Abstract 4003.
results of the phase 3 CALGB/SWOG 80702 trial showed.
The trial included 2,526 patients randomized to either 6 or 12 cycles of adjuvant FOLFOX with either celecoxib or placebo. The 3-year disease-free survival (DFS) rate was 76.3% for patients on celecoxib and 73.4% for those on placebo. The 5-year overall survival (OS) was 84% and 81.8%, respectively.
“The addition of celecoxib to FOLFOX adjuvant therapy in stage III colon cancer did not significantly improve disease-free or overall survival,” Jeffrey A. Meyerhardt, MD, of the Dana-Farber Cancer Institute in Boston, said while presenting the results as part of the American Society of Clinical Oncology virtual scientific program.
“We did not detect a significant interaction between celecoxib and duration of FOLFOX therapy for disease-free survival. Similarly, we did not detect a significant interaction between celecoxib and duration of FOLFOX therapy for overall survival,” Dr. Meyerhardt said.
“Simply put, celecoxib should not be used for the secondary prevention of colon cancer,” said invited discussant Christopher Lieu, MD, of the University of Colorado Cancer Center, Aurora.
Trial details
The 80702 trial was designed to test whether the COX-2 inhibitor celecoxib could help further reduce the risk of recurrence when added to adjuvant chemotherapy with 3 or 6 months of FOLFOX. Data on the FOLFOX portion of the trial were previously reported as part of the International Duration Evaluation of Adjuvant Therapy collaboration (N Engl J Med. 2018;378:1177-88).
The trial enrolled 2,526 patients with resected stage III colon cancer. They were randomized to receive 3 or 6 months (6 or 12 cycles) of FOLFOX with either concurrent celecoxib at 400 mg daily (n = 1,265) or placebo (n = 1,261) for 3 years from the start of the trial.
The primary endpoint of 3-year DFS did not differ between the groups (hazard ratio, 0.90; P = .16). Likewise, 5-year OS rates did not differ significantly (HR, 0.89; P = .22).
As Dr. Meyerhardt said, there were no significant interactions detected among any subgroups for DFS or OS, including by age, N or T stage, risk group, concurrent low-dose aspirin use, sex, race/ethnicity, baseline performance status, FOLFOX duration, body mass index, or tumor location.
Rates of toxicities were similar between the groups, except for a higher incidence of hypertension of any grade with celecoxib during FOLFOX therapy (14.6% vs. 10.9%, P = .01) and a grade 2 or greater creatinine increase with celecoxib after FOLFOX (1.7% vs. 0.5%, P = .01).
About 40% of patients completed all 3 years of celecoxib or placebo. Reasons for discontinuation included recurrent disease, adverse events, patient withdrawal from the study, physician decision, or other complicating disease.
Why didn’t it work?
Previous studies have indicated that aspirin and cyclooxygenase (COX)-2 inhibitors are associated with a reduced risk of colorectal polyps and cancer, Dr. Lieu said. So why didn’t celecoxib improve survival in the current trial?
“There are obviously COX-1 and COX-independent targets that aspirin hit that celecoxib does not, and its survival impact of affecting these targets is still largely unclear,” Dr. Lieu said.
He added that ongoing trials – including the Add-Aspirin and ASCOLT studies – should provide more insight.
The current trial was sponsored by the Alliance for Clinical Trials in Oncology in collaboration with the National Cancer Institute. Pfizer provided the celecoxib and placebo. Dr. Meyerhardt disclosed relationships with Cota Healthcare, Taiho Pharmaceutical, and Array BioPharma. Dr. Lieu disclosed relationships with Foundation Medicine, Ipsen, Merck, and Immune Design.
SOURCE: Meyerhardt JA et al. ASCO 2020, Abstract 4003.
FROM ASCO 2020
Secondary surgery extends OS in recurrent ovarian cancer
The trial, AGO DESKTOP III/ENGOT ov20, is the first prospective, randomized study showing an overall survival benefit for debulking surgery in patients with recurrent ovarian cancer.
Among 406 patients in first relapse, the median overall survival was 53.7 months for those randomized to cytoreductive surgery plus chemotherapy and 46 months for patients randomized to chemotherapy alone (P = .02).
“The overall survival benefit was highest and exclusively seen in the cohort with complete resection, indicating the importance of a thorough selection process of both the right patient and the right center,” said investigator Andreas du Bois, MD, of the Kliniken Essen-Mitte (Germany).
The median survival gain for patients with platinum-free intervals of more than 6 months who undergo complete resection is nearly 16 months “and is worth going for,” he added.
Dr. du Bois presented these results as part of the American Society of Clinical Oncology virtual scientific program (Abstract 6000).
In another trial, SOC-1, that was also presented in the virtual program, investigators reported a progression-free survival advantage of 5.5 months for patients with recurrent ovarian cancer who underwent debulking surgery, compared with those who did not (Abstract 6001).
Different trials, different results
The invited discussant for Dr. du Bois’s presentation was Robert L. Coleman, MD, chief scientific officer of the U.S. Oncology Network in The Woodlands, Tex., who was the principal investigator of the GOG-0213 trial (N Engl J Med. 2019;381:1929-39).
That trial did not show an overall survival advantage to secondary surgical cytoreduction followed by chemotherapy, compared with chemotherapy alone, among 485 women with platinum-sensitive recurrent ovarian cancer.
Referring to both AGO DESKTOP III and SOC-1, Dr. Coleman noted that, “while only DESKTOP III met its primary endpoint of improving overall survival, both demonstrated a benefit on PFS [progression-free survival].” Both trials also support a triage algorithm for selecting the approximately 75% of patients who are likely to benefit from secondary cytoreductive surgery.
“However, the price paid for being wrong is substantial, with no benefit seen in progression-free survival and possibly a detriment in overall survival. Because of these observations, both [presenters of SOC-1 and AGO DESKTOP III data] recommended that procedures be limited to select women having surgery performed at sites of excellence,” Dr. Coleman said.
Potential explanations for the differential findings of a secondary surgery benefit in DESKTOP III and SOC-1 versus GOG-0213 include the use of a selection algorithm in the former versus investigator selection based on clinical parameters and imaging in the latter.
In addition, “while platinum-based therapy was the rule in all trials, the use of concomitant and maintenance bevacizumab, a regimen found to improve overall survival in GOG-0213, was used in substantially higher numbers of patients in that trial relative to the two current trials,” Dr. Coleman said.
The GOG-0213 trial also demonstrated an advantage for adjuvant therapy with platinum-based chemotherapy and bevacizumab, which was given to 84% of patients in GOG-0213. That trial had a median overall survival for patients who did not undergo surgery of 65.7 months, compared with 46 months in AGO DESKTOP III and 53.9 months in SOC-1, Dr. Coleman said.
Third time’s a charm
As its name implies, the AGO DESKTOP III trial is the third in a series. AGO DESKTOP I developed the hypothesis that a positive AGO score – consisting of an Eastern Cooperative Oncology Group performance status score of 0, complete resection during first-line therapy, and ascites less than 500 mL – could be predictive of favorable outcomes with debulking surgery (Ann Surg Oncol. 2006 Dec;13[12]:1702-10).
AGO DESKTOP II was a prospective, multicenter trial testing the score in patients with platinum-free intervals of more than 6 months (Int J Gynecol Cancer. 2011 Feb;21[2]:289-95). In this trial, 51% of patients had a positive AGO score, and the score was shown to predict, with 95% probability, complete resectability in two-thirds of these patients, Dr. Du Bois said.
In AGO DESKTOP III, 407 patients were prospectively randomized to second-line chemotherapy alone (n = 201) or to cytoreductive surgery (n = 206) followed by the same chemotherapy, with platinum-containing regimens highly recommended.
Patient characteristics were well balanced between the arms. Nearly all patients (99%) in each arm had prior platinum exposure, and 75% had a platinum-free interval of more than 12 months (a median of 21.1 months in the surgery arm versus 18.7 months in the no-surgery arm).
Complete resections extend OS
There were 8 patients (4%) in the chemotherapy-only arm and 14 (6.8%) in the surgery arm who were noncompliant with randomization. The complete resection rate was 74.2%.
Following randomization, 88.8% of patients in the surgery arm and 90% in the no-surgery arm received platinum-containing chemotherapy; 22.8% and 23.4%, respectively, received bevacizumab; and 3.9% and 6.0% received a poly (ADP-ribose) polymerase inhibitor.
The median overall survival in the intention-to-treat population was 53.7 months in the surgery arm and 46 months in the no-surgery arm, an absolute difference of 7.7 months (hazard ratio, 0.75; P = .02).
The median progression-free survival, assessed in the intention-to-treat population after database closure in January 2020, was 18.4 months with surgery and 14 months without (HR, 0.66; P < .001).
A post hoc analysis showed the importance of complete versus partial resection. The median overall survival was 61.9 months in patients with complete resections and 28.8 months for patients with residual tumor after cytoreductive surgery, an absolute difference of nearly 3 years (HR, 0.40; P < .001).
Comparing only those patients with complete resections with patients who did not undergo surgery, the respective median overall survival was 61.9 months and 46 months (HR, 0.57; P < .001).
AGO DESKTOP III was sponsored by the AGO study group in collaboration with other oncology groups, Medac, and GlaxoSmithKline. Dr. du Bois and Dr. Coleman disclosed relationships with many companies.
SOURCE: du Bois A et al. ASCO 2020, Abstract 6000.
The trial, AGO DESKTOP III/ENGOT ov20, is the first prospective, randomized study showing an overall survival benefit for debulking surgery in patients with recurrent ovarian cancer.
Among 406 patients in first relapse, the median overall survival was 53.7 months for those randomized to cytoreductive surgery plus chemotherapy and 46 months for patients randomized to chemotherapy alone (P = .02).
“The overall survival benefit was highest and exclusively seen in the cohort with complete resection, indicating the importance of a thorough selection process of both the right patient and the right center,” said investigator Andreas du Bois, MD, of the Kliniken Essen-Mitte (Germany).
The median survival gain for patients with platinum-free intervals of more than 6 months who undergo complete resection is nearly 16 months “and is worth going for,” he added.
Dr. du Bois presented these results as part of the American Society of Clinical Oncology virtual scientific program (Abstract 6000).
In another trial, SOC-1, that was also presented in the virtual program, investigators reported a progression-free survival advantage of 5.5 months for patients with recurrent ovarian cancer who underwent debulking surgery, compared with those who did not (Abstract 6001).
Different trials, different results
The invited discussant for Dr. du Bois’s presentation was Robert L. Coleman, MD, chief scientific officer of the U.S. Oncology Network in The Woodlands, Tex., who was the principal investigator of the GOG-0213 trial (N Engl J Med. 2019;381:1929-39).
That trial did not show an overall survival advantage to secondary surgical cytoreduction followed by chemotherapy, compared with chemotherapy alone, among 485 women with platinum-sensitive recurrent ovarian cancer.
Referring to both AGO DESKTOP III and SOC-1, Dr. Coleman noted that, “while only DESKTOP III met its primary endpoint of improving overall survival, both demonstrated a benefit on PFS [progression-free survival].” Both trials also support a triage algorithm for selecting the approximately 75% of patients who are likely to benefit from secondary cytoreductive surgery.
“However, the price paid for being wrong is substantial, with no benefit seen in progression-free survival and possibly a detriment in overall survival. Because of these observations, both [presenters of SOC-1 and AGO DESKTOP III data] recommended that procedures be limited to select women having surgery performed at sites of excellence,” Dr. Coleman said.
Potential explanations for the differential findings of a secondary surgery benefit in DESKTOP III and SOC-1 versus GOG-0213 include the use of a selection algorithm in the former versus investigator selection based on clinical parameters and imaging in the latter.
In addition, “while platinum-based therapy was the rule in all trials, the use of concomitant and maintenance bevacizumab, a regimen found to improve overall survival in GOG-0213, was used in substantially higher numbers of patients in that trial relative to the two current trials,” Dr. Coleman said.
The GOG-0213 trial also demonstrated an advantage for adjuvant therapy with platinum-based chemotherapy and bevacizumab, which was given to 84% of patients in GOG-0213. That trial had a median overall survival for patients who did not undergo surgery of 65.7 months, compared with 46 months in AGO DESKTOP III and 53.9 months in SOC-1, Dr. Coleman said.
Third time’s a charm
As its name implies, the AGO DESKTOP III trial is the third in a series. AGO DESKTOP I developed the hypothesis that a positive AGO score – consisting of an Eastern Cooperative Oncology Group performance status score of 0, complete resection during first-line therapy, and ascites less than 500 mL – could be predictive of favorable outcomes with debulking surgery (Ann Surg Oncol. 2006 Dec;13[12]:1702-10).
AGO DESKTOP II was a prospective, multicenter trial testing the score in patients with platinum-free intervals of more than 6 months (Int J Gynecol Cancer. 2011 Feb;21[2]:289-95). In this trial, 51% of patients had a positive AGO score, and the score was shown to predict, with 95% probability, complete resectability in two-thirds of these patients, Dr. Du Bois said.
In AGO DESKTOP III, 407 patients were prospectively randomized to second-line chemotherapy alone (n = 201) or to cytoreductive surgery (n = 206) followed by the same chemotherapy, with platinum-containing regimens highly recommended.
Patient characteristics were well balanced between the arms. Nearly all patients (99%) in each arm had prior platinum exposure, and 75% had a platinum-free interval of more than 12 months (a median of 21.1 months in the surgery arm versus 18.7 months in the no-surgery arm).
Complete resections extend OS
There were 8 patients (4%) in the chemotherapy-only arm and 14 (6.8%) in the surgery arm who were noncompliant with randomization. The complete resection rate was 74.2%.
Following randomization, 88.8% of patients in the surgery arm and 90% in the no-surgery arm received platinum-containing chemotherapy; 22.8% and 23.4%, respectively, received bevacizumab; and 3.9% and 6.0% received a poly (ADP-ribose) polymerase inhibitor.
The median overall survival in the intention-to-treat population was 53.7 months in the surgery arm and 46 months in the no-surgery arm, an absolute difference of 7.7 months (hazard ratio, 0.75; P = .02).
The median progression-free survival, assessed in the intention-to-treat population after database closure in January 2020, was 18.4 months with surgery and 14 months without (HR, 0.66; P < .001).
A post hoc analysis showed the importance of complete versus partial resection. The median overall survival was 61.9 months in patients with complete resections and 28.8 months for patients with residual tumor after cytoreductive surgery, an absolute difference of nearly 3 years (HR, 0.40; P < .001).
Comparing only those patients with complete resections with patients who did not undergo surgery, the respective median overall survival was 61.9 months and 46 months (HR, 0.57; P < .001).
AGO DESKTOP III was sponsored by the AGO study group in collaboration with other oncology groups, Medac, and GlaxoSmithKline. Dr. du Bois and Dr. Coleman disclosed relationships with many companies.
SOURCE: du Bois A et al. ASCO 2020, Abstract 6000.
The trial, AGO DESKTOP III/ENGOT ov20, is the first prospective, randomized study showing an overall survival benefit for debulking surgery in patients with recurrent ovarian cancer.
Among 406 patients in first relapse, the median overall survival was 53.7 months for those randomized to cytoreductive surgery plus chemotherapy and 46 months for patients randomized to chemotherapy alone (P = .02).
“The overall survival benefit was highest and exclusively seen in the cohort with complete resection, indicating the importance of a thorough selection process of both the right patient and the right center,” said investigator Andreas du Bois, MD, of the Kliniken Essen-Mitte (Germany).
The median survival gain for patients with platinum-free intervals of more than 6 months who undergo complete resection is nearly 16 months “and is worth going for,” he added.
Dr. du Bois presented these results as part of the American Society of Clinical Oncology virtual scientific program (Abstract 6000).
In another trial, SOC-1, that was also presented in the virtual program, investigators reported a progression-free survival advantage of 5.5 months for patients with recurrent ovarian cancer who underwent debulking surgery, compared with those who did not (Abstract 6001).
Different trials, different results
The invited discussant for Dr. du Bois’s presentation was Robert L. Coleman, MD, chief scientific officer of the U.S. Oncology Network in The Woodlands, Tex., who was the principal investigator of the GOG-0213 trial (N Engl J Med. 2019;381:1929-39).
That trial did not show an overall survival advantage to secondary surgical cytoreduction followed by chemotherapy, compared with chemotherapy alone, among 485 women with platinum-sensitive recurrent ovarian cancer.
Referring to both AGO DESKTOP III and SOC-1, Dr. Coleman noted that, “while only DESKTOP III met its primary endpoint of improving overall survival, both demonstrated a benefit on PFS [progression-free survival].” Both trials also support a triage algorithm for selecting the approximately 75% of patients who are likely to benefit from secondary cytoreductive surgery.
“However, the price paid for being wrong is substantial, with no benefit seen in progression-free survival and possibly a detriment in overall survival. Because of these observations, both [presenters of SOC-1 and AGO DESKTOP III data] recommended that procedures be limited to select women having surgery performed at sites of excellence,” Dr. Coleman said.
Potential explanations for the differential findings of a secondary surgery benefit in DESKTOP III and SOC-1 versus GOG-0213 include the use of a selection algorithm in the former versus investigator selection based on clinical parameters and imaging in the latter.
In addition, “while platinum-based therapy was the rule in all trials, the use of concomitant and maintenance bevacizumab, a regimen found to improve overall survival in GOG-0213, was used in substantially higher numbers of patients in that trial relative to the two current trials,” Dr. Coleman said.
The GOG-0213 trial also demonstrated an advantage for adjuvant therapy with platinum-based chemotherapy and bevacizumab, which was given to 84% of patients in GOG-0213. That trial had a median overall survival for patients who did not undergo surgery of 65.7 months, compared with 46 months in AGO DESKTOP III and 53.9 months in SOC-1, Dr. Coleman said.
Third time’s a charm
As its name implies, the AGO DESKTOP III trial is the third in a series. AGO DESKTOP I developed the hypothesis that a positive AGO score – consisting of an Eastern Cooperative Oncology Group performance status score of 0, complete resection during first-line therapy, and ascites less than 500 mL – could be predictive of favorable outcomes with debulking surgery (Ann Surg Oncol. 2006 Dec;13[12]:1702-10).
AGO DESKTOP II was a prospective, multicenter trial testing the score in patients with platinum-free intervals of more than 6 months (Int J Gynecol Cancer. 2011 Feb;21[2]:289-95). In this trial, 51% of patients had a positive AGO score, and the score was shown to predict, with 95% probability, complete resectability in two-thirds of these patients, Dr. Du Bois said.
In AGO DESKTOP III, 407 patients were prospectively randomized to second-line chemotherapy alone (n = 201) or to cytoreductive surgery (n = 206) followed by the same chemotherapy, with platinum-containing regimens highly recommended.
Patient characteristics were well balanced between the arms. Nearly all patients (99%) in each arm had prior platinum exposure, and 75% had a platinum-free interval of more than 12 months (a median of 21.1 months in the surgery arm versus 18.7 months in the no-surgery arm).
Complete resections extend OS
There were 8 patients (4%) in the chemotherapy-only arm and 14 (6.8%) in the surgery arm who were noncompliant with randomization. The complete resection rate was 74.2%.
Following randomization, 88.8% of patients in the surgery arm and 90% in the no-surgery arm received platinum-containing chemotherapy; 22.8% and 23.4%, respectively, received bevacizumab; and 3.9% and 6.0% received a poly (ADP-ribose) polymerase inhibitor.
The median overall survival in the intention-to-treat population was 53.7 months in the surgery arm and 46 months in the no-surgery arm, an absolute difference of 7.7 months (hazard ratio, 0.75; P = .02).
The median progression-free survival, assessed in the intention-to-treat population after database closure in January 2020, was 18.4 months with surgery and 14 months without (HR, 0.66; P < .001).
A post hoc analysis showed the importance of complete versus partial resection. The median overall survival was 61.9 months in patients with complete resections and 28.8 months for patients with residual tumor after cytoreductive surgery, an absolute difference of nearly 3 years (HR, 0.40; P < .001).
Comparing only those patients with complete resections with patients who did not undergo surgery, the respective median overall survival was 61.9 months and 46 months (HR, 0.57; P < .001).
AGO DESKTOP III was sponsored by the AGO study group in collaboration with other oncology groups, Medac, and GlaxoSmithKline. Dr. du Bois and Dr. Coleman disclosed relationships with many companies.
SOURCE: du Bois A et al. ASCO 2020, Abstract 6000.
FROM ASCO 2020
Updated BEACON: Doublet as good as triplet in metastatic CRC
The BEACON study tested both a doublet and a triplet of drugs for patients with previously treated BRAF V600E–mutated metastatic colorectal cancer (CRC).
New results from that trial, with an updated survival analysis, show that the doublet is sufficient and that patients can safely be treated with a combination of the BRAF inhibitor encorafenib (Braftovi, Array BioPharma) and the EGFR inhibitor monoclonal antibody cetuximab (Erbitux, Eli Lilly).
This means that the increased toxicity from the addition of the MEK inhibitor binimetinib (Mektovi, Array BioPharma) can be avoided and that good outcomes can be maintained.
The new results were presented as part of the virtual scientific program of the 2020 American Society of Clinical Oncology annual meeting.
Study discussant Michael S. Lee, MD, from the University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, said he “would consider encorafenib and cetuximab now the standard of care in the second line and beyond in BRAF-mutant colorectal cancer.
“I would give the doublet rather than the triplet because of the comparable survival and better side effect profile,” he said.
“This is immediately practice changing, given the FDA approval of encorafenib and cetuximab,” commented Autumn J. McRee, MD, UNC Lineberger Comprehensive Cancer Center.
This is a “clinically relevant” trial, and it demonstrates that the “poorest prognostic group in colorectal cancer now has viable options,” she said at a Highlights of the Day session.
“We will await the results of the ANCHOR-CRC trial to see if we should be using this targeted approach in earlier lines of therapy,” she added.
New survival data
The primary analysis of BEACON CRC, presented at the 2019 World Conference on Gastrointestinal Cancer, showed that use of the triplet therapy was associated with a 48% improvement in overall survival in comparison with standard chemotherapy.
Although that was also linked to improved quality of life, questions have been raised as to whether the benefits are worth the cost, and one commentator singled the study out for harsh criticism.
Scott Kopetz, MD, PhD, from the University of Texas MD Anderson Cancer Center, Houston, presented the updated survival results from BEACON CRC, which included data from an additional 6 months of follow-up.
“We know that the V600E mutation in BRAF occurs in about 10%-15% of patients and is associated with a poor prognosis,” Dr. Kopetz commented.
“BRAF inhibitors alone are not effective,” he noted. He said preclinical models point toward an approach that targets multiple pathways, including BRAF, MEK, and EGFR.
The BEACON study had three arms, each with 205 patients, as follows:
- Encorafenib plus binimetinib plus cetuximab
- Encorafenib plus cetixumab
- A control arm of FOLFIRI plus cetuximab or irinotecan plus cetuximab.
The three arms of the trial were relatively well balanced with respect to patient characteristics, Dr. Kopetz commented. The median age of the patients ranged from 60 to 62 years, and 48%-57% of the patients were women.
Of note, between 5% and 10% of the cases were characterized by high microsatellite instability, and 34%-35% of patients had received more than one prior line of therapy.
The data now presented at ASCO represent a post hoc updated analysis that includes 6 months of additional follow-up since the primary analysis was presented, Dr. Kopetz explained.
After a median follow-up of 12.8 months, 13% of triplet therapy patients, 14% of those who received doublet therapy, and 3% of control patients were still on treatment.
The updated analysis shows that median overall survival with the doublet therapy was 9.3 months versus 5.9 months for the control group (hazard ratio, 0.61). The benefit was seen across all subgroups, including those based on the number of prior regimens.
Dr. Kopetz pointed out that overall survival was numerically superior to that seen in the primary analysis, which was 8.4 months.
The updated survival analysis for the triplet therapy indicated that the median overall survival was 9.3 months versus 5.9 months in the control arm (HR, 0.60). Again, this was consistent across subgroups.
In the primary analysis, the median overall survival with the triplet therapy was 9.0 months.
The team also compared the triplet and doublet therapies, finding that, “in contrast to what was seen in the primary analysis ... we see numerically identical median overall survival with the two arms.” The result was sustained across subgroups.
However, there were indications that there may be survival benefits with the triplet in certain patient subgroups, including those with Eastern Cooperative Oncology Group performance status 1, those in whom three or more organs are involved, those with higher baseline levels of C-reactive protein, and those with partially resected or unresected disease.
Progression-free survival was comparable between the two treatment groups, at 4.5 months with the triplet therapy and 4.3 months with the doublet, compared with just 1.5 months in the control arm.
The updated analysis also showed that the objective response rate was 27% with triplet therapy versus 20% with the doublet and 2% in the control arm. In both the doublet and triplet arms, the majority of responses were partial.
With regard to safety, Dr. Kopetz said that the updated data regarding adverse events were in general “consistent with the previously reported safety profile.”
He added it is “notable” that the triplet therapy “had slightly higher rates of GI toxicity and anemia,” which was not seen with the doublet, something that is “again associated with the known safety profile of a MEK inhibitor.”
The study was funded by Pfizer. Dr. Kopetz has stock and other ownership interests with numerous pharmaceutical companies. Other authors, as well as Dr. Lee and Dr. McRee, have also reported relevant financial relationships.
This article first appeared on Medscape.com.
The BEACON study tested both a doublet and a triplet of drugs for patients with previously treated BRAF V600E–mutated metastatic colorectal cancer (CRC).
New results from that trial, with an updated survival analysis, show that the doublet is sufficient and that patients can safely be treated with a combination of the BRAF inhibitor encorafenib (Braftovi, Array BioPharma) and the EGFR inhibitor monoclonal antibody cetuximab (Erbitux, Eli Lilly).
This means that the increased toxicity from the addition of the MEK inhibitor binimetinib (Mektovi, Array BioPharma) can be avoided and that good outcomes can be maintained.
The new results were presented as part of the virtual scientific program of the 2020 American Society of Clinical Oncology annual meeting.
Study discussant Michael S. Lee, MD, from the University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, said he “would consider encorafenib and cetuximab now the standard of care in the second line and beyond in BRAF-mutant colorectal cancer.
“I would give the doublet rather than the triplet because of the comparable survival and better side effect profile,” he said.
“This is immediately practice changing, given the FDA approval of encorafenib and cetuximab,” commented Autumn J. McRee, MD, UNC Lineberger Comprehensive Cancer Center.
This is a “clinically relevant” trial, and it demonstrates that the “poorest prognostic group in colorectal cancer now has viable options,” she said at a Highlights of the Day session.
“We will await the results of the ANCHOR-CRC trial to see if we should be using this targeted approach in earlier lines of therapy,” she added.
New survival data
The primary analysis of BEACON CRC, presented at the 2019 World Conference on Gastrointestinal Cancer, showed that use of the triplet therapy was associated with a 48% improvement in overall survival in comparison with standard chemotherapy.
Although that was also linked to improved quality of life, questions have been raised as to whether the benefits are worth the cost, and one commentator singled the study out for harsh criticism.
Scott Kopetz, MD, PhD, from the University of Texas MD Anderson Cancer Center, Houston, presented the updated survival results from BEACON CRC, which included data from an additional 6 months of follow-up.
“We know that the V600E mutation in BRAF occurs in about 10%-15% of patients and is associated with a poor prognosis,” Dr. Kopetz commented.
“BRAF inhibitors alone are not effective,” he noted. He said preclinical models point toward an approach that targets multiple pathways, including BRAF, MEK, and EGFR.
The BEACON study had three arms, each with 205 patients, as follows:
- Encorafenib plus binimetinib plus cetuximab
- Encorafenib plus cetixumab
- A control arm of FOLFIRI plus cetuximab or irinotecan plus cetuximab.
The three arms of the trial were relatively well balanced with respect to patient characteristics, Dr. Kopetz commented. The median age of the patients ranged from 60 to 62 years, and 48%-57% of the patients were women.
Of note, between 5% and 10% of the cases were characterized by high microsatellite instability, and 34%-35% of patients had received more than one prior line of therapy.
The data now presented at ASCO represent a post hoc updated analysis that includes 6 months of additional follow-up since the primary analysis was presented, Dr. Kopetz explained.
After a median follow-up of 12.8 months, 13% of triplet therapy patients, 14% of those who received doublet therapy, and 3% of control patients were still on treatment.
The updated analysis shows that median overall survival with the doublet therapy was 9.3 months versus 5.9 months for the control group (hazard ratio, 0.61). The benefit was seen across all subgroups, including those based on the number of prior regimens.
Dr. Kopetz pointed out that overall survival was numerically superior to that seen in the primary analysis, which was 8.4 months.
The updated survival analysis for the triplet therapy indicated that the median overall survival was 9.3 months versus 5.9 months in the control arm (HR, 0.60). Again, this was consistent across subgroups.
In the primary analysis, the median overall survival with the triplet therapy was 9.0 months.
The team also compared the triplet and doublet therapies, finding that, “in contrast to what was seen in the primary analysis ... we see numerically identical median overall survival with the two arms.” The result was sustained across subgroups.
However, there were indications that there may be survival benefits with the triplet in certain patient subgroups, including those with Eastern Cooperative Oncology Group performance status 1, those in whom three or more organs are involved, those with higher baseline levels of C-reactive protein, and those with partially resected or unresected disease.
Progression-free survival was comparable between the two treatment groups, at 4.5 months with the triplet therapy and 4.3 months with the doublet, compared with just 1.5 months in the control arm.
The updated analysis also showed that the objective response rate was 27% with triplet therapy versus 20% with the doublet and 2% in the control arm. In both the doublet and triplet arms, the majority of responses were partial.
With regard to safety, Dr. Kopetz said that the updated data regarding adverse events were in general “consistent with the previously reported safety profile.”
He added it is “notable” that the triplet therapy “had slightly higher rates of GI toxicity and anemia,” which was not seen with the doublet, something that is “again associated with the known safety profile of a MEK inhibitor.”
The study was funded by Pfizer. Dr. Kopetz has stock and other ownership interests with numerous pharmaceutical companies. Other authors, as well as Dr. Lee and Dr. McRee, have also reported relevant financial relationships.
This article first appeared on Medscape.com.
The BEACON study tested both a doublet and a triplet of drugs for patients with previously treated BRAF V600E–mutated metastatic colorectal cancer (CRC).
New results from that trial, with an updated survival analysis, show that the doublet is sufficient and that patients can safely be treated with a combination of the BRAF inhibitor encorafenib (Braftovi, Array BioPharma) and the EGFR inhibitor monoclonal antibody cetuximab (Erbitux, Eli Lilly).
This means that the increased toxicity from the addition of the MEK inhibitor binimetinib (Mektovi, Array BioPharma) can be avoided and that good outcomes can be maintained.
The new results were presented as part of the virtual scientific program of the 2020 American Society of Clinical Oncology annual meeting.
Study discussant Michael S. Lee, MD, from the University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, said he “would consider encorafenib and cetuximab now the standard of care in the second line and beyond in BRAF-mutant colorectal cancer.
“I would give the doublet rather than the triplet because of the comparable survival and better side effect profile,” he said.
“This is immediately practice changing, given the FDA approval of encorafenib and cetuximab,” commented Autumn J. McRee, MD, UNC Lineberger Comprehensive Cancer Center.
This is a “clinically relevant” trial, and it demonstrates that the “poorest prognostic group in colorectal cancer now has viable options,” she said at a Highlights of the Day session.
“We will await the results of the ANCHOR-CRC trial to see if we should be using this targeted approach in earlier lines of therapy,” she added.
New survival data
The primary analysis of BEACON CRC, presented at the 2019 World Conference on Gastrointestinal Cancer, showed that use of the triplet therapy was associated with a 48% improvement in overall survival in comparison with standard chemotherapy.
Although that was also linked to improved quality of life, questions have been raised as to whether the benefits are worth the cost, and one commentator singled the study out for harsh criticism.
Scott Kopetz, MD, PhD, from the University of Texas MD Anderson Cancer Center, Houston, presented the updated survival results from BEACON CRC, which included data from an additional 6 months of follow-up.
“We know that the V600E mutation in BRAF occurs in about 10%-15% of patients and is associated with a poor prognosis,” Dr. Kopetz commented.
“BRAF inhibitors alone are not effective,” he noted. He said preclinical models point toward an approach that targets multiple pathways, including BRAF, MEK, and EGFR.
The BEACON study had three arms, each with 205 patients, as follows:
- Encorafenib plus binimetinib plus cetuximab
- Encorafenib plus cetixumab
- A control arm of FOLFIRI plus cetuximab or irinotecan plus cetuximab.
The three arms of the trial were relatively well balanced with respect to patient characteristics, Dr. Kopetz commented. The median age of the patients ranged from 60 to 62 years, and 48%-57% of the patients were women.
Of note, between 5% and 10% of the cases were characterized by high microsatellite instability, and 34%-35% of patients had received more than one prior line of therapy.
The data now presented at ASCO represent a post hoc updated analysis that includes 6 months of additional follow-up since the primary analysis was presented, Dr. Kopetz explained.
After a median follow-up of 12.8 months, 13% of triplet therapy patients, 14% of those who received doublet therapy, and 3% of control patients were still on treatment.
The updated analysis shows that median overall survival with the doublet therapy was 9.3 months versus 5.9 months for the control group (hazard ratio, 0.61). The benefit was seen across all subgroups, including those based on the number of prior regimens.
Dr. Kopetz pointed out that overall survival was numerically superior to that seen in the primary analysis, which was 8.4 months.
The updated survival analysis for the triplet therapy indicated that the median overall survival was 9.3 months versus 5.9 months in the control arm (HR, 0.60). Again, this was consistent across subgroups.
In the primary analysis, the median overall survival with the triplet therapy was 9.0 months.
The team also compared the triplet and doublet therapies, finding that, “in contrast to what was seen in the primary analysis ... we see numerically identical median overall survival with the two arms.” The result was sustained across subgroups.
However, there were indications that there may be survival benefits with the triplet in certain patient subgroups, including those with Eastern Cooperative Oncology Group performance status 1, those in whom three or more organs are involved, those with higher baseline levels of C-reactive protein, and those with partially resected or unresected disease.
Progression-free survival was comparable between the two treatment groups, at 4.5 months with the triplet therapy and 4.3 months with the doublet, compared with just 1.5 months in the control arm.
The updated analysis also showed that the objective response rate was 27% with triplet therapy versus 20% with the doublet and 2% in the control arm. In both the doublet and triplet arms, the majority of responses were partial.
With regard to safety, Dr. Kopetz said that the updated data regarding adverse events were in general “consistent with the previously reported safety profile.”
He added it is “notable” that the triplet therapy “had slightly higher rates of GI toxicity and anemia,” which was not seen with the doublet, something that is “again associated with the known safety profile of a MEK inhibitor.”
The study was funded by Pfizer. Dr. Kopetz has stock and other ownership interests with numerous pharmaceutical companies. Other authors, as well as Dr. Lee and Dr. McRee, have also reported relevant financial relationships.
This article first appeared on Medscape.com.
FROM ASCO 2020
Germline testing in advanced cancer can lead to targeted treatment
The study involved 11,974 patients with various tumor types. All the patients underwent germline genetic testing from 2015 to 2019 at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York, using the next-generation sequencing panel MSK-IMPACT.
This testing showed that 17.1% of patients had variants in cancer predisposition genes, and 7.1%-8.6% had variants that could potentially be targeted.
“Of course, these numbers are not static,” commented lead author Zsofia K. Stadler, MD, a medical oncologist at MSKCC. “And with the emergence of novel targeted treatments with new FDA indications, the therapeutic actionability of germline variants is likely to increase over time.
“Our study demonstrates the first comprehensive assessment of the clinical utility of germline alterations for therapeutic actionability in a population of patients with advanced cancer,” she added.
Dr. Stadler presented the study results during a virtual scientific program of the American Society of Clinical Oncology 2020.
Testing for somatic mutations is evolving as the standard of care in many cancer types, and somatic genomic testing is rapidly becoming an integral part of the regimen for patients with advanced disease. Some studies suggest that 9%-11% of patients harbor actionable genetic alterations, as determined on the basis of tumor profiling.
“The take-home message from this is that now, more than ever before, germline testing is indicated for the selection of cancer treatment,” said Erin Wysong Hofstatter, MD, from Yale University, New Haven, Conn., in a Highlights of the Day session.
An emerging indication for germline testing is the selection of treatment in the advanced setting, she noted. “And it is important to know your test. Remember that tumor sequencing is not a substitute for comprehensive germline testing.”
Implications in cancer treatment
For their study, Dr. Stadler and colleagues reviewed the medical records of patients with likely pathogenic/pathogenic germline (LP/P) alterations in genes that had known therapeutic targets so as to identify germline-targeted treatment either in a clinical or research setting.
“Since 2015, patients undergoing MSK-IMPACT may also choose to provide additional consent for secondary germline genetic analysis, wherein up to 88 genes known to be associated with cancer predisposition are analyzed,” she said. “Likely pathogenic and pathogenic germline alterations identified are disclosed to the patient and treating physician via the Clinical Genetic Service.”
A total of 2043 (17.1%) patients who harbored LP/P variants in a cancer predisposition gene were identified. Of these, 11% of patients harbored pathogenic alterations in high or moderate penetrance cancer predisposition genes. When the analysis was limited to genes with targeted therapeutic actionability, or what the authors defined as tier 1 and tier 2 genes, 7.1% of patients (n = 849) harbored a targetable pathogenic germline alteration.
BRCA alterations accounted for half (52%) of the findings, and 20% were associated with Lynch syndrome.
The tier 2 genes, which included PALB2, ATM, RAD51C, and RAD51D, accounted for about a quarter of the findings. Dr. Hofstatter noted that, using strict criteria, 7.1% of patients (n = 849) were found to harbor a pathogenic alteration and a targetable gene. Using less stringent criteria, additional tier 3 genes and additional genes associated with DNA homologous recombination repair brought the number up to 8.6% (n = 1,003).
Therapeutic action
For determining therapeutic actionability, the strict criteria were used; 593 patients (4.95%) with recurrent or metastatic disease were identified. For these patients, consideration of a targeted therapy, either as part of standard care or as part of an investigation or research protocol, was important.
Of this group, 44% received therapy targeting the germline alteration. Regarding specific genes, 50% of BRCA1/2 carriers and 58% of Lynch syndrome patients received targeted treatment. With respect to tier 2 genes, 40% of patients with PALB2, 19% with ATM, and 37% with RAD51C or 51D received a poly (ADP-ribose) polymerase (PARP) inhibitor.
Among patients with a BRCA1/2 mutation who received a PARP inhibitor, 55.1% had breast or ovarian cancer, and 44.8% had other tumor types, including pancreas, prostate, bile duct, gastric cancers. These patients received the drug in a research setting.
For patients with PALB2 alterations who received PARP inhibitors, 53.3% had breast or pancreas cancer, and 46.7% had cancer of the prostate, ovary, or an unknown primary.
Looking ahead
The discussant for the paper, Funda Meric-Bernstam, MD, chair of the Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center, Houston, pointed out that most of the BRCA-positive patients had cancers traditionally associated with the mutation. “There were no patients with PTEN mutations treated, and interestingly, no patients with NF1 were treated,” she said. “But actionability is evolving, as the MEK inhibitor selumitinib was recently approved for NF1.”
Some questions remain unanswered, she noted, such as: “What percentage of patients undergoing tumor-normal testing signed a germline protocol?” and “Does the population introduce a bias – such as younger patients, family history, and so on?”
It is also unknown what percentage of germline alterations were known in comparison with those identified through tumor/normal testing. Also of importance is the fact that in this study, the results of germline testing were delivered in an academic setting, she emphasized. “What if they were delivered elsewhere? What would be the impact of identifying these alterations in an environment with less access to trials?
“But to be fair, it is not easy to seek the germline mutations,” Dr. Meric-Bernstam continued. “These studies were done under institutional review board protocols, and it is important to note that most profiling is done as standard of care without consenting and soliciting patient preference on the return of germline results.”
An infrastructure is needed to return/counsel/offer cascade testing, and “analyses need to be facilitated to ensure that findings can be acted upon in a timely fashion,” she added.
The study was supported by MSKCC internal funding. Dr. Stadler reported relationships (institutional) with Adverum, Alimera Sciences, Allergan, Biomarin, Fortress Biotech, Genentech/Roche, Novartis, Optos, Regeneron, Regenxbio, and Spark Therapeutics. Dr. Meric-Bernstram reported relationships with numerous pharmaceutical companies.
This article first appeared on Medscape.com.
The study involved 11,974 patients with various tumor types. All the patients underwent germline genetic testing from 2015 to 2019 at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York, using the next-generation sequencing panel MSK-IMPACT.
This testing showed that 17.1% of patients had variants in cancer predisposition genes, and 7.1%-8.6% had variants that could potentially be targeted.
“Of course, these numbers are not static,” commented lead author Zsofia K. Stadler, MD, a medical oncologist at MSKCC. “And with the emergence of novel targeted treatments with new FDA indications, the therapeutic actionability of germline variants is likely to increase over time.
“Our study demonstrates the first comprehensive assessment of the clinical utility of germline alterations for therapeutic actionability in a population of patients with advanced cancer,” she added.
Dr. Stadler presented the study results during a virtual scientific program of the American Society of Clinical Oncology 2020.
Testing for somatic mutations is evolving as the standard of care in many cancer types, and somatic genomic testing is rapidly becoming an integral part of the regimen for patients with advanced disease. Some studies suggest that 9%-11% of patients harbor actionable genetic alterations, as determined on the basis of tumor profiling.
“The take-home message from this is that now, more than ever before, germline testing is indicated for the selection of cancer treatment,” said Erin Wysong Hofstatter, MD, from Yale University, New Haven, Conn., in a Highlights of the Day session.
An emerging indication for germline testing is the selection of treatment in the advanced setting, she noted. “And it is important to know your test. Remember that tumor sequencing is not a substitute for comprehensive germline testing.”
Implications in cancer treatment
For their study, Dr. Stadler and colleagues reviewed the medical records of patients with likely pathogenic/pathogenic germline (LP/P) alterations in genes that had known therapeutic targets so as to identify germline-targeted treatment either in a clinical or research setting.
“Since 2015, patients undergoing MSK-IMPACT may also choose to provide additional consent for secondary germline genetic analysis, wherein up to 88 genes known to be associated with cancer predisposition are analyzed,” she said. “Likely pathogenic and pathogenic germline alterations identified are disclosed to the patient and treating physician via the Clinical Genetic Service.”
A total of 2043 (17.1%) patients who harbored LP/P variants in a cancer predisposition gene were identified. Of these, 11% of patients harbored pathogenic alterations in high or moderate penetrance cancer predisposition genes. When the analysis was limited to genes with targeted therapeutic actionability, or what the authors defined as tier 1 and tier 2 genes, 7.1% of patients (n = 849) harbored a targetable pathogenic germline alteration.
BRCA alterations accounted for half (52%) of the findings, and 20% were associated with Lynch syndrome.
The tier 2 genes, which included PALB2, ATM, RAD51C, and RAD51D, accounted for about a quarter of the findings. Dr. Hofstatter noted that, using strict criteria, 7.1% of patients (n = 849) were found to harbor a pathogenic alteration and a targetable gene. Using less stringent criteria, additional tier 3 genes and additional genes associated with DNA homologous recombination repair brought the number up to 8.6% (n = 1,003).
Therapeutic action
For determining therapeutic actionability, the strict criteria were used; 593 patients (4.95%) with recurrent or metastatic disease were identified. For these patients, consideration of a targeted therapy, either as part of standard care or as part of an investigation or research protocol, was important.
Of this group, 44% received therapy targeting the germline alteration. Regarding specific genes, 50% of BRCA1/2 carriers and 58% of Lynch syndrome patients received targeted treatment. With respect to tier 2 genes, 40% of patients with PALB2, 19% with ATM, and 37% with RAD51C or 51D received a poly (ADP-ribose) polymerase (PARP) inhibitor.
Among patients with a BRCA1/2 mutation who received a PARP inhibitor, 55.1% had breast or ovarian cancer, and 44.8% had other tumor types, including pancreas, prostate, bile duct, gastric cancers. These patients received the drug in a research setting.
For patients with PALB2 alterations who received PARP inhibitors, 53.3% had breast or pancreas cancer, and 46.7% had cancer of the prostate, ovary, or an unknown primary.
Looking ahead
The discussant for the paper, Funda Meric-Bernstam, MD, chair of the Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center, Houston, pointed out that most of the BRCA-positive patients had cancers traditionally associated with the mutation. “There were no patients with PTEN mutations treated, and interestingly, no patients with NF1 were treated,” she said. “But actionability is evolving, as the MEK inhibitor selumitinib was recently approved for NF1.”
Some questions remain unanswered, she noted, such as: “What percentage of patients undergoing tumor-normal testing signed a germline protocol?” and “Does the population introduce a bias – such as younger patients, family history, and so on?”
It is also unknown what percentage of germline alterations were known in comparison with those identified through tumor/normal testing. Also of importance is the fact that in this study, the results of germline testing were delivered in an academic setting, she emphasized. “What if they were delivered elsewhere? What would be the impact of identifying these alterations in an environment with less access to trials?
“But to be fair, it is not easy to seek the germline mutations,” Dr. Meric-Bernstam continued. “These studies were done under institutional review board protocols, and it is important to note that most profiling is done as standard of care without consenting and soliciting patient preference on the return of germline results.”
An infrastructure is needed to return/counsel/offer cascade testing, and “analyses need to be facilitated to ensure that findings can be acted upon in a timely fashion,” she added.
The study was supported by MSKCC internal funding. Dr. Stadler reported relationships (institutional) with Adverum, Alimera Sciences, Allergan, Biomarin, Fortress Biotech, Genentech/Roche, Novartis, Optos, Regeneron, Regenxbio, and Spark Therapeutics. Dr. Meric-Bernstram reported relationships with numerous pharmaceutical companies.
This article first appeared on Medscape.com.
The study involved 11,974 patients with various tumor types. All the patients underwent germline genetic testing from 2015 to 2019 at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York, using the next-generation sequencing panel MSK-IMPACT.
This testing showed that 17.1% of patients had variants in cancer predisposition genes, and 7.1%-8.6% had variants that could potentially be targeted.
“Of course, these numbers are not static,” commented lead author Zsofia K. Stadler, MD, a medical oncologist at MSKCC. “And with the emergence of novel targeted treatments with new FDA indications, the therapeutic actionability of germline variants is likely to increase over time.
“Our study demonstrates the first comprehensive assessment of the clinical utility of germline alterations for therapeutic actionability in a population of patients with advanced cancer,” she added.
Dr. Stadler presented the study results during a virtual scientific program of the American Society of Clinical Oncology 2020.
Testing for somatic mutations is evolving as the standard of care in many cancer types, and somatic genomic testing is rapidly becoming an integral part of the regimen for patients with advanced disease. Some studies suggest that 9%-11% of patients harbor actionable genetic alterations, as determined on the basis of tumor profiling.
“The take-home message from this is that now, more than ever before, germline testing is indicated for the selection of cancer treatment,” said Erin Wysong Hofstatter, MD, from Yale University, New Haven, Conn., in a Highlights of the Day session.
An emerging indication for germline testing is the selection of treatment in the advanced setting, she noted. “And it is important to know your test. Remember that tumor sequencing is not a substitute for comprehensive germline testing.”
Implications in cancer treatment
For their study, Dr. Stadler and colleagues reviewed the medical records of patients with likely pathogenic/pathogenic germline (LP/P) alterations in genes that had known therapeutic targets so as to identify germline-targeted treatment either in a clinical or research setting.
“Since 2015, patients undergoing MSK-IMPACT may also choose to provide additional consent for secondary germline genetic analysis, wherein up to 88 genes known to be associated with cancer predisposition are analyzed,” she said. “Likely pathogenic and pathogenic germline alterations identified are disclosed to the patient and treating physician via the Clinical Genetic Service.”
A total of 2043 (17.1%) patients who harbored LP/P variants in a cancer predisposition gene were identified. Of these, 11% of patients harbored pathogenic alterations in high or moderate penetrance cancer predisposition genes. When the analysis was limited to genes with targeted therapeutic actionability, or what the authors defined as tier 1 and tier 2 genes, 7.1% of patients (n = 849) harbored a targetable pathogenic germline alteration.
BRCA alterations accounted for half (52%) of the findings, and 20% were associated with Lynch syndrome.
The tier 2 genes, which included PALB2, ATM, RAD51C, and RAD51D, accounted for about a quarter of the findings. Dr. Hofstatter noted that, using strict criteria, 7.1% of patients (n = 849) were found to harbor a pathogenic alteration and a targetable gene. Using less stringent criteria, additional tier 3 genes and additional genes associated with DNA homologous recombination repair brought the number up to 8.6% (n = 1,003).
Therapeutic action
For determining therapeutic actionability, the strict criteria were used; 593 patients (4.95%) with recurrent or metastatic disease were identified. For these patients, consideration of a targeted therapy, either as part of standard care or as part of an investigation or research protocol, was important.
Of this group, 44% received therapy targeting the germline alteration. Regarding specific genes, 50% of BRCA1/2 carriers and 58% of Lynch syndrome patients received targeted treatment. With respect to tier 2 genes, 40% of patients with PALB2, 19% with ATM, and 37% with RAD51C or 51D received a poly (ADP-ribose) polymerase (PARP) inhibitor.
Among patients with a BRCA1/2 mutation who received a PARP inhibitor, 55.1% had breast or ovarian cancer, and 44.8% had other tumor types, including pancreas, prostate, bile duct, gastric cancers. These patients received the drug in a research setting.
For patients with PALB2 alterations who received PARP inhibitors, 53.3% had breast or pancreas cancer, and 46.7% had cancer of the prostate, ovary, or an unknown primary.
Looking ahead
The discussant for the paper, Funda Meric-Bernstam, MD, chair of the Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center, Houston, pointed out that most of the BRCA-positive patients had cancers traditionally associated with the mutation. “There were no patients with PTEN mutations treated, and interestingly, no patients with NF1 were treated,” she said. “But actionability is evolving, as the MEK inhibitor selumitinib was recently approved for NF1.”
Some questions remain unanswered, she noted, such as: “What percentage of patients undergoing tumor-normal testing signed a germline protocol?” and “Does the population introduce a bias – such as younger patients, family history, and so on?”
It is also unknown what percentage of germline alterations were known in comparison with those identified through tumor/normal testing. Also of importance is the fact that in this study, the results of germline testing were delivered in an academic setting, she emphasized. “What if they were delivered elsewhere? What would be the impact of identifying these alterations in an environment with less access to trials?
“But to be fair, it is not easy to seek the germline mutations,” Dr. Meric-Bernstam continued. “These studies were done under institutional review board protocols, and it is important to note that most profiling is done as standard of care without consenting and soliciting patient preference on the return of germline results.”
An infrastructure is needed to return/counsel/offer cascade testing, and “analyses need to be facilitated to ensure that findings can be acted upon in a timely fashion,” she added.
The study was supported by MSKCC internal funding. Dr. Stadler reported relationships (institutional) with Adverum, Alimera Sciences, Allergan, Biomarin, Fortress Biotech, Genentech/Roche, Novartis, Optos, Regeneron, Regenxbio, and Spark Therapeutics. Dr. Meric-Bernstram reported relationships with numerous pharmaceutical companies.
This article first appeared on Medscape.com.
FROM ASCO 2020
Need HER2-positive testing in CRC; trastuzumab deruxtecan shows benefit
Testing for HER2 in patients with colorectal cancer (CRC) should become a new standard of care, say experts discussing new results from a phase 2 trial showing benefit with trastuzumab deruxtecan (T-DXd, marketed as Enhertu, AstraZeneca/Daiichi Sankyo).
This drug is approved in the United States for use in the treatment of unresectable or metastatic HER2-positive breast cancer in patients who have already received two or more prior anti–HER2-based regimens in the metastatic setting.
Results come from a phase 2 study, dubbed DESTINY-CRC01, in patients with previously treated HER2+ advanced CRC.
The results show that, in patients with the highest degree of HER2 positivity, T-DXd was associated with an objective response rate of over 45% and a median progression-free survival (PFS) of almost 7 months.
They “demonstrate, in our opinion, the potential of T-DXd as a treatment option” for patients with advanced HER2-positive colorectal cancer that is refractory to standard therapies, said lead investigator Salvatore Siena, MD, from Niguarda Cancer Center, in Milan, Italy.
He presented the results at the 2020 annual meeting of the American Society of Clinical Oncology, held virtually because of the coronavirus pandemic.
At the same time, results from another study, this time in gastric cancer patients, were published online in the New England Journal of Medicine.
Interstitial lung disease as adverse event
The safety profile of T-DXd seen in the colorectal trial “is consistent with what has been previously reported,” said Siena, adding that most of the adverse events were low grade. But he noted there was also a serious adverse effect – interstitial lung disease (ILD). This occurred in 6% of patients, two of whom died. This is “an important risk and requires careful monitoring and proper intervention,” he emphasized.
The ILD adverse effect in this study is “a concern…and something to consider,” commented discussant for the study Michael S. Lee, MD, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill. But he added that these are the “the best data so far for subsequent anti-HER2 therapy in colorectal cancer”.
Also, the dose of drug used in this trial was higher than that approved for breast cancer, and the incidence of ILD “begs the question of whether we should be using a lower dose in this patient population,” said Autumn J. McRee, MD, also from Lineberger, in a highlights session at the meeting.
“The question here really is whether an HER2-specific approach is superior to what we would offer to these patients in the standard of care setting,” McRee said.
She noted that the patients in DESTINY-CRC01 were “heavily pretreated…and if you think about what our options are in the refractory setting, we do have two approved treatments: regorafenib [Stivarga, Bayer] and TAS-102 [Lonsurf, Taiho Oncology].”
The current data suggest, however, that T-DXd is associated with a trend toward higher response rates and improved survival outcomes, as well as lower monthly costs.
“Without a doubt, this trial is clinically relevant,” she said, adding that it’s “important not to miss these patients.”
“They are rare…but I would argue that testing for HER2 amplification in colorectal cancer should be considered standard of care,” she said.
She added that, based on the current evidence, the trial “may be” practice changing, although it is “still to be determined how to sequence HER2 targeted therapies.”
Study details
The trial was conducted in 78 patients with previously treated unresectable and/or metastatic CRC that was HER2 expressing, RAS/BRAF wild type, and patients had to have received at least two prior regimens, including prior anti-HER2 treatment. Patients with current or suspected ILD were excluded.
Patients were divided into three cohorts based on the degree of HER2 positivity:
- HER2+ with immunohistochemistry (IHC) scoring 3+ or IHC2+/in-situ-hybridization (ISH)+ (cohort A, n = 53)
- HER2 IHC2+/ISH– (cohort B, n = 7)
- HER2 IHC1+ (cohort C, n = 18)
All patients received T-DXd at 6.4 mg/kg intravenously every 3 weeks until progression or intolerable toxicity.
Across the three cohorts, the median age was 58.5 years, and nearly half (47.4%) of patients were female. The vast majority (98.7%) of patents had ECOG performance status 0 or 1, and the primary tumor site was the left colon or rectum in 89.7%.
Siena noted that “the median number of prior lines of standard therapies was four, ranging from two to 11.” All patients had previously received irinotecan and oxaliplatin, and 20.5% had received an anti-HER2 drug.
At the data cutoff on August 9, 2019, 38.5% of patients remained on treatment. The reason for discontinuation was progressive disease in 41%, and clinical progression in 9%.
Siena reported that the overall response rate, as confirmed by independent central review, was 45.3% in cohort A, with all but one of the 24 responders having a partial response. No responses were recorded in cohorts B and C.
Stable disease was seen in 37.7% of cohort A patients, giving a disease control rate of 83%. The median duration of response was not reached.
Median PFS was 6.9 months in cohort A, and the medial overall survival was not reached.
In terms of safety, 50.9% of patients in cohort A and 48.7% patients overall experienced drug-related treatment emergent adverse events, with 22.6% and 17.9%, respectively, having serious drug-related events.
The most common treatment-emergent adverse events were nausea, anemia, reduced neutrophil count, fatigue, and decreased appetite.
There were two deaths related to the study drug, as determined by investigator assessment: one from pneumonitis and one as a result of ILD, with both occurring in cohort A.
Looking specifically at ILD, Siena said there were five events – two grade 2, one grade 3, and two grade 5 – at a median time to reported onset of 80 days. All patients received corticosteroids, as per the study protocol, and two recovered.
Study discussant Lee commented that biomarker testing, such as for HER2, “is part of our standard of care for colorectal cancer,” although studies such as the current one are providing new data to “better refine” treatment approaches.
Lee said that, overall, T-DXd had a response rate and PFS survival “that looked similar to prior data from previous single arm phase 2 studies,” with response rates generally ranging from 30% to 50%, “and this compares favorably with other standard of care options” for chemotherapy-refractory patients.
Nevertheless, there are several ongoing questions related to the treatment of HER2 amplified metastatic CRC patients, some of which are being addressed in the ongoing SWOG S1613 study.
Lee said that, for now, he would recommend that patients with HER2 amplification enroll in a clinical trial, if possible. “However, if that’s not feasible, there are a range of options to consider,” including trastuzumab plus lapatinib (Tykerb, Novartis), or trastuzumab plus pembrolizumab (Keytruda, Merck).
However, “none of these options are FDA approved so there will be issues potentially with financial toxicity and other regulatory issues,” he said.
The study was funded by Daiichi Sankyo Co, Ltd.
Siena reports stock and other ownership interests with Guardant Health and Myriad Genetics; a consulting or advisory role with Amgen, Bayer, Bristol-Myers Squibb, CheckmAb, Clovis Oncology, Daiichi Sankyo, Incyte, Merck, Novartis, Roche/Genentech, Seattle Genetics; research funding from MSD Oncology (Inst); patents, royalties, and other intellectual property from Amgen; and travel, accommodations, expenses from Amgen, Bayer, and Roche. Other coauthors report potential conflicts of interest. The full list can be found with the original article.
Lee reports: Research Funding – Amgen (Inst); Bristol-Myers Squibb (Inst); EMD Serono (Inst); Exelixis (Inst); Genentech/Roche (Inst); Pfizer (Inst); Travel, Accommodations, Expenses – Genentech/Roche.
McRee reports honoraria from Cor2Ed and Onc Live; research funding from AstraZeneca (Inst), BioMed Valley Discoveries (Inst), Boston Biomedical (Inst), Inovio Pharmaceuticals (Inst), Merck (Inst), Novartis (Inst), Rgenix (Inst), and Takeda (Inst); and travel, accommodations, expenses from Cor2Ed.
This article first appeared on Medscape.com.
Testing for HER2 in patients with colorectal cancer (CRC) should become a new standard of care, say experts discussing new results from a phase 2 trial showing benefit with trastuzumab deruxtecan (T-DXd, marketed as Enhertu, AstraZeneca/Daiichi Sankyo).
This drug is approved in the United States for use in the treatment of unresectable or metastatic HER2-positive breast cancer in patients who have already received two or more prior anti–HER2-based regimens in the metastatic setting.
Results come from a phase 2 study, dubbed DESTINY-CRC01, in patients with previously treated HER2+ advanced CRC.
The results show that, in patients with the highest degree of HER2 positivity, T-DXd was associated with an objective response rate of over 45% and a median progression-free survival (PFS) of almost 7 months.
They “demonstrate, in our opinion, the potential of T-DXd as a treatment option” for patients with advanced HER2-positive colorectal cancer that is refractory to standard therapies, said lead investigator Salvatore Siena, MD, from Niguarda Cancer Center, in Milan, Italy.
He presented the results at the 2020 annual meeting of the American Society of Clinical Oncology, held virtually because of the coronavirus pandemic.
At the same time, results from another study, this time in gastric cancer patients, were published online in the New England Journal of Medicine.
Interstitial lung disease as adverse event
The safety profile of T-DXd seen in the colorectal trial “is consistent with what has been previously reported,” said Siena, adding that most of the adverse events were low grade. But he noted there was also a serious adverse effect – interstitial lung disease (ILD). This occurred in 6% of patients, two of whom died. This is “an important risk and requires careful monitoring and proper intervention,” he emphasized.
The ILD adverse effect in this study is “a concern…and something to consider,” commented discussant for the study Michael S. Lee, MD, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill. But he added that these are the “the best data so far for subsequent anti-HER2 therapy in colorectal cancer”.
Also, the dose of drug used in this trial was higher than that approved for breast cancer, and the incidence of ILD “begs the question of whether we should be using a lower dose in this patient population,” said Autumn J. McRee, MD, also from Lineberger, in a highlights session at the meeting.
“The question here really is whether an HER2-specific approach is superior to what we would offer to these patients in the standard of care setting,” McRee said.
She noted that the patients in DESTINY-CRC01 were “heavily pretreated…and if you think about what our options are in the refractory setting, we do have two approved treatments: regorafenib [Stivarga, Bayer] and TAS-102 [Lonsurf, Taiho Oncology].”
The current data suggest, however, that T-DXd is associated with a trend toward higher response rates and improved survival outcomes, as well as lower monthly costs.
“Without a doubt, this trial is clinically relevant,” she said, adding that it’s “important not to miss these patients.”
“They are rare…but I would argue that testing for HER2 amplification in colorectal cancer should be considered standard of care,” she said.
She added that, based on the current evidence, the trial “may be” practice changing, although it is “still to be determined how to sequence HER2 targeted therapies.”
Study details
The trial was conducted in 78 patients with previously treated unresectable and/or metastatic CRC that was HER2 expressing, RAS/BRAF wild type, and patients had to have received at least two prior regimens, including prior anti-HER2 treatment. Patients with current or suspected ILD were excluded.
Patients were divided into three cohorts based on the degree of HER2 positivity:
- HER2+ with immunohistochemistry (IHC) scoring 3+ or IHC2+/in-situ-hybridization (ISH)+ (cohort A, n = 53)
- HER2 IHC2+/ISH– (cohort B, n = 7)
- HER2 IHC1+ (cohort C, n = 18)
All patients received T-DXd at 6.4 mg/kg intravenously every 3 weeks until progression or intolerable toxicity.
Across the three cohorts, the median age was 58.5 years, and nearly half (47.4%) of patients were female. The vast majority (98.7%) of patents had ECOG performance status 0 or 1, and the primary tumor site was the left colon or rectum in 89.7%.
Siena noted that “the median number of prior lines of standard therapies was four, ranging from two to 11.” All patients had previously received irinotecan and oxaliplatin, and 20.5% had received an anti-HER2 drug.
At the data cutoff on August 9, 2019, 38.5% of patients remained on treatment. The reason for discontinuation was progressive disease in 41%, and clinical progression in 9%.
Siena reported that the overall response rate, as confirmed by independent central review, was 45.3% in cohort A, with all but one of the 24 responders having a partial response. No responses were recorded in cohorts B and C.
Stable disease was seen in 37.7% of cohort A patients, giving a disease control rate of 83%. The median duration of response was not reached.
Median PFS was 6.9 months in cohort A, and the medial overall survival was not reached.
In terms of safety, 50.9% of patients in cohort A and 48.7% patients overall experienced drug-related treatment emergent adverse events, with 22.6% and 17.9%, respectively, having serious drug-related events.
The most common treatment-emergent adverse events were nausea, anemia, reduced neutrophil count, fatigue, and decreased appetite.
There were two deaths related to the study drug, as determined by investigator assessment: one from pneumonitis and one as a result of ILD, with both occurring in cohort A.
Looking specifically at ILD, Siena said there were five events – two grade 2, one grade 3, and two grade 5 – at a median time to reported onset of 80 days. All patients received corticosteroids, as per the study protocol, and two recovered.
Study discussant Lee commented that biomarker testing, such as for HER2, “is part of our standard of care for colorectal cancer,” although studies such as the current one are providing new data to “better refine” treatment approaches.
Lee said that, overall, T-DXd had a response rate and PFS survival “that looked similar to prior data from previous single arm phase 2 studies,” with response rates generally ranging from 30% to 50%, “and this compares favorably with other standard of care options” for chemotherapy-refractory patients.
Nevertheless, there are several ongoing questions related to the treatment of HER2 amplified metastatic CRC patients, some of which are being addressed in the ongoing SWOG S1613 study.
Lee said that, for now, he would recommend that patients with HER2 amplification enroll in a clinical trial, if possible. “However, if that’s not feasible, there are a range of options to consider,” including trastuzumab plus lapatinib (Tykerb, Novartis), or trastuzumab plus pembrolizumab (Keytruda, Merck).
However, “none of these options are FDA approved so there will be issues potentially with financial toxicity and other regulatory issues,” he said.
The study was funded by Daiichi Sankyo Co, Ltd.
Siena reports stock and other ownership interests with Guardant Health and Myriad Genetics; a consulting or advisory role with Amgen, Bayer, Bristol-Myers Squibb, CheckmAb, Clovis Oncology, Daiichi Sankyo, Incyte, Merck, Novartis, Roche/Genentech, Seattle Genetics; research funding from MSD Oncology (Inst); patents, royalties, and other intellectual property from Amgen; and travel, accommodations, expenses from Amgen, Bayer, and Roche. Other coauthors report potential conflicts of interest. The full list can be found with the original article.
Lee reports: Research Funding – Amgen (Inst); Bristol-Myers Squibb (Inst); EMD Serono (Inst); Exelixis (Inst); Genentech/Roche (Inst); Pfizer (Inst); Travel, Accommodations, Expenses – Genentech/Roche.
McRee reports honoraria from Cor2Ed and Onc Live; research funding from AstraZeneca (Inst), BioMed Valley Discoveries (Inst), Boston Biomedical (Inst), Inovio Pharmaceuticals (Inst), Merck (Inst), Novartis (Inst), Rgenix (Inst), and Takeda (Inst); and travel, accommodations, expenses from Cor2Ed.
This article first appeared on Medscape.com.
Testing for HER2 in patients with colorectal cancer (CRC) should become a new standard of care, say experts discussing new results from a phase 2 trial showing benefit with trastuzumab deruxtecan (T-DXd, marketed as Enhertu, AstraZeneca/Daiichi Sankyo).
This drug is approved in the United States for use in the treatment of unresectable or metastatic HER2-positive breast cancer in patients who have already received two or more prior anti–HER2-based regimens in the metastatic setting.
Results come from a phase 2 study, dubbed DESTINY-CRC01, in patients with previously treated HER2+ advanced CRC.
The results show that, in patients with the highest degree of HER2 positivity, T-DXd was associated with an objective response rate of over 45% and a median progression-free survival (PFS) of almost 7 months.
They “demonstrate, in our opinion, the potential of T-DXd as a treatment option” for patients with advanced HER2-positive colorectal cancer that is refractory to standard therapies, said lead investigator Salvatore Siena, MD, from Niguarda Cancer Center, in Milan, Italy.
He presented the results at the 2020 annual meeting of the American Society of Clinical Oncology, held virtually because of the coronavirus pandemic.
At the same time, results from another study, this time in gastric cancer patients, were published online in the New England Journal of Medicine.
Interstitial lung disease as adverse event
The safety profile of T-DXd seen in the colorectal trial “is consistent with what has been previously reported,” said Siena, adding that most of the adverse events were low grade. But he noted there was also a serious adverse effect – interstitial lung disease (ILD). This occurred in 6% of patients, two of whom died. This is “an important risk and requires careful monitoring and proper intervention,” he emphasized.
The ILD adverse effect in this study is “a concern…and something to consider,” commented discussant for the study Michael S. Lee, MD, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill. But he added that these are the “the best data so far for subsequent anti-HER2 therapy in colorectal cancer”.
Also, the dose of drug used in this trial was higher than that approved for breast cancer, and the incidence of ILD “begs the question of whether we should be using a lower dose in this patient population,” said Autumn J. McRee, MD, also from Lineberger, in a highlights session at the meeting.
“The question here really is whether an HER2-specific approach is superior to what we would offer to these patients in the standard of care setting,” McRee said.
She noted that the patients in DESTINY-CRC01 were “heavily pretreated…and if you think about what our options are in the refractory setting, we do have two approved treatments: regorafenib [Stivarga, Bayer] and TAS-102 [Lonsurf, Taiho Oncology].”
The current data suggest, however, that T-DXd is associated with a trend toward higher response rates and improved survival outcomes, as well as lower monthly costs.
“Without a doubt, this trial is clinically relevant,” she said, adding that it’s “important not to miss these patients.”
“They are rare…but I would argue that testing for HER2 amplification in colorectal cancer should be considered standard of care,” she said.
She added that, based on the current evidence, the trial “may be” practice changing, although it is “still to be determined how to sequence HER2 targeted therapies.”
Study details
The trial was conducted in 78 patients with previously treated unresectable and/or metastatic CRC that was HER2 expressing, RAS/BRAF wild type, and patients had to have received at least two prior regimens, including prior anti-HER2 treatment. Patients with current or suspected ILD were excluded.
Patients were divided into three cohorts based on the degree of HER2 positivity:
- HER2+ with immunohistochemistry (IHC) scoring 3+ or IHC2+/in-situ-hybridization (ISH)+ (cohort A, n = 53)
- HER2 IHC2+/ISH– (cohort B, n = 7)
- HER2 IHC1+ (cohort C, n = 18)
All patients received T-DXd at 6.4 mg/kg intravenously every 3 weeks until progression or intolerable toxicity.
Across the three cohorts, the median age was 58.5 years, and nearly half (47.4%) of patients were female. The vast majority (98.7%) of patents had ECOG performance status 0 or 1, and the primary tumor site was the left colon or rectum in 89.7%.
Siena noted that “the median number of prior lines of standard therapies was four, ranging from two to 11.” All patients had previously received irinotecan and oxaliplatin, and 20.5% had received an anti-HER2 drug.
At the data cutoff on August 9, 2019, 38.5% of patients remained on treatment. The reason for discontinuation was progressive disease in 41%, and clinical progression in 9%.
Siena reported that the overall response rate, as confirmed by independent central review, was 45.3% in cohort A, with all but one of the 24 responders having a partial response. No responses were recorded in cohorts B and C.
Stable disease was seen in 37.7% of cohort A patients, giving a disease control rate of 83%. The median duration of response was not reached.
Median PFS was 6.9 months in cohort A, and the medial overall survival was not reached.
In terms of safety, 50.9% of patients in cohort A and 48.7% patients overall experienced drug-related treatment emergent adverse events, with 22.6% and 17.9%, respectively, having serious drug-related events.
The most common treatment-emergent adverse events were nausea, anemia, reduced neutrophil count, fatigue, and decreased appetite.
There were two deaths related to the study drug, as determined by investigator assessment: one from pneumonitis and one as a result of ILD, with both occurring in cohort A.
Looking specifically at ILD, Siena said there were five events – two grade 2, one grade 3, and two grade 5 – at a median time to reported onset of 80 days. All patients received corticosteroids, as per the study protocol, and two recovered.
Study discussant Lee commented that biomarker testing, such as for HER2, “is part of our standard of care for colorectal cancer,” although studies such as the current one are providing new data to “better refine” treatment approaches.
Lee said that, overall, T-DXd had a response rate and PFS survival “that looked similar to prior data from previous single arm phase 2 studies,” with response rates generally ranging from 30% to 50%, “and this compares favorably with other standard of care options” for chemotherapy-refractory patients.
Nevertheless, there are several ongoing questions related to the treatment of HER2 amplified metastatic CRC patients, some of which are being addressed in the ongoing SWOG S1613 study.
Lee said that, for now, he would recommend that patients with HER2 amplification enroll in a clinical trial, if possible. “However, if that’s not feasible, there are a range of options to consider,” including trastuzumab plus lapatinib (Tykerb, Novartis), or trastuzumab plus pembrolizumab (Keytruda, Merck).
However, “none of these options are FDA approved so there will be issues potentially with financial toxicity and other regulatory issues,” he said.
The study was funded by Daiichi Sankyo Co, Ltd.
Siena reports stock and other ownership interests with Guardant Health and Myriad Genetics; a consulting or advisory role with Amgen, Bayer, Bristol-Myers Squibb, CheckmAb, Clovis Oncology, Daiichi Sankyo, Incyte, Merck, Novartis, Roche/Genentech, Seattle Genetics; research funding from MSD Oncology (Inst); patents, royalties, and other intellectual property from Amgen; and travel, accommodations, expenses from Amgen, Bayer, and Roche. Other coauthors report potential conflicts of interest. The full list can be found with the original article.
Lee reports: Research Funding – Amgen (Inst); Bristol-Myers Squibb (Inst); EMD Serono (Inst); Exelixis (Inst); Genentech/Roche (Inst); Pfizer (Inst); Travel, Accommodations, Expenses – Genentech/Roche.
McRee reports honoraria from Cor2Ed and Onc Live; research funding from AstraZeneca (Inst), BioMed Valley Discoveries (Inst), Boston Biomedical (Inst), Inovio Pharmaceuticals (Inst), Merck (Inst), Novartis (Inst), Rgenix (Inst), and Takeda (Inst); and travel, accommodations, expenses from Cor2Ed.
This article first appeared on Medscape.com.
FROM ASCO 2020
Treating primary tumor doesn’t improve OS in stage IV breast cancer
In patients with newly diagnosed stage IV breast cancer and an intact primary tumor, locoregional therapy after optimal systemic therapy does not improve survival or quality of life, results of the phase 3 E2108 trial suggest.
Among 256 patients with stage IV breast cancer with intact primary tumors who had no disease progression for 4-8 months after the start of optimal systemic therapy, there were no significant differences in overall survival or progression-free survival between patients randomized to receive locoregional therapy and those who did not receive the locoregional treatment.
Although patients who did not receive locoregional treatment had a 150% higher rate of local recurrence/progression, health-related quality of life (HRQOL) was actually worse at 18 months among the patients who underwent locoregional therapy. There were no HRQOL differences at 6 months, 12 months, or 30 months of follow-up.
Seema A. Khan, MD, of Northwestern University, Chicago, reported these results during a plenary session broadcast as a part of the American Society of Clinical Oncology virtual scientific program.
“There is no hint here of an advantage in terms of survival with the use of early locoregional therapy for the primary site,” Dr. Khan said.
Although neither the E2108 trial nor similar trials showed an overall survival advantage for locoregional therapy, as many as 20% of patients who are treated with systemic therapy alone may need locoregional therapy with surgery and/or radiation at some point for palliation or progression, said invited discussant Julia R. White, MD, professor of radiation oncology at the Ohio State University, Columbus.
“Locoregional therapy should be reserved for these patients that become symptomatic or progress locally. There may be a role for routine locoregional therapy for de novo oligometastatic breast cancer in combination with systemic therapy plus ablative therapy” to secure long-term remission or cure, questions that are being addressed in ongoing clinical trials, Dr. White said.
Past data
An estimated 6% of newly diagnosed breast cancer patients present with stage IV disease and an intact primary tumor.
The rationale for locoregional therapy of the primary tumor in patients with metastatic disease is based on retrospective data suggesting a survival advantage. However, the studies were biased because of younger patient populations with small tumors, a higher proportion of estrogen receptor–positive disease, and a generally lower metastatic burden than that seen in the E2108 population, according to Dr. Khan.
She went on to cite two randomized trials with differing outcomes. One trial showed no survival advantage with locoregional therapy at 2 years (Lancet Oncol. 2015 Oct;16[13]:1380-8). The other showed an improvement in survival with locoregional therapy at 5 years (Ann Surg Oncol. 2018 Oct;25[11]:3141-9).
E2108 details
In the E2108 trial, patients first received optimal systemic therapy based on individual patient and disease features. Patients who had no disease progression or distant disease for at least 4-8 months of therapy were then randomized to additional therapy.
In one randomized arm, patients received continued systemic therapy alone. The other arm received early local therapy, which included complete tumor resection with free surgical margins and postoperative radiotherapy according to the standard of care.
A total of 390 patients were registered, and 256 went on to randomization. Of those subjects, 131 were randomized to the continued systemic therapy arm and 125 to the early local therapy arm. All patients in each arm were included in the efficacy analysis.
In all, 59.6% of randomized patients had hormone receptor–positive/HER2-negative disease, 8.2% had triple-negative disease, and 32.2% had HER2-positive disease. Metastases included bone-only disease in 37.9% of patients, visceral-only disease in 24.2%, and 40.9% in both sites.
Among the patients randomized to early local therapy, 14 did not have surgery for personal, clinical, or insurance reasons. Of the 109 who went on to surgery, 87 had clear surgical margins, and 74 received locoregional radiation therapy.
Survival, progression, and HRQOL
At a median follow-up of 53 months, the median overall survival was 54 months in each arm. There was no significant difference in survival between the study arms, with superimposable survival curves (hazard ratio, 1.09; P = .63).
An analysis of overall survival by tumor type showed that, for the 20 women with triple-negative disease, survival was worse with early local therapy (HR, 3.50). There were no differences in survival either for the 79 patients with HER2-positive disease or for the 137 patients with hormone receptor–positive/HER2-negative disease.
Locoregional progression occurred in 25.6% of patients assigned to continued systemic therapy, compared with 10.2% assigned to early local therapy. However, progression-free survival was virtually identical between the study arms (P = .40).
At most time points, there were no significant between-arm differences in HRQOL. The exception was at 18 months of follow-up, when the HRQOL was significantly lower among patients who had undergone early local therapy (P = .001).
“Based on available data, locoregional therapy for the primary tumor should not be offered to women with stage IV breast cancer with the expectation of a survival benefit. When systemic disease is well controlled with systemic therapy but the primary site is progressing, as does happen occasionally, locoregional treatment can be considered,” Dr. Khan concluded.
She noted there is an ongoing trial of similar design in Japan (JCOG-1017), with results expected in 2022.
The current trial was supported by the National Cancer Institute and Canadian Cancer Society. Dr. Khan reported no conflicts of interest. Dr. White reported institutional research funding from Intraop Medical.
SOURCE: Khan SA et al. ASCO 2020, Abstract LBA2.
In patients with newly diagnosed stage IV breast cancer and an intact primary tumor, locoregional therapy after optimal systemic therapy does not improve survival or quality of life, results of the phase 3 E2108 trial suggest.
Among 256 patients with stage IV breast cancer with intact primary tumors who had no disease progression for 4-8 months after the start of optimal systemic therapy, there were no significant differences in overall survival or progression-free survival between patients randomized to receive locoregional therapy and those who did not receive the locoregional treatment.
Although patients who did not receive locoregional treatment had a 150% higher rate of local recurrence/progression, health-related quality of life (HRQOL) was actually worse at 18 months among the patients who underwent locoregional therapy. There were no HRQOL differences at 6 months, 12 months, or 30 months of follow-up.
Seema A. Khan, MD, of Northwestern University, Chicago, reported these results during a plenary session broadcast as a part of the American Society of Clinical Oncology virtual scientific program.
“There is no hint here of an advantage in terms of survival with the use of early locoregional therapy for the primary site,” Dr. Khan said.
Although neither the E2108 trial nor similar trials showed an overall survival advantage for locoregional therapy, as many as 20% of patients who are treated with systemic therapy alone may need locoregional therapy with surgery and/or radiation at some point for palliation or progression, said invited discussant Julia R. White, MD, professor of radiation oncology at the Ohio State University, Columbus.
“Locoregional therapy should be reserved for these patients that become symptomatic or progress locally. There may be a role for routine locoregional therapy for de novo oligometastatic breast cancer in combination with systemic therapy plus ablative therapy” to secure long-term remission or cure, questions that are being addressed in ongoing clinical trials, Dr. White said.
Past data
An estimated 6% of newly diagnosed breast cancer patients present with stage IV disease and an intact primary tumor.
The rationale for locoregional therapy of the primary tumor in patients with metastatic disease is based on retrospective data suggesting a survival advantage. However, the studies were biased because of younger patient populations with small tumors, a higher proportion of estrogen receptor–positive disease, and a generally lower metastatic burden than that seen in the E2108 population, according to Dr. Khan.
She went on to cite two randomized trials with differing outcomes. One trial showed no survival advantage with locoregional therapy at 2 years (Lancet Oncol. 2015 Oct;16[13]:1380-8). The other showed an improvement in survival with locoregional therapy at 5 years (Ann Surg Oncol. 2018 Oct;25[11]:3141-9).
E2108 details
In the E2108 trial, patients first received optimal systemic therapy based on individual patient and disease features. Patients who had no disease progression or distant disease for at least 4-8 months of therapy were then randomized to additional therapy.
In one randomized arm, patients received continued systemic therapy alone. The other arm received early local therapy, which included complete tumor resection with free surgical margins and postoperative radiotherapy according to the standard of care.
A total of 390 patients were registered, and 256 went on to randomization. Of those subjects, 131 were randomized to the continued systemic therapy arm and 125 to the early local therapy arm. All patients in each arm were included in the efficacy analysis.
In all, 59.6% of randomized patients had hormone receptor–positive/HER2-negative disease, 8.2% had triple-negative disease, and 32.2% had HER2-positive disease. Metastases included bone-only disease in 37.9% of patients, visceral-only disease in 24.2%, and 40.9% in both sites.
Among the patients randomized to early local therapy, 14 did not have surgery for personal, clinical, or insurance reasons. Of the 109 who went on to surgery, 87 had clear surgical margins, and 74 received locoregional radiation therapy.
Survival, progression, and HRQOL
At a median follow-up of 53 months, the median overall survival was 54 months in each arm. There was no significant difference in survival between the study arms, with superimposable survival curves (hazard ratio, 1.09; P = .63).
An analysis of overall survival by tumor type showed that, for the 20 women with triple-negative disease, survival was worse with early local therapy (HR, 3.50). There were no differences in survival either for the 79 patients with HER2-positive disease or for the 137 patients with hormone receptor–positive/HER2-negative disease.
Locoregional progression occurred in 25.6% of patients assigned to continued systemic therapy, compared with 10.2% assigned to early local therapy. However, progression-free survival was virtually identical between the study arms (P = .40).
At most time points, there were no significant between-arm differences in HRQOL. The exception was at 18 months of follow-up, when the HRQOL was significantly lower among patients who had undergone early local therapy (P = .001).
“Based on available data, locoregional therapy for the primary tumor should not be offered to women with stage IV breast cancer with the expectation of a survival benefit. When systemic disease is well controlled with systemic therapy but the primary site is progressing, as does happen occasionally, locoregional treatment can be considered,” Dr. Khan concluded.
She noted there is an ongoing trial of similar design in Japan (JCOG-1017), with results expected in 2022.
The current trial was supported by the National Cancer Institute and Canadian Cancer Society. Dr. Khan reported no conflicts of interest. Dr. White reported institutional research funding from Intraop Medical.
SOURCE: Khan SA et al. ASCO 2020, Abstract LBA2.
In patients with newly diagnosed stage IV breast cancer and an intact primary tumor, locoregional therapy after optimal systemic therapy does not improve survival or quality of life, results of the phase 3 E2108 trial suggest.
Among 256 patients with stage IV breast cancer with intact primary tumors who had no disease progression for 4-8 months after the start of optimal systemic therapy, there were no significant differences in overall survival or progression-free survival between patients randomized to receive locoregional therapy and those who did not receive the locoregional treatment.
Although patients who did not receive locoregional treatment had a 150% higher rate of local recurrence/progression, health-related quality of life (HRQOL) was actually worse at 18 months among the patients who underwent locoregional therapy. There were no HRQOL differences at 6 months, 12 months, or 30 months of follow-up.
Seema A. Khan, MD, of Northwestern University, Chicago, reported these results during a plenary session broadcast as a part of the American Society of Clinical Oncology virtual scientific program.
“There is no hint here of an advantage in terms of survival with the use of early locoregional therapy for the primary site,” Dr. Khan said.
Although neither the E2108 trial nor similar trials showed an overall survival advantage for locoregional therapy, as many as 20% of patients who are treated with systemic therapy alone may need locoregional therapy with surgery and/or radiation at some point for palliation or progression, said invited discussant Julia R. White, MD, professor of radiation oncology at the Ohio State University, Columbus.
“Locoregional therapy should be reserved for these patients that become symptomatic or progress locally. There may be a role for routine locoregional therapy for de novo oligometastatic breast cancer in combination with systemic therapy plus ablative therapy” to secure long-term remission or cure, questions that are being addressed in ongoing clinical trials, Dr. White said.
Past data
An estimated 6% of newly diagnosed breast cancer patients present with stage IV disease and an intact primary tumor.
The rationale for locoregional therapy of the primary tumor in patients with metastatic disease is based on retrospective data suggesting a survival advantage. However, the studies were biased because of younger patient populations with small tumors, a higher proportion of estrogen receptor–positive disease, and a generally lower metastatic burden than that seen in the E2108 population, according to Dr. Khan.
She went on to cite two randomized trials with differing outcomes. One trial showed no survival advantage with locoregional therapy at 2 years (Lancet Oncol. 2015 Oct;16[13]:1380-8). The other showed an improvement in survival with locoregional therapy at 5 years (Ann Surg Oncol. 2018 Oct;25[11]:3141-9).
E2108 details
In the E2108 trial, patients first received optimal systemic therapy based on individual patient and disease features. Patients who had no disease progression or distant disease for at least 4-8 months of therapy were then randomized to additional therapy.
In one randomized arm, patients received continued systemic therapy alone. The other arm received early local therapy, which included complete tumor resection with free surgical margins and postoperative radiotherapy according to the standard of care.
A total of 390 patients were registered, and 256 went on to randomization. Of those subjects, 131 were randomized to the continued systemic therapy arm and 125 to the early local therapy arm. All patients in each arm were included in the efficacy analysis.
In all, 59.6% of randomized patients had hormone receptor–positive/HER2-negative disease, 8.2% had triple-negative disease, and 32.2% had HER2-positive disease. Metastases included bone-only disease in 37.9% of patients, visceral-only disease in 24.2%, and 40.9% in both sites.
Among the patients randomized to early local therapy, 14 did not have surgery for personal, clinical, or insurance reasons. Of the 109 who went on to surgery, 87 had clear surgical margins, and 74 received locoregional radiation therapy.
Survival, progression, and HRQOL
At a median follow-up of 53 months, the median overall survival was 54 months in each arm. There was no significant difference in survival between the study arms, with superimposable survival curves (hazard ratio, 1.09; P = .63).
An analysis of overall survival by tumor type showed that, for the 20 women with triple-negative disease, survival was worse with early local therapy (HR, 3.50). There were no differences in survival either for the 79 patients with HER2-positive disease or for the 137 patients with hormone receptor–positive/HER2-negative disease.
Locoregional progression occurred in 25.6% of patients assigned to continued systemic therapy, compared with 10.2% assigned to early local therapy. However, progression-free survival was virtually identical between the study arms (P = .40).
At most time points, there were no significant between-arm differences in HRQOL. The exception was at 18 months of follow-up, when the HRQOL was significantly lower among patients who had undergone early local therapy (P = .001).
“Based on available data, locoregional therapy for the primary tumor should not be offered to women with stage IV breast cancer with the expectation of a survival benefit. When systemic disease is well controlled with systemic therapy but the primary site is progressing, as does happen occasionally, locoregional treatment can be considered,” Dr. Khan concluded.
She noted there is an ongoing trial of similar design in Japan (JCOG-1017), with results expected in 2022.
The current trial was supported by the National Cancer Institute and Canadian Cancer Society. Dr. Khan reported no conflicts of interest. Dr. White reported institutional research funding from Intraop Medical.
SOURCE: Khan SA et al. ASCO 2020, Abstract LBA2.
FROM ASCO 2020
Pembrolizumab prolonged PFS vs. brentuximab vedotin in r/r Hodgkin lymphoma
Pembrolizumab treatment significantly improved progression-free survival versus brentuximab vedotin in a randomized, phase 3 trial including patients with relapsed or refractory classical Hodgkin lymphoma, an investigator has reported.
Median progression-free survival (PFS) was 13.2 versus 8.3 months in favor of pembrolizumab, according to the report on the KEYNOTE-204 trial, which included patients with classical Hodgkin lymphoma who either had relapsed after autologous stem cell transplant (SCT) or were ineligible for autologous SCT.
of Princess Margaret Cancer Centre in Toronto.
“This PFS benefit extended to key subgroups, including those ineligible for autologous transplant, patients with primary refractory disease, and patients who were brentuximab-vedotin naive,” Dr. Kuruvilla added in his presentation, which was part of the American Society of Clinical Oncology virtual scientific program.
Pneumonitis was more frequent in the pembrolizumab arm, but “appeared in general to be quite well managed” among patients who experienced this adverse event, according to Dr. Kuruvilla, who said that treatment with the programmed death–1 inhibitor should be considered “the preferred treatment option and the new standard of care” for patients with relapsed/refractory classic Hodgkin lymphoma who have relapsed after autologous SCT or are ineligible for it.
Although the pneumonitis findings are important to keep in mind, results of KEYNOTE-204 are indeed “practice defining” and immediately impactful, said Mark J. Roschewski, MD, clinical investigator in the lymphoid malignancies branch at the Center for Cancer Research, part of the National Cancer Institute, Bethesda, Md.
“I would select pembrolizumab over brentuximab for this patient population, particularly those that are refractory to chemotherapy,” he said in a commentary on the study also included in the virtual ASCO proceedings.
“There may be specific patient populations that I’d reconsider, such as those that might be at high risk for lung toxicity,” he added. “They may not be suitable for this, but it’s something to at least to be aware of.”
Although the antibody-drug conjugate brentuximab vedotin has been considered the standard of care for patients with relapse after autologous SCT, there has historically been no standard of care for patients who are ineligible for transplant because of chemorefractory disease, advanced age, or comorbidities, Dr. Kuruvilla said in his presentation.
In the KEYNOTE-204 study, 304 patients with relapsed/refractory classic Hodgkin lymphoma were randomized to receive either pembrolizumab 200 mg or brentuximab at 1.8 mg/kg intravenously every 3 weeks for up to 35 cycles.
The median age of patients was 36 years in the pembrolizumab arm and 35 years in the brentuximab vedotin arm, according to the report. Approximately 37% of the patients had previously undergone autologous SCT. About 40% had been refractory to frontline therapy, while 28% relapsed within 12 months of therapy and 32% relapsed later than 12 months.
Median PFS by blinded independent central review was 13.2 versus 8.3 months in the pembrolizumab and brentuximab arms, respectively (hazard ratio, 0.65; 95% confidence interval, 0.48-0.88; P = .00271), Dr. Kuruvilla reported.
The benefit extended to “key subgroups” in the trial, he added, including those who were ineligible for autologous SCT, those with primary refractory disease, and those who were naive to brentuximab vedotin, with HRs of 0.61, 0.52, and 0.67, respectively.
Pembrolizumab was also associated with more durable responses versus brentuximab vedotin, according to the investigator.
The overall response rate was 65.6% and 54.2%, respectively, for pembrolizumab and brentuximab, although this difference of approximately 11 percentage points did not meet criteria for statistical significance, he said. Duration of response was 20.7 months or pembrolizumab and 13.8 months for brentuximab.
The rate of serious treatment-related adverse events was similar between groups, according to Dr. Kuruvilla, who reported grade 3-5 events occurring in 19.6% and 25.0% of the pembrolizumab and brentuximab arms. Serious treatment-related adverse events were numerically more frequent in the pembrolizumab arm (16.2% vs. 10.5%) and there was one treatment-related death caused by pneumonia, seen in the pembrolizumab arm.
Pneumonitis occurred in 2.6% of the brentuximab-treated patients and in 10.8% of pembrolizumab-treated patients, of which half of cases were grade 3-4, according to the report.
In the pembrolizumab arm, pneumonitis was felt to be drug-related in 15 of 16 cases, according to Dr. Kuruvilla, who added that 15 of 16 patients required corticosteroid therapy. “This has led to the resolution of the pneumonitis in 12 of 16 patients, with ongoing resolution in one further patient.”
Research funding for KEYNOTE-204 came from Merck Sharp & Dohme. Dr. Kuruvilla provided disclosures related to Merck and a variety of other pharmaceutical companies. Dr. Roschewski said he had no relationships to disclose.
SOURCE: Kuruvilla J et al. ASCO 2020, Abstract 8005.
Pembrolizumab treatment significantly improved progression-free survival versus brentuximab vedotin in a randomized, phase 3 trial including patients with relapsed or refractory classical Hodgkin lymphoma, an investigator has reported.
Median progression-free survival (PFS) was 13.2 versus 8.3 months in favor of pembrolizumab, according to the report on the KEYNOTE-204 trial, which included patients with classical Hodgkin lymphoma who either had relapsed after autologous stem cell transplant (SCT) or were ineligible for autologous SCT.
of Princess Margaret Cancer Centre in Toronto.
“This PFS benefit extended to key subgroups, including those ineligible for autologous transplant, patients with primary refractory disease, and patients who were brentuximab-vedotin naive,” Dr. Kuruvilla added in his presentation, which was part of the American Society of Clinical Oncology virtual scientific program.
Pneumonitis was more frequent in the pembrolizumab arm, but “appeared in general to be quite well managed” among patients who experienced this adverse event, according to Dr. Kuruvilla, who said that treatment with the programmed death–1 inhibitor should be considered “the preferred treatment option and the new standard of care” for patients with relapsed/refractory classic Hodgkin lymphoma who have relapsed after autologous SCT or are ineligible for it.
Although the pneumonitis findings are important to keep in mind, results of KEYNOTE-204 are indeed “practice defining” and immediately impactful, said Mark J. Roschewski, MD, clinical investigator in the lymphoid malignancies branch at the Center for Cancer Research, part of the National Cancer Institute, Bethesda, Md.
“I would select pembrolizumab over brentuximab for this patient population, particularly those that are refractory to chemotherapy,” he said in a commentary on the study also included in the virtual ASCO proceedings.
“There may be specific patient populations that I’d reconsider, such as those that might be at high risk for lung toxicity,” he added. “They may not be suitable for this, but it’s something to at least to be aware of.”
Although the antibody-drug conjugate brentuximab vedotin has been considered the standard of care for patients with relapse after autologous SCT, there has historically been no standard of care for patients who are ineligible for transplant because of chemorefractory disease, advanced age, or comorbidities, Dr. Kuruvilla said in his presentation.
In the KEYNOTE-204 study, 304 patients with relapsed/refractory classic Hodgkin lymphoma were randomized to receive either pembrolizumab 200 mg or brentuximab at 1.8 mg/kg intravenously every 3 weeks for up to 35 cycles.
The median age of patients was 36 years in the pembrolizumab arm and 35 years in the brentuximab vedotin arm, according to the report. Approximately 37% of the patients had previously undergone autologous SCT. About 40% had been refractory to frontline therapy, while 28% relapsed within 12 months of therapy and 32% relapsed later than 12 months.
Median PFS by blinded independent central review was 13.2 versus 8.3 months in the pembrolizumab and brentuximab arms, respectively (hazard ratio, 0.65; 95% confidence interval, 0.48-0.88; P = .00271), Dr. Kuruvilla reported.
The benefit extended to “key subgroups” in the trial, he added, including those who were ineligible for autologous SCT, those with primary refractory disease, and those who were naive to brentuximab vedotin, with HRs of 0.61, 0.52, and 0.67, respectively.
Pembrolizumab was also associated with more durable responses versus brentuximab vedotin, according to the investigator.
The overall response rate was 65.6% and 54.2%, respectively, for pembrolizumab and brentuximab, although this difference of approximately 11 percentage points did not meet criteria for statistical significance, he said. Duration of response was 20.7 months or pembrolizumab and 13.8 months for brentuximab.
The rate of serious treatment-related adverse events was similar between groups, according to Dr. Kuruvilla, who reported grade 3-5 events occurring in 19.6% and 25.0% of the pembrolizumab and brentuximab arms. Serious treatment-related adverse events were numerically more frequent in the pembrolizumab arm (16.2% vs. 10.5%) and there was one treatment-related death caused by pneumonia, seen in the pembrolizumab arm.
Pneumonitis occurred in 2.6% of the brentuximab-treated patients and in 10.8% of pembrolizumab-treated patients, of which half of cases were grade 3-4, according to the report.
In the pembrolizumab arm, pneumonitis was felt to be drug-related in 15 of 16 cases, according to Dr. Kuruvilla, who added that 15 of 16 patients required corticosteroid therapy. “This has led to the resolution of the pneumonitis in 12 of 16 patients, with ongoing resolution in one further patient.”
Research funding for KEYNOTE-204 came from Merck Sharp & Dohme. Dr. Kuruvilla provided disclosures related to Merck and a variety of other pharmaceutical companies. Dr. Roschewski said he had no relationships to disclose.
SOURCE: Kuruvilla J et al. ASCO 2020, Abstract 8005.
Pembrolizumab treatment significantly improved progression-free survival versus brentuximab vedotin in a randomized, phase 3 trial including patients with relapsed or refractory classical Hodgkin lymphoma, an investigator has reported.
Median progression-free survival (PFS) was 13.2 versus 8.3 months in favor of pembrolizumab, according to the report on the KEYNOTE-204 trial, which included patients with classical Hodgkin lymphoma who either had relapsed after autologous stem cell transplant (SCT) or were ineligible for autologous SCT.
of Princess Margaret Cancer Centre in Toronto.
“This PFS benefit extended to key subgroups, including those ineligible for autologous transplant, patients with primary refractory disease, and patients who were brentuximab-vedotin naive,” Dr. Kuruvilla added in his presentation, which was part of the American Society of Clinical Oncology virtual scientific program.
Pneumonitis was more frequent in the pembrolizumab arm, but “appeared in general to be quite well managed” among patients who experienced this adverse event, according to Dr. Kuruvilla, who said that treatment with the programmed death–1 inhibitor should be considered “the preferred treatment option and the new standard of care” for patients with relapsed/refractory classic Hodgkin lymphoma who have relapsed after autologous SCT or are ineligible for it.
Although the pneumonitis findings are important to keep in mind, results of KEYNOTE-204 are indeed “practice defining” and immediately impactful, said Mark J. Roschewski, MD, clinical investigator in the lymphoid malignancies branch at the Center for Cancer Research, part of the National Cancer Institute, Bethesda, Md.
“I would select pembrolizumab over brentuximab for this patient population, particularly those that are refractory to chemotherapy,” he said in a commentary on the study also included in the virtual ASCO proceedings.
“There may be specific patient populations that I’d reconsider, such as those that might be at high risk for lung toxicity,” he added. “They may not be suitable for this, but it’s something to at least to be aware of.”
Although the antibody-drug conjugate brentuximab vedotin has been considered the standard of care for patients with relapse after autologous SCT, there has historically been no standard of care for patients who are ineligible for transplant because of chemorefractory disease, advanced age, or comorbidities, Dr. Kuruvilla said in his presentation.
In the KEYNOTE-204 study, 304 patients with relapsed/refractory classic Hodgkin lymphoma were randomized to receive either pembrolizumab 200 mg or brentuximab at 1.8 mg/kg intravenously every 3 weeks for up to 35 cycles.
The median age of patients was 36 years in the pembrolizumab arm and 35 years in the brentuximab vedotin arm, according to the report. Approximately 37% of the patients had previously undergone autologous SCT. About 40% had been refractory to frontline therapy, while 28% relapsed within 12 months of therapy and 32% relapsed later than 12 months.
Median PFS by blinded independent central review was 13.2 versus 8.3 months in the pembrolizumab and brentuximab arms, respectively (hazard ratio, 0.65; 95% confidence interval, 0.48-0.88; P = .00271), Dr. Kuruvilla reported.
The benefit extended to “key subgroups” in the trial, he added, including those who were ineligible for autologous SCT, those with primary refractory disease, and those who were naive to brentuximab vedotin, with HRs of 0.61, 0.52, and 0.67, respectively.
Pembrolizumab was also associated with more durable responses versus brentuximab vedotin, according to the investigator.
The overall response rate was 65.6% and 54.2%, respectively, for pembrolizumab and brentuximab, although this difference of approximately 11 percentage points did not meet criteria for statistical significance, he said. Duration of response was 20.7 months or pembrolizumab and 13.8 months for brentuximab.
The rate of serious treatment-related adverse events was similar between groups, according to Dr. Kuruvilla, who reported grade 3-5 events occurring in 19.6% and 25.0% of the pembrolizumab and brentuximab arms. Serious treatment-related adverse events were numerically more frequent in the pembrolizumab arm (16.2% vs. 10.5%) and there was one treatment-related death caused by pneumonia, seen in the pembrolizumab arm.
Pneumonitis occurred in 2.6% of the brentuximab-treated patients and in 10.8% of pembrolizumab-treated patients, of which half of cases were grade 3-4, according to the report.
In the pembrolizumab arm, pneumonitis was felt to be drug-related in 15 of 16 cases, according to Dr. Kuruvilla, who added that 15 of 16 patients required corticosteroid therapy. “This has led to the resolution of the pneumonitis in 12 of 16 patients, with ongoing resolution in one further patient.”
Research funding for KEYNOTE-204 came from Merck Sharp & Dohme. Dr. Kuruvilla provided disclosures related to Merck and a variety of other pharmaceutical companies. Dr. Roschewski said he had no relationships to disclose.
SOURCE: Kuruvilla J et al. ASCO 2020, Abstract 8005.
FROM ASCO 2020
Pyrotinib bests lapatinib in HER2+ metastatic breast cancer
PFS was extended by nearly 6 months among patients who received pyrotinib, a novel pan-HER2 inhibitor, combined with capecitabine. Grade 3 diarrhea occurred in nearly 31% of patients receiving the pyrotinib-capecitabine combination, though none of the patients discontinued treatment due to this adverse event.
Binghe Xu, MD, PhD, of the National Cancer Center/Cancer Hospital at the Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, presented these results, from the phase 3 PHOEBE trial, as part of the American Society of Clinical Oncology virtual scientific program.
The value of pyrotinib
Although there are already many targeted therapies for HER2-positive metastatic breast cancer, accessibility can be an issue, with drugs such as pertuzumab and trastuzumab emtansine (T-DM1) not available in all regions of the world, according to Dr. Xu.
“Before we initiated this clinical trial, lapatinib plus capecitabine was the only second-line standard of care against HER2-positive metastatic breast cancer in China,” he said.
Based, in part, on results of the PHOEBE trial, the combination of pyrotinib and capecitabine was approved in China as a second-line standard of care for patients with HER2-positive metastatic breast cancer, according to Dr. Xu.
Pyrotinib has now demonstrated “clinical value” in two phase 3 clinical trials, but its value in relation to pertuzumab, T-DM1, tucatinib, trastuzumab deruxtecan, or neratinib is less clear, said Aleix Prat, MD, PhD, of Hospital Clinic of Barcelona.
“Also, in my opinion, the toxicity profile needs attention,” Dr. Prat said in a discussion of the PHOEBE results that was also part of the virtual ASCO meeting.
The 31% incidence of grade 3 diarrhea was “very similar,” he said, to what was seen in PHENIX, another phase 3 trial of pyrotinib plus capecitabine that was presented at the 2019 ASCO annual meeting (J Clin Oncol 37, 2019 suppl; abstr 1001).
“What is the current therapy landscape? In my opinion, today, the first line remains taxane, trastuzumab, and pertuzumab; the second line T-DM1; and the third line tucatinib, trastuzumab, and capecitabine, with other treatment strategies reserved for later lines,” Dr. Prat said.
Study details
PHOEBE included 267 patients with HER2-positive metastatic breast cancer. They had previously received trastuzumab and taxanes, and/or anthracyclines, with up to two prior lines of chemotherapy for metastatic disease.
The patients’ median age was 50 years, 79% had visceral metastases at screening, and about 26% had trastuzumab resistance, Dr. Xu said. Resistance was defined as relapse within 6 months after adjuvant treatment or progression within 3 months of treatment for metastatic disease.
A statistically significant and clinically meaningful improvement was seen in PFS, the primary endpoint of the study, Dr. Xu said.
Median PFS by blinded independent central review was 12.5 months for the pyrotinib-capecitabine combination, compared with 6.8 months for lapatinib-capecitabine (hazard ratio, 0.39; 95% confidence interval, 0.27-0.56; P < .0001).
The PFS benefit was consistently observed across all predefined subgroups, including by trastuzumab resistance.
In trastuzumab-resistant patients, the median PFS was 12.5 months for the pyrotinib combination and 6.9 months for the lapatinib combination (HR, 0.60; 95% CI, 0.29-1.21). In patients without trastuzumab resistance, the median PFS was 12.5 months and 5.6 months, respectively (HR, 0.33; 95% CI, 0.21-0.51).
Although overall survival (OS) data were not yet mature, there was a “strong trend” toward a benefit with pyrotinib, Dr. Xu said. The 12-month OS rate was 91.3% for the pyrotinib combination and 77.4% for lapatinib. The median OS was not reached in either arm at the time of analysis.
Treatment-related adverse events of grade 3 or greater occurred in 57.5% of the pyrotinib arm and 34.1% of the lapatinib arm.
Diarrhea was the most common grade 3 or greater treatment-related adverse event, occurring in 30.6% of patients in the pyrotinib arm and 8.3% of those in the lapatinib arm. No grade 4 or 5 diarrhea was seen.
Overall, diarrhea occurred in 94.8% of patients in the pyrotinib arm and 62.1% of those in the lapatinib arm. However, pyrotinib-associated diarrhea was generally of low severity, occurred early, had a short duration, was reversible, and did not lead to treatment termination, according to Dr. Xu.
This study was funded by Jiangsu Hengrui Medicine Co. Ltd. Dr. Xu reported additional disclosures related to AstraZeneca, Eisai, Pfizer, and Roche. Dr. Prat disclosed relationships with Amgen, Daiichi Sankyo, Lilly, MSD Oncology, and other companies.
SOURCE: Xu B et al. ASCO 2020, Abstract 1003
PFS was extended by nearly 6 months among patients who received pyrotinib, a novel pan-HER2 inhibitor, combined with capecitabine. Grade 3 diarrhea occurred in nearly 31% of patients receiving the pyrotinib-capecitabine combination, though none of the patients discontinued treatment due to this adverse event.
Binghe Xu, MD, PhD, of the National Cancer Center/Cancer Hospital at the Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, presented these results, from the phase 3 PHOEBE trial, as part of the American Society of Clinical Oncology virtual scientific program.
The value of pyrotinib
Although there are already many targeted therapies for HER2-positive metastatic breast cancer, accessibility can be an issue, with drugs such as pertuzumab and trastuzumab emtansine (T-DM1) not available in all regions of the world, according to Dr. Xu.
“Before we initiated this clinical trial, lapatinib plus capecitabine was the only second-line standard of care against HER2-positive metastatic breast cancer in China,” he said.
Based, in part, on results of the PHOEBE trial, the combination of pyrotinib and capecitabine was approved in China as a second-line standard of care for patients with HER2-positive metastatic breast cancer, according to Dr. Xu.
Pyrotinib has now demonstrated “clinical value” in two phase 3 clinical trials, but its value in relation to pertuzumab, T-DM1, tucatinib, trastuzumab deruxtecan, or neratinib is less clear, said Aleix Prat, MD, PhD, of Hospital Clinic of Barcelona.
“Also, in my opinion, the toxicity profile needs attention,” Dr. Prat said in a discussion of the PHOEBE results that was also part of the virtual ASCO meeting.
The 31% incidence of grade 3 diarrhea was “very similar,” he said, to what was seen in PHENIX, another phase 3 trial of pyrotinib plus capecitabine that was presented at the 2019 ASCO annual meeting (J Clin Oncol 37, 2019 suppl; abstr 1001).
“What is the current therapy landscape? In my opinion, today, the first line remains taxane, trastuzumab, and pertuzumab; the second line T-DM1; and the third line tucatinib, trastuzumab, and capecitabine, with other treatment strategies reserved for later lines,” Dr. Prat said.
Study details
PHOEBE included 267 patients with HER2-positive metastatic breast cancer. They had previously received trastuzumab and taxanes, and/or anthracyclines, with up to two prior lines of chemotherapy for metastatic disease.
The patients’ median age was 50 years, 79% had visceral metastases at screening, and about 26% had trastuzumab resistance, Dr. Xu said. Resistance was defined as relapse within 6 months after adjuvant treatment or progression within 3 months of treatment for metastatic disease.
A statistically significant and clinically meaningful improvement was seen in PFS, the primary endpoint of the study, Dr. Xu said.
Median PFS by blinded independent central review was 12.5 months for the pyrotinib-capecitabine combination, compared with 6.8 months for lapatinib-capecitabine (hazard ratio, 0.39; 95% confidence interval, 0.27-0.56; P < .0001).
The PFS benefit was consistently observed across all predefined subgroups, including by trastuzumab resistance.
In trastuzumab-resistant patients, the median PFS was 12.5 months for the pyrotinib combination and 6.9 months for the lapatinib combination (HR, 0.60; 95% CI, 0.29-1.21). In patients without trastuzumab resistance, the median PFS was 12.5 months and 5.6 months, respectively (HR, 0.33; 95% CI, 0.21-0.51).
Although overall survival (OS) data were not yet mature, there was a “strong trend” toward a benefit with pyrotinib, Dr. Xu said. The 12-month OS rate was 91.3% for the pyrotinib combination and 77.4% for lapatinib. The median OS was not reached in either arm at the time of analysis.
Treatment-related adverse events of grade 3 or greater occurred in 57.5% of the pyrotinib arm and 34.1% of the lapatinib arm.
Diarrhea was the most common grade 3 or greater treatment-related adverse event, occurring in 30.6% of patients in the pyrotinib arm and 8.3% of those in the lapatinib arm. No grade 4 or 5 diarrhea was seen.
Overall, diarrhea occurred in 94.8% of patients in the pyrotinib arm and 62.1% of those in the lapatinib arm. However, pyrotinib-associated diarrhea was generally of low severity, occurred early, had a short duration, was reversible, and did not lead to treatment termination, according to Dr. Xu.
This study was funded by Jiangsu Hengrui Medicine Co. Ltd. Dr. Xu reported additional disclosures related to AstraZeneca, Eisai, Pfizer, and Roche. Dr. Prat disclosed relationships with Amgen, Daiichi Sankyo, Lilly, MSD Oncology, and other companies.
SOURCE: Xu B et al. ASCO 2020, Abstract 1003
PFS was extended by nearly 6 months among patients who received pyrotinib, a novel pan-HER2 inhibitor, combined with capecitabine. Grade 3 diarrhea occurred in nearly 31% of patients receiving the pyrotinib-capecitabine combination, though none of the patients discontinued treatment due to this adverse event.
Binghe Xu, MD, PhD, of the National Cancer Center/Cancer Hospital at the Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, presented these results, from the phase 3 PHOEBE trial, as part of the American Society of Clinical Oncology virtual scientific program.
The value of pyrotinib
Although there are already many targeted therapies for HER2-positive metastatic breast cancer, accessibility can be an issue, with drugs such as pertuzumab and trastuzumab emtansine (T-DM1) not available in all regions of the world, according to Dr. Xu.
“Before we initiated this clinical trial, lapatinib plus capecitabine was the only second-line standard of care against HER2-positive metastatic breast cancer in China,” he said.
Based, in part, on results of the PHOEBE trial, the combination of pyrotinib and capecitabine was approved in China as a second-line standard of care for patients with HER2-positive metastatic breast cancer, according to Dr. Xu.
Pyrotinib has now demonstrated “clinical value” in two phase 3 clinical trials, but its value in relation to pertuzumab, T-DM1, tucatinib, trastuzumab deruxtecan, or neratinib is less clear, said Aleix Prat, MD, PhD, of Hospital Clinic of Barcelona.
“Also, in my opinion, the toxicity profile needs attention,” Dr. Prat said in a discussion of the PHOEBE results that was also part of the virtual ASCO meeting.
The 31% incidence of grade 3 diarrhea was “very similar,” he said, to what was seen in PHENIX, another phase 3 trial of pyrotinib plus capecitabine that was presented at the 2019 ASCO annual meeting (J Clin Oncol 37, 2019 suppl; abstr 1001).
“What is the current therapy landscape? In my opinion, today, the first line remains taxane, trastuzumab, and pertuzumab; the second line T-DM1; and the third line tucatinib, trastuzumab, and capecitabine, with other treatment strategies reserved for later lines,” Dr. Prat said.
Study details
PHOEBE included 267 patients with HER2-positive metastatic breast cancer. They had previously received trastuzumab and taxanes, and/or anthracyclines, with up to two prior lines of chemotherapy for metastatic disease.
The patients’ median age was 50 years, 79% had visceral metastases at screening, and about 26% had trastuzumab resistance, Dr. Xu said. Resistance was defined as relapse within 6 months after adjuvant treatment or progression within 3 months of treatment for metastatic disease.
A statistically significant and clinically meaningful improvement was seen in PFS, the primary endpoint of the study, Dr. Xu said.
Median PFS by blinded independent central review was 12.5 months for the pyrotinib-capecitabine combination, compared with 6.8 months for lapatinib-capecitabine (hazard ratio, 0.39; 95% confidence interval, 0.27-0.56; P < .0001).
The PFS benefit was consistently observed across all predefined subgroups, including by trastuzumab resistance.
In trastuzumab-resistant patients, the median PFS was 12.5 months for the pyrotinib combination and 6.9 months for the lapatinib combination (HR, 0.60; 95% CI, 0.29-1.21). In patients without trastuzumab resistance, the median PFS was 12.5 months and 5.6 months, respectively (HR, 0.33; 95% CI, 0.21-0.51).
Although overall survival (OS) data were not yet mature, there was a “strong trend” toward a benefit with pyrotinib, Dr. Xu said. The 12-month OS rate was 91.3% for the pyrotinib combination and 77.4% for lapatinib. The median OS was not reached in either arm at the time of analysis.
Treatment-related adverse events of grade 3 or greater occurred in 57.5% of the pyrotinib arm and 34.1% of the lapatinib arm.
Diarrhea was the most common grade 3 or greater treatment-related adverse event, occurring in 30.6% of patients in the pyrotinib arm and 8.3% of those in the lapatinib arm. No grade 4 or 5 diarrhea was seen.
Overall, diarrhea occurred in 94.8% of patients in the pyrotinib arm and 62.1% of those in the lapatinib arm. However, pyrotinib-associated diarrhea was generally of low severity, occurred early, had a short duration, was reversible, and did not lead to treatment termination, according to Dr. Xu.
This study was funded by Jiangsu Hengrui Medicine Co. Ltd. Dr. Xu reported additional disclosures related to AstraZeneca, Eisai, Pfizer, and Roche. Dr. Prat disclosed relationships with Amgen, Daiichi Sankyo, Lilly, MSD Oncology, and other companies.
SOURCE: Xu B et al. ASCO 2020, Abstract 1003
FROM ASCO 2020
Expanding the role of PARP inhibitors in breast cancer
For patients with BRCA-like triple-negative breast cancer (TNBC), adding veliparib to cisplatin chemotherapy may extend survival, based on results from the phase 3 SWOG S1416 trial.
All patients with BRCA-like TNBC had a significant improvement in progression-free survival (PFS) when they received veliparib plus cisplatin. Previously untreated patients with BRCA-like TNBC had a significant improvement in overall survival (OS) as well.
The results are a “very positive step towards expanding the role of PARP inhibitors beyond germline BRCA in breast cancer,” reported lead author Priyanka Sharma, MD, of the University of Kansas Medical Center in Kansas City, who presented the findings as part of the American Society of Clinical Oncology virtual scientific program.
According to Dr. Sharma, PARP inhibitors have demonstrated efficacy for certain patients with BRCA wild-type ovarian cancer, such as those with homologous recombination deficiency, which also occurs in approximately half of patients with BRCA wild-type TNBC. In TNBC, homologous recombination deficiency and other aberrations lead to a BRCA-like disease phenotype, which may respond to PARP inhibitors.
Dr. Sharma noted that previous attempts to use PARP inhibitors for BRCA wild-type TNBC have revealed obstacles, such as the inefficacy of PARP inhibitor monotherapy and dose-limiting myelosuppression when PARP inhibitors were added to chemotherapy. The issue of bone marrow toxicity may be mitigated by veliparib, which has minimal PARP-trapping activity, she explained.
“A phase 1 trial has demonstrated that adequate doses of cisplatin can be delivered safely in combination with the near-maximal single-agent dose of veliparib in patients with metastatic TNBC,” Dr. Sharma said.
She and her colleagues put this finding to the test in a phase 3 trial that enrolled 335 patients with metastatic and/or loco-regionally recurrent TNBC or BRCA-associated HER2-negative breast cancer. Patients could be previously untreated or have received one prior cytotoxic chemotherapy for metastatic disease.
Of the patients enrolled, 321 met eligibility criteria, 294 had germline BRCA testing, and 209 had BRCA-like assessment.
Patients were divided into the following groups: germline BRCA-associated disease (n = 37), BRCA-like disease (n = 99), non-BRCA-like disease (n = 110), and unclassified (n = 75).
In each group, patients were randomized in a 1:1 ratio to receive cisplatin (75 mg/m2on day 1) plus veliparib (300 mg twice daily on days 1-14) every 3 weeks, or cisplatin with placebo. The primary endpoint was PFS.
Results
Among patients with BRCA-like disease, there was a significant improvement in PFS and a trend toward improved OS when veliparib was added to cisplatin. The median PFS was 5.9 months with veliparib and 4.2 months with placebo (P = .006). The median OS was 14.0 months and 12.1 months, respectively (P = .067).
Among patients with previously untreated BRCA-like disease, there were significant improvements in both PFS and OS.
The median PFS in this group was 6.1 months with veliparib and 4.2 months with placebo (P = .008). The 12-month PFS rates were 23% and 3%, respectively.
The median OS in this group was 17.8 months with veliparib and 10.3 months with placebo (P = .048). The 24-month OS rates were 43% and 20%, respectively.
There were no survival benefits with veliparib among patients with unclassified disease, non-BRCA-like disease, or BRCA-associated disease.
Dr. Sharma noted that the lack of significant improvement in the BRCA-associated group was likely due to the small sample size. “FDA approval of PARP inhibitors for treatment of germline BRCA-associated metastatic breast cancer during the course of this trial impacted accrual to this group,” she said.
Veliparib was associated with a higher rate of grade 3-4 hematologic toxicities, including neutropenia (46% vs. 19%), leukopenia (27% vs. 7%), anemia (23% vs. 7%), and thrombocytopenia (19% vs. 3%).
Dr. Sharma said results from this trial should prompt further research. “The combination of veliparib plus cisplatin warrants further evaluation in larger randomized trials for patients with BRCA-like phenotype TNBC,” she said.
Invited discussant Catherine M. Kelly, MB BCh, of Mater Misericordiae University Hospital in Dublin, called the trial “an ambitious study” that has created a “valuable tissue bank” for future translational research. She agreed that more work is necessary.
“Further research is needed to identify the optimal homologous recombination deficiency biomarkers critical in the early treatment-naive and in the advanced treatment-exposed disease settings,” Dr. Kelly said.
SWOG S1416 was funded by the National Institutes of Health and AbbVie. Dr. Sharma disclosed relationships with AstraZeneca, Merck, Novartis, and other companies. Dr. Kelly reported affiliations with Pfizer, Novartis, Roche, and MSD Oncology.
SOURCE: Sharma et al. ASCO 2020, Abstract 1001.
For patients with BRCA-like triple-negative breast cancer (TNBC), adding veliparib to cisplatin chemotherapy may extend survival, based on results from the phase 3 SWOG S1416 trial.
All patients with BRCA-like TNBC had a significant improvement in progression-free survival (PFS) when they received veliparib plus cisplatin. Previously untreated patients with BRCA-like TNBC had a significant improvement in overall survival (OS) as well.
The results are a “very positive step towards expanding the role of PARP inhibitors beyond germline BRCA in breast cancer,” reported lead author Priyanka Sharma, MD, of the University of Kansas Medical Center in Kansas City, who presented the findings as part of the American Society of Clinical Oncology virtual scientific program.
According to Dr. Sharma, PARP inhibitors have demonstrated efficacy for certain patients with BRCA wild-type ovarian cancer, such as those with homologous recombination deficiency, which also occurs in approximately half of patients with BRCA wild-type TNBC. In TNBC, homologous recombination deficiency and other aberrations lead to a BRCA-like disease phenotype, which may respond to PARP inhibitors.
Dr. Sharma noted that previous attempts to use PARP inhibitors for BRCA wild-type TNBC have revealed obstacles, such as the inefficacy of PARP inhibitor monotherapy and dose-limiting myelosuppression when PARP inhibitors were added to chemotherapy. The issue of bone marrow toxicity may be mitigated by veliparib, which has minimal PARP-trapping activity, she explained.
“A phase 1 trial has demonstrated that adequate doses of cisplatin can be delivered safely in combination with the near-maximal single-agent dose of veliparib in patients with metastatic TNBC,” Dr. Sharma said.
She and her colleagues put this finding to the test in a phase 3 trial that enrolled 335 patients with metastatic and/or loco-regionally recurrent TNBC or BRCA-associated HER2-negative breast cancer. Patients could be previously untreated or have received one prior cytotoxic chemotherapy for metastatic disease.
Of the patients enrolled, 321 met eligibility criteria, 294 had germline BRCA testing, and 209 had BRCA-like assessment.
Patients were divided into the following groups: germline BRCA-associated disease (n = 37), BRCA-like disease (n = 99), non-BRCA-like disease (n = 110), and unclassified (n = 75).
In each group, patients were randomized in a 1:1 ratio to receive cisplatin (75 mg/m2on day 1) plus veliparib (300 mg twice daily on days 1-14) every 3 weeks, or cisplatin with placebo. The primary endpoint was PFS.
Results
Among patients with BRCA-like disease, there was a significant improvement in PFS and a trend toward improved OS when veliparib was added to cisplatin. The median PFS was 5.9 months with veliparib and 4.2 months with placebo (P = .006). The median OS was 14.0 months and 12.1 months, respectively (P = .067).
Among patients with previously untreated BRCA-like disease, there were significant improvements in both PFS and OS.
The median PFS in this group was 6.1 months with veliparib and 4.2 months with placebo (P = .008). The 12-month PFS rates were 23% and 3%, respectively.
The median OS in this group was 17.8 months with veliparib and 10.3 months with placebo (P = .048). The 24-month OS rates were 43% and 20%, respectively.
There were no survival benefits with veliparib among patients with unclassified disease, non-BRCA-like disease, or BRCA-associated disease.
Dr. Sharma noted that the lack of significant improvement in the BRCA-associated group was likely due to the small sample size. “FDA approval of PARP inhibitors for treatment of germline BRCA-associated metastatic breast cancer during the course of this trial impacted accrual to this group,” she said.
Veliparib was associated with a higher rate of grade 3-4 hematologic toxicities, including neutropenia (46% vs. 19%), leukopenia (27% vs. 7%), anemia (23% vs. 7%), and thrombocytopenia (19% vs. 3%).
Dr. Sharma said results from this trial should prompt further research. “The combination of veliparib plus cisplatin warrants further evaluation in larger randomized trials for patients with BRCA-like phenotype TNBC,” she said.
Invited discussant Catherine M. Kelly, MB BCh, of Mater Misericordiae University Hospital in Dublin, called the trial “an ambitious study” that has created a “valuable tissue bank” for future translational research. She agreed that more work is necessary.
“Further research is needed to identify the optimal homologous recombination deficiency biomarkers critical in the early treatment-naive and in the advanced treatment-exposed disease settings,” Dr. Kelly said.
SWOG S1416 was funded by the National Institutes of Health and AbbVie. Dr. Sharma disclosed relationships with AstraZeneca, Merck, Novartis, and other companies. Dr. Kelly reported affiliations with Pfizer, Novartis, Roche, and MSD Oncology.
SOURCE: Sharma et al. ASCO 2020, Abstract 1001.
For patients with BRCA-like triple-negative breast cancer (TNBC), adding veliparib to cisplatin chemotherapy may extend survival, based on results from the phase 3 SWOG S1416 trial.
All patients with BRCA-like TNBC had a significant improvement in progression-free survival (PFS) when they received veliparib plus cisplatin. Previously untreated patients with BRCA-like TNBC had a significant improvement in overall survival (OS) as well.
The results are a “very positive step towards expanding the role of PARP inhibitors beyond germline BRCA in breast cancer,” reported lead author Priyanka Sharma, MD, of the University of Kansas Medical Center in Kansas City, who presented the findings as part of the American Society of Clinical Oncology virtual scientific program.
According to Dr. Sharma, PARP inhibitors have demonstrated efficacy for certain patients with BRCA wild-type ovarian cancer, such as those with homologous recombination deficiency, which also occurs in approximately half of patients with BRCA wild-type TNBC. In TNBC, homologous recombination deficiency and other aberrations lead to a BRCA-like disease phenotype, which may respond to PARP inhibitors.
Dr. Sharma noted that previous attempts to use PARP inhibitors for BRCA wild-type TNBC have revealed obstacles, such as the inefficacy of PARP inhibitor monotherapy and dose-limiting myelosuppression when PARP inhibitors were added to chemotherapy. The issue of bone marrow toxicity may be mitigated by veliparib, which has minimal PARP-trapping activity, she explained.
“A phase 1 trial has demonstrated that adequate doses of cisplatin can be delivered safely in combination with the near-maximal single-agent dose of veliparib in patients with metastatic TNBC,” Dr. Sharma said.
She and her colleagues put this finding to the test in a phase 3 trial that enrolled 335 patients with metastatic and/or loco-regionally recurrent TNBC or BRCA-associated HER2-negative breast cancer. Patients could be previously untreated or have received one prior cytotoxic chemotherapy for metastatic disease.
Of the patients enrolled, 321 met eligibility criteria, 294 had germline BRCA testing, and 209 had BRCA-like assessment.
Patients were divided into the following groups: germline BRCA-associated disease (n = 37), BRCA-like disease (n = 99), non-BRCA-like disease (n = 110), and unclassified (n = 75).
In each group, patients were randomized in a 1:1 ratio to receive cisplatin (75 mg/m2on day 1) plus veliparib (300 mg twice daily on days 1-14) every 3 weeks, or cisplatin with placebo. The primary endpoint was PFS.
Results
Among patients with BRCA-like disease, there was a significant improvement in PFS and a trend toward improved OS when veliparib was added to cisplatin. The median PFS was 5.9 months with veliparib and 4.2 months with placebo (P = .006). The median OS was 14.0 months and 12.1 months, respectively (P = .067).
Among patients with previously untreated BRCA-like disease, there were significant improvements in both PFS and OS.
The median PFS in this group was 6.1 months with veliparib and 4.2 months with placebo (P = .008). The 12-month PFS rates were 23% and 3%, respectively.
The median OS in this group was 17.8 months with veliparib and 10.3 months with placebo (P = .048). The 24-month OS rates were 43% and 20%, respectively.
There were no survival benefits with veliparib among patients with unclassified disease, non-BRCA-like disease, or BRCA-associated disease.
Dr. Sharma noted that the lack of significant improvement in the BRCA-associated group was likely due to the small sample size. “FDA approval of PARP inhibitors for treatment of germline BRCA-associated metastatic breast cancer during the course of this trial impacted accrual to this group,” she said.
Veliparib was associated with a higher rate of grade 3-4 hematologic toxicities, including neutropenia (46% vs. 19%), leukopenia (27% vs. 7%), anemia (23% vs. 7%), and thrombocytopenia (19% vs. 3%).
Dr. Sharma said results from this trial should prompt further research. “The combination of veliparib plus cisplatin warrants further evaluation in larger randomized trials for patients with BRCA-like phenotype TNBC,” she said.
Invited discussant Catherine M. Kelly, MB BCh, of Mater Misericordiae University Hospital in Dublin, called the trial “an ambitious study” that has created a “valuable tissue bank” for future translational research. She agreed that more work is necessary.
“Further research is needed to identify the optimal homologous recombination deficiency biomarkers critical in the early treatment-naive and in the advanced treatment-exposed disease settings,” Dr. Kelly said.
SWOG S1416 was funded by the National Institutes of Health and AbbVie. Dr. Sharma disclosed relationships with AstraZeneca, Merck, Novartis, and other companies. Dr. Kelly reported affiliations with Pfizer, Novartis, Roche, and MSD Oncology.
SOURCE: Sharma et al. ASCO 2020, Abstract 1001.
FROM ASCO 2020