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‘Unprecedented’ 3-year sustained survival with lung cancer combo treatment
The durable overall survival (OS) benefit and the well-tolerated safety profile of the durvalumab with EP therapy further establishes the combination as the standard of care for the first-line treatment of ES-SCLC, Luis Paz-Ares, MD, reported at the 2021 European Society for Medical Oncology Congress on Sept. 18 (abstract LBA61).
At 3 years, there is more than three times the survival in patients with durvalumab and EP versus EP, and at the same time, the adverse-event profile continues to be favorable,” said Dr. Paz-Ares of Universidad Complutense & Ciberonc, Madrid.
This is the longest follow-up reported to date for a phase 3 trial of a programmed death–ligand 1 inhibitor and EP in this setting, he said.
The CASPIAN trial included 805 treatment-naive patients with ES-SCLC who were randomized 1:1:1 to receive 1,500 mg of durvalumab with EP every 3 weeks, 1,500 mg of durvalumab at 75 mg of tremelimumab and EP every 3 weeks, or EP alone. Patients in the durvalumab arms received four cycles of treatment followed by maintenance durvalumab, and those in the EP-only arm received up to six cycles of EP.
Primary outcomes data from the trial showed a significant overall survival benefit with durvalumab and EP versus EP alone (hazard ratio, 0.73), as did a subsequent analysis after a median follow-up of 25.1 mo (HR, 0.75).
Durvalumab with tremelimumab and EP numerically improved overall survival versus EP (HR, 0.82), but did not reach statistical significance.
At median follow up of 39.4 months, the durvalumab and EP combination showed sustained improvement in overall survival versus EP alone (HR, 0.71).
Median overall survival was 12.9 versus 10.5 months. OS was 22.9% versus 13.9% at 24 months, and 17.6% versus 5.8% at 36 months with durvalumab with EP versus EP, respectively, Dr. Paz-Ares said.
Durvalumab plus tremelimumab plus EP continued to numerically improve overall survival, compared with EP alone (HR, 0.81); median OS in that arm was 10.4 months, and 15.3% of patients were alive at 36 months, he noted.
Serious adverse events occurred in 32.5%, 47.4%, and 36.5% of patients in the durvalumab with EP, durvalumab plus tremelimumab plus EP, and EP arms respectively, and adverse events leading to death occurred in 5.3%, 10.9%, and 6.0%, respectively.
The findings are “really encouraging and unprecedented, frankly,” said session chair Alfredo Addeo, MD, of University Hospital, Geneva.
“They are setting the bar for competitors,” he said, referencing the IMpower 133 trial looking at atezolizumab with chemotherapy in ES-SCLC.
The CASPIAN study was funded by AstraZeneca. Dr. Paz-Ares reported relationships with multiple pharmaceutical companies.
The durable overall survival (OS) benefit and the well-tolerated safety profile of the durvalumab with EP therapy further establishes the combination as the standard of care for the first-line treatment of ES-SCLC, Luis Paz-Ares, MD, reported at the 2021 European Society for Medical Oncology Congress on Sept. 18 (abstract LBA61).
At 3 years, there is more than three times the survival in patients with durvalumab and EP versus EP, and at the same time, the adverse-event profile continues to be favorable,” said Dr. Paz-Ares of Universidad Complutense & Ciberonc, Madrid.
This is the longest follow-up reported to date for a phase 3 trial of a programmed death–ligand 1 inhibitor and EP in this setting, he said.
The CASPIAN trial included 805 treatment-naive patients with ES-SCLC who were randomized 1:1:1 to receive 1,500 mg of durvalumab with EP every 3 weeks, 1,500 mg of durvalumab at 75 mg of tremelimumab and EP every 3 weeks, or EP alone. Patients in the durvalumab arms received four cycles of treatment followed by maintenance durvalumab, and those in the EP-only arm received up to six cycles of EP.
Primary outcomes data from the trial showed a significant overall survival benefit with durvalumab and EP versus EP alone (hazard ratio, 0.73), as did a subsequent analysis after a median follow-up of 25.1 mo (HR, 0.75).
Durvalumab with tremelimumab and EP numerically improved overall survival versus EP (HR, 0.82), but did not reach statistical significance.
At median follow up of 39.4 months, the durvalumab and EP combination showed sustained improvement in overall survival versus EP alone (HR, 0.71).
Median overall survival was 12.9 versus 10.5 months. OS was 22.9% versus 13.9% at 24 months, and 17.6% versus 5.8% at 36 months with durvalumab with EP versus EP, respectively, Dr. Paz-Ares said.
Durvalumab plus tremelimumab plus EP continued to numerically improve overall survival, compared with EP alone (HR, 0.81); median OS in that arm was 10.4 months, and 15.3% of patients were alive at 36 months, he noted.
Serious adverse events occurred in 32.5%, 47.4%, and 36.5% of patients in the durvalumab with EP, durvalumab plus tremelimumab plus EP, and EP arms respectively, and adverse events leading to death occurred in 5.3%, 10.9%, and 6.0%, respectively.
The findings are “really encouraging and unprecedented, frankly,” said session chair Alfredo Addeo, MD, of University Hospital, Geneva.
“They are setting the bar for competitors,” he said, referencing the IMpower 133 trial looking at atezolizumab with chemotherapy in ES-SCLC.
The CASPIAN study was funded by AstraZeneca. Dr. Paz-Ares reported relationships with multiple pharmaceutical companies.
The durable overall survival (OS) benefit and the well-tolerated safety profile of the durvalumab with EP therapy further establishes the combination as the standard of care for the first-line treatment of ES-SCLC, Luis Paz-Ares, MD, reported at the 2021 European Society for Medical Oncology Congress on Sept. 18 (abstract LBA61).
At 3 years, there is more than three times the survival in patients with durvalumab and EP versus EP, and at the same time, the adverse-event profile continues to be favorable,” said Dr. Paz-Ares of Universidad Complutense & Ciberonc, Madrid.
This is the longest follow-up reported to date for a phase 3 trial of a programmed death–ligand 1 inhibitor and EP in this setting, he said.
The CASPIAN trial included 805 treatment-naive patients with ES-SCLC who were randomized 1:1:1 to receive 1,500 mg of durvalumab with EP every 3 weeks, 1,500 mg of durvalumab at 75 mg of tremelimumab and EP every 3 weeks, or EP alone. Patients in the durvalumab arms received four cycles of treatment followed by maintenance durvalumab, and those in the EP-only arm received up to six cycles of EP.
Primary outcomes data from the trial showed a significant overall survival benefit with durvalumab and EP versus EP alone (hazard ratio, 0.73), as did a subsequent analysis after a median follow-up of 25.1 mo (HR, 0.75).
Durvalumab with tremelimumab and EP numerically improved overall survival versus EP (HR, 0.82), but did not reach statistical significance.
At median follow up of 39.4 months, the durvalumab and EP combination showed sustained improvement in overall survival versus EP alone (HR, 0.71).
Median overall survival was 12.9 versus 10.5 months. OS was 22.9% versus 13.9% at 24 months, and 17.6% versus 5.8% at 36 months with durvalumab with EP versus EP, respectively, Dr. Paz-Ares said.
Durvalumab plus tremelimumab plus EP continued to numerically improve overall survival, compared with EP alone (HR, 0.81); median OS in that arm was 10.4 months, and 15.3% of patients were alive at 36 months, he noted.
Serious adverse events occurred in 32.5%, 47.4%, and 36.5% of patients in the durvalumab with EP, durvalumab plus tremelimumab plus EP, and EP arms respectively, and adverse events leading to death occurred in 5.3%, 10.9%, and 6.0%, respectively.
The findings are “really encouraging and unprecedented, frankly,” said session chair Alfredo Addeo, MD, of University Hospital, Geneva.
“They are setting the bar for competitors,” he said, referencing the IMpower 133 trial looking at atezolizumab with chemotherapy in ES-SCLC.
The CASPIAN study was funded by AstraZeneca. Dr. Paz-Ares reported relationships with multiple pharmaceutical companies.
FROM ESMO 2021
Novel trastuzumab duocarmazine significantly improved survival in advanced HER2-positive breast cancer
Based on significant progression-free survival (PFS) benefits shown in the phase 3 TULIP trial, trastuzumab duocarmazine (SYD985) may provide a new treatment option among HER2-positive metastatic breast cancer patients, according to Cristina Saura, MD, head of the breast cancer program at Vall d’Hebron University Hospital, Barcelona. Dr. Saura presented the results of the TULIP trial (abstract LBA15) on Sept. 19 at the 2021 European Society for Medical Oncology Congress.
Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate that consists of trastuzumab and a drug containing duocarmycin. Its three-way mechanism of action includes uptake of the antibody-drug conjugate by internalization and intracellular release of duocarmycin with two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.
While one physician described the results as encouraging, another said the treatment is not nearly ready for primetime.
“It is encouraging to observe clinically meaningful and potentially practice changing progression-free survival improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, Massachusetts General Hospital, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years including T-DXd, neratinib, tucatinib, and margetuximab. Trastuzumab duocarmazine could eventually be another option.”
Fatima Cardoso, MD, director of the breast cancer unit at the Breast Cancer Research Foundation, New York, said: “At this time there is only a minor 2-month difference in progression-free survival and a nonsignificant overall difference. With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
Two or more prior therapies for metastatic breast cancer
TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to trastuzumab duocarmazine (1.2 mg/kg every 21 days, 291 patients) or physician’s choice (146 patients) of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.
Longer PFS with trastuzumab duocarmazine
Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed PFS was significantly longer in the trastuzumab duocarmazine group at 7.0 months versus 4.9 months for physicians choice treatment (hazard ratio, 0.64; 95% confidence interval, 0.49-0.84; P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for trastuzumab duocarmazine over physician’s choice across all categories (except for Eastern Cooperative Oncology Group status 2). Analysis of PFS by investigators showed a similar benefit for trastuzumab duocarmazine (6.9 months vs. 4.6 months; HR, 0.60; P < .001).
A first look at median overall survival showed a nonsignificant advantage for trastuzumab duocarmazine (20.4 months vs. 16.3 months (HR, 0.83; 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for trastuzumab duocarmazine and 29.5% for physician’s choice with reductions in target lesion measurement at 70.2% and 32.2% for trastuzumab duocarmazine and physician’s choice, respectively. The clinical benefit rates were 38.5% for trastuzumab duocarmazine and 32.2% for physician’s choice.
Ocular toxicity
Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for trastuzumab duocarmazine were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%) and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with trastuzumab duocarmazine, including two grade 5 events.
Eye toxicity led to discontinuations in 20.8% of trastuzumab duocarmazine patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of trastuzumab duocarmazine patients. Six fatalities (2.1%) were reported in the trastuzumab duocarmazine group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.
Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.
TULIP was funded by Byondis. Dr. Saura disclosed numerous financial interests including support from AstraZeneca and Daiichi Sankyo.
Based on significant progression-free survival (PFS) benefits shown in the phase 3 TULIP trial, trastuzumab duocarmazine (SYD985) may provide a new treatment option among HER2-positive metastatic breast cancer patients, according to Cristina Saura, MD, head of the breast cancer program at Vall d’Hebron University Hospital, Barcelona. Dr. Saura presented the results of the TULIP trial (abstract LBA15) on Sept. 19 at the 2021 European Society for Medical Oncology Congress.
Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate that consists of trastuzumab and a drug containing duocarmycin. Its three-way mechanism of action includes uptake of the antibody-drug conjugate by internalization and intracellular release of duocarmycin with two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.
While one physician described the results as encouraging, another said the treatment is not nearly ready for primetime.
“It is encouraging to observe clinically meaningful and potentially practice changing progression-free survival improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, Massachusetts General Hospital, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years including T-DXd, neratinib, tucatinib, and margetuximab. Trastuzumab duocarmazine could eventually be another option.”
Fatima Cardoso, MD, director of the breast cancer unit at the Breast Cancer Research Foundation, New York, said: “At this time there is only a minor 2-month difference in progression-free survival and a nonsignificant overall difference. With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
Two or more prior therapies for metastatic breast cancer
TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to trastuzumab duocarmazine (1.2 mg/kg every 21 days, 291 patients) or physician’s choice (146 patients) of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.
Longer PFS with trastuzumab duocarmazine
Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed PFS was significantly longer in the trastuzumab duocarmazine group at 7.0 months versus 4.9 months for physicians choice treatment (hazard ratio, 0.64; 95% confidence interval, 0.49-0.84; P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for trastuzumab duocarmazine over physician’s choice across all categories (except for Eastern Cooperative Oncology Group status 2). Analysis of PFS by investigators showed a similar benefit for trastuzumab duocarmazine (6.9 months vs. 4.6 months; HR, 0.60; P < .001).
A first look at median overall survival showed a nonsignificant advantage for trastuzumab duocarmazine (20.4 months vs. 16.3 months (HR, 0.83; 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for trastuzumab duocarmazine and 29.5% for physician’s choice with reductions in target lesion measurement at 70.2% and 32.2% for trastuzumab duocarmazine and physician’s choice, respectively. The clinical benefit rates were 38.5% for trastuzumab duocarmazine and 32.2% for physician’s choice.
Ocular toxicity
Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for trastuzumab duocarmazine were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%) and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with trastuzumab duocarmazine, including two grade 5 events.
Eye toxicity led to discontinuations in 20.8% of trastuzumab duocarmazine patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of trastuzumab duocarmazine patients. Six fatalities (2.1%) were reported in the trastuzumab duocarmazine group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.
Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.
TULIP was funded by Byondis. Dr. Saura disclosed numerous financial interests including support from AstraZeneca and Daiichi Sankyo.
Based on significant progression-free survival (PFS) benefits shown in the phase 3 TULIP trial, trastuzumab duocarmazine (SYD985) may provide a new treatment option among HER2-positive metastatic breast cancer patients, according to Cristina Saura, MD, head of the breast cancer program at Vall d’Hebron University Hospital, Barcelona. Dr. Saura presented the results of the TULIP trial (abstract LBA15) on Sept. 19 at the 2021 European Society for Medical Oncology Congress.
Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate that consists of trastuzumab and a drug containing duocarmycin. Its three-way mechanism of action includes uptake of the antibody-drug conjugate by internalization and intracellular release of duocarmycin with two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.
While one physician described the results as encouraging, another said the treatment is not nearly ready for primetime.
“It is encouraging to observe clinically meaningful and potentially practice changing progression-free survival improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, Massachusetts General Hospital, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years including T-DXd, neratinib, tucatinib, and margetuximab. Trastuzumab duocarmazine could eventually be another option.”
Fatima Cardoso, MD, director of the breast cancer unit at the Breast Cancer Research Foundation, New York, said: “At this time there is only a minor 2-month difference in progression-free survival and a nonsignificant overall difference. With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
Two or more prior therapies for metastatic breast cancer
TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to trastuzumab duocarmazine (1.2 mg/kg every 21 days, 291 patients) or physician’s choice (146 patients) of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.
Longer PFS with trastuzumab duocarmazine
Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed PFS was significantly longer in the trastuzumab duocarmazine group at 7.0 months versus 4.9 months for physicians choice treatment (hazard ratio, 0.64; 95% confidence interval, 0.49-0.84; P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for trastuzumab duocarmazine over physician’s choice across all categories (except for Eastern Cooperative Oncology Group status 2). Analysis of PFS by investigators showed a similar benefit for trastuzumab duocarmazine (6.9 months vs. 4.6 months; HR, 0.60; P < .001).
A first look at median overall survival showed a nonsignificant advantage for trastuzumab duocarmazine (20.4 months vs. 16.3 months (HR, 0.83; 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for trastuzumab duocarmazine and 29.5% for physician’s choice with reductions in target lesion measurement at 70.2% and 32.2% for trastuzumab duocarmazine and physician’s choice, respectively. The clinical benefit rates were 38.5% for trastuzumab duocarmazine and 32.2% for physician’s choice.
Ocular toxicity
Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for trastuzumab duocarmazine were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%) and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with trastuzumab duocarmazine, including two grade 5 events.
Eye toxicity led to discontinuations in 20.8% of trastuzumab duocarmazine patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of trastuzumab duocarmazine patients. Six fatalities (2.1%) were reported in the trastuzumab duocarmazine group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.
Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.
TULIP was funded by Byondis. Dr. Saura disclosed numerous financial interests including support from AstraZeneca and Daiichi Sankyo.
FROM ESMO 2021
Treatment shows 'important improvements' in triple-negative breast cancer
But as a subanalysis of data from the randomized, phase 3 study showed, sacituzumab govitecan was associated with significantly better progression-free survival (PFS) and overall survival among patients without an initial TNBC diagnosis, with efficacy similar to that seen in the overall study population and in patients without known brain metastases, reported Joyce O’Shaughnessy, MD, at the 2021 European Society for Medical Oncology Congress. In her presentation (abstract 258P), Dr. O’Shaughnessy, who is an oncologist with the Texas Oncology–Baylor Charles A. Sammons Cancer Center in Dallas, said that it’s not uncommon to see acquired triple-negative breast cancer in patients who have hormone receptor–positive disease initially and then later on, develop triple-negative breast cancer.
“That is why at the time of metastatic diagnosis we always say that patients should have repeat receptor [testing], because it’s been well described that a subset of hormone receptor–positive breast can become triple negative under pressure from endocrine therapy,” said ASCENT coinvestigator Aditya Bardia, MD, MPH, Massachusetts General Hospital, Boston, in an interview
Coinvestigator Kevine Punie, MD, from University Hospitals Leuven (Belgium), said that “triple-negative breast cancer is a diagnosis of exclusion. This is a heterogenous disease where several biological subsets are merged.”
“It was important to perform this subgroup analysis to reassure us that the treatment effect we see from [sacituzumab govitecan] in the overall population is also observed in this specific subgroup of patients where biologically we’re treating a different disease,” he said in an interview.
Antibody-drug conjugate
Sacituzumab govitecan consists of an antibody targeted to the trophoblast antigen 2 cell surface receptor found on most breast cancer cells, plus the topoisomerase-1 inhibitor SN-38 as its toxic payload.
In the primary intent-to-treat (ITT) analysis of ASCENT, sacituzumab significantly prolonged PFS with a median of 4.8 versus 1.7 months for patients treated with the physician’s choice of either capecitabine, eribulin, vinorelbine, or gemcitabine. The difference translated into an HR for progression with the antibody-drug conjugate of 0.41 (P < .00001).
The subgroup analysis looked at outcomes for 70 patients randomized to sacituzumab govitecan and 78 randomized to single-agent chemotherapy who did not have an initial diagnosis of TNBC.
In all, 27% of patients in this subgroup in the sacituzumab arm and 29% in the chemotherapy arm had received a prior line of treatment with a CDK4/6 inhibitor.
At the time of data cutoff in March 2020, four patients (6%) in the sacituzumab arm remained on treatment versus no patient in the chemotherapy arm. The most common reason for treatment discontinuation was disease progression, which occurred in 84% and 72% of patients, respectively.
The median treatment duration was 5.1 months in the sacituzumab and 1.2 months in the chemotherapy arm. The median duration of follow-up was 10.6 and 6.1 months, respectively.
Progression-free survival, overall survival results
For all patients without an initial TNBC diagnosis, the median PFS was 4.6 months with sacituzumab versus 2.3 months with chemotherapy, which translated into a hazard ratio for progression of 0.48 (95% confidence interval, 0.32-0.72). The progression-free benefit with the antibody-drug conjugate was similar to that seen in the intent-to-treat population, as noted before, and among the overall population of patients in the study with no known brain metastases (HR, 5.6 vs. 1.7, respectively; P < .001).
The objective response rates were 21% in the sacituzumab and 5% in the chemotherapy arm. Objective responses were not affected by the prior use of CDK 4/6 inhibitors.
Median overall survival in this subgroup was 12.4 months with the antibody-drug conjugate versus 6.7 months with chemotherapy (95% CI, 0.30-0.64).
The investigators reported that the safety profile was manageable in this subgroup of patients, with a low rate of treatment discontinuations because of adverse events (5%) and no treatment-related deaths with sacituzumab govitecan.
Health-related quality of life
In a separate poster (abstract 257P) presented at the meeting, the ASCENT investigators reported health-related quality of life results in the overall population.
The mean European Organization for the Research and Treatment of Cancer quality of life questionnaire subscale scores at baseline were similar between treatment arms.
For the major domains of global health status, physical and emotional functioning as well as lower symptomatic impact of fatigue, pain, dyspnea, and insomnia, sacituzumab govitecan showed “significantly and meaningfully greater improvement” than the physician’s choice of chemotherapy, the investigators found.
Of individual symptoms, only diarrhea was worse with the antibody-drug conjugate.
“These were important improvements,” Dr. Punie said, “because we saw improvements in the primary health-related quality of life domains such as global health status. We also saw that the time to clinically meaningful deterioration of quality of life domains were significantly longer for patients treated with [sacituzumab govitecan].”
“Patients who received sacituzumab govitecan had better health-related quality of life as compared to the control arm, and that’s a very important result, because in the metastatic setting our goal is twofold: We want to prolong survival, and we want patients to have improved quality of life,” Dr. Bardia said.
The Ascent trial is sponsored by Gilead Sciences. Dr. Punie disclosed relationships with multiple companies/organizations, not including Gilead. Dr. Bardia disclosed contracted research for Gilead and others, as well as other relationships.
But as a subanalysis of data from the randomized, phase 3 study showed, sacituzumab govitecan was associated with significantly better progression-free survival (PFS) and overall survival among patients without an initial TNBC diagnosis, with efficacy similar to that seen in the overall study population and in patients without known brain metastases, reported Joyce O’Shaughnessy, MD, at the 2021 European Society for Medical Oncology Congress. In her presentation (abstract 258P), Dr. O’Shaughnessy, who is an oncologist with the Texas Oncology–Baylor Charles A. Sammons Cancer Center in Dallas, said that it’s not uncommon to see acquired triple-negative breast cancer in patients who have hormone receptor–positive disease initially and then later on, develop triple-negative breast cancer.
“That is why at the time of metastatic diagnosis we always say that patients should have repeat receptor [testing], because it’s been well described that a subset of hormone receptor–positive breast can become triple negative under pressure from endocrine therapy,” said ASCENT coinvestigator Aditya Bardia, MD, MPH, Massachusetts General Hospital, Boston, in an interview
Coinvestigator Kevine Punie, MD, from University Hospitals Leuven (Belgium), said that “triple-negative breast cancer is a diagnosis of exclusion. This is a heterogenous disease where several biological subsets are merged.”
“It was important to perform this subgroup analysis to reassure us that the treatment effect we see from [sacituzumab govitecan] in the overall population is also observed in this specific subgroup of patients where biologically we’re treating a different disease,” he said in an interview.
Antibody-drug conjugate
Sacituzumab govitecan consists of an antibody targeted to the trophoblast antigen 2 cell surface receptor found on most breast cancer cells, plus the topoisomerase-1 inhibitor SN-38 as its toxic payload.
In the primary intent-to-treat (ITT) analysis of ASCENT, sacituzumab significantly prolonged PFS with a median of 4.8 versus 1.7 months for patients treated with the physician’s choice of either capecitabine, eribulin, vinorelbine, or gemcitabine. The difference translated into an HR for progression with the antibody-drug conjugate of 0.41 (P < .00001).
The subgroup analysis looked at outcomes for 70 patients randomized to sacituzumab govitecan and 78 randomized to single-agent chemotherapy who did not have an initial diagnosis of TNBC.
In all, 27% of patients in this subgroup in the sacituzumab arm and 29% in the chemotherapy arm had received a prior line of treatment with a CDK4/6 inhibitor.
At the time of data cutoff in March 2020, four patients (6%) in the sacituzumab arm remained on treatment versus no patient in the chemotherapy arm. The most common reason for treatment discontinuation was disease progression, which occurred in 84% and 72% of patients, respectively.
The median treatment duration was 5.1 months in the sacituzumab and 1.2 months in the chemotherapy arm. The median duration of follow-up was 10.6 and 6.1 months, respectively.
Progression-free survival, overall survival results
For all patients without an initial TNBC diagnosis, the median PFS was 4.6 months with sacituzumab versus 2.3 months with chemotherapy, which translated into a hazard ratio for progression of 0.48 (95% confidence interval, 0.32-0.72). The progression-free benefit with the antibody-drug conjugate was similar to that seen in the intent-to-treat population, as noted before, and among the overall population of patients in the study with no known brain metastases (HR, 5.6 vs. 1.7, respectively; P < .001).
The objective response rates were 21% in the sacituzumab and 5% in the chemotherapy arm. Objective responses were not affected by the prior use of CDK 4/6 inhibitors.
Median overall survival in this subgroup was 12.4 months with the antibody-drug conjugate versus 6.7 months with chemotherapy (95% CI, 0.30-0.64).
The investigators reported that the safety profile was manageable in this subgroup of patients, with a low rate of treatment discontinuations because of adverse events (5%) and no treatment-related deaths with sacituzumab govitecan.
Health-related quality of life
In a separate poster (abstract 257P) presented at the meeting, the ASCENT investigators reported health-related quality of life results in the overall population.
The mean European Organization for the Research and Treatment of Cancer quality of life questionnaire subscale scores at baseline were similar between treatment arms.
For the major domains of global health status, physical and emotional functioning as well as lower symptomatic impact of fatigue, pain, dyspnea, and insomnia, sacituzumab govitecan showed “significantly and meaningfully greater improvement” than the physician’s choice of chemotherapy, the investigators found.
Of individual symptoms, only diarrhea was worse with the antibody-drug conjugate.
“These were important improvements,” Dr. Punie said, “because we saw improvements in the primary health-related quality of life domains such as global health status. We also saw that the time to clinically meaningful deterioration of quality of life domains were significantly longer for patients treated with [sacituzumab govitecan].”
“Patients who received sacituzumab govitecan had better health-related quality of life as compared to the control arm, and that’s a very important result, because in the metastatic setting our goal is twofold: We want to prolong survival, and we want patients to have improved quality of life,” Dr. Bardia said.
The Ascent trial is sponsored by Gilead Sciences. Dr. Punie disclosed relationships with multiple companies/organizations, not including Gilead. Dr. Bardia disclosed contracted research for Gilead and others, as well as other relationships.
But as a subanalysis of data from the randomized, phase 3 study showed, sacituzumab govitecan was associated with significantly better progression-free survival (PFS) and overall survival among patients without an initial TNBC diagnosis, with efficacy similar to that seen in the overall study population and in patients without known brain metastases, reported Joyce O’Shaughnessy, MD, at the 2021 European Society for Medical Oncology Congress. In her presentation (abstract 258P), Dr. O’Shaughnessy, who is an oncologist with the Texas Oncology–Baylor Charles A. Sammons Cancer Center in Dallas, said that it’s not uncommon to see acquired triple-negative breast cancer in patients who have hormone receptor–positive disease initially and then later on, develop triple-negative breast cancer.
“That is why at the time of metastatic diagnosis we always say that patients should have repeat receptor [testing], because it’s been well described that a subset of hormone receptor–positive breast can become triple negative under pressure from endocrine therapy,” said ASCENT coinvestigator Aditya Bardia, MD, MPH, Massachusetts General Hospital, Boston, in an interview
Coinvestigator Kevine Punie, MD, from University Hospitals Leuven (Belgium), said that “triple-negative breast cancer is a diagnosis of exclusion. This is a heterogenous disease where several biological subsets are merged.”
“It was important to perform this subgroup analysis to reassure us that the treatment effect we see from [sacituzumab govitecan] in the overall population is also observed in this specific subgroup of patients where biologically we’re treating a different disease,” he said in an interview.
Antibody-drug conjugate
Sacituzumab govitecan consists of an antibody targeted to the trophoblast antigen 2 cell surface receptor found on most breast cancer cells, plus the topoisomerase-1 inhibitor SN-38 as its toxic payload.
In the primary intent-to-treat (ITT) analysis of ASCENT, sacituzumab significantly prolonged PFS with a median of 4.8 versus 1.7 months for patients treated with the physician’s choice of either capecitabine, eribulin, vinorelbine, or gemcitabine. The difference translated into an HR for progression with the antibody-drug conjugate of 0.41 (P < .00001).
The subgroup analysis looked at outcomes for 70 patients randomized to sacituzumab govitecan and 78 randomized to single-agent chemotherapy who did not have an initial diagnosis of TNBC.
In all, 27% of patients in this subgroup in the sacituzumab arm and 29% in the chemotherapy arm had received a prior line of treatment with a CDK4/6 inhibitor.
At the time of data cutoff in March 2020, four patients (6%) in the sacituzumab arm remained on treatment versus no patient in the chemotherapy arm. The most common reason for treatment discontinuation was disease progression, which occurred in 84% and 72% of patients, respectively.
The median treatment duration was 5.1 months in the sacituzumab and 1.2 months in the chemotherapy arm. The median duration of follow-up was 10.6 and 6.1 months, respectively.
Progression-free survival, overall survival results
For all patients without an initial TNBC diagnosis, the median PFS was 4.6 months with sacituzumab versus 2.3 months with chemotherapy, which translated into a hazard ratio for progression of 0.48 (95% confidence interval, 0.32-0.72). The progression-free benefit with the antibody-drug conjugate was similar to that seen in the intent-to-treat population, as noted before, and among the overall population of patients in the study with no known brain metastases (HR, 5.6 vs. 1.7, respectively; P < .001).
The objective response rates were 21% in the sacituzumab and 5% in the chemotherapy arm. Objective responses were not affected by the prior use of CDK 4/6 inhibitors.
Median overall survival in this subgroup was 12.4 months with the antibody-drug conjugate versus 6.7 months with chemotherapy (95% CI, 0.30-0.64).
The investigators reported that the safety profile was manageable in this subgroup of patients, with a low rate of treatment discontinuations because of adverse events (5%) and no treatment-related deaths with sacituzumab govitecan.
Health-related quality of life
In a separate poster (abstract 257P) presented at the meeting, the ASCENT investigators reported health-related quality of life results in the overall population.
The mean European Organization for the Research and Treatment of Cancer quality of life questionnaire subscale scores at baseline were similar between treatment arms.
For the major domains of global health status, physical and emotional functioning as well as lower symptomatic impact of fatigue, pain, dyspnea, and insomnia, sacituzumab govitecan showed “significantly and meaningfully greater improvement” than the physician’s choice of chemotherapy, the investigators found.
Of individual symptoms, only diarrhea was worse with the antibody-drug conjugate.
“These were important improvements,” Dr. Punie said, “because we saw improvements in the primary health-related quality of life domains such as global health status. We also saw that the time to clinically meaningful deterioration of quality of life domains were significantly longer for patients treated with [sacituzumab govitecan].”
“Patients who received sacituzumab govitecan had better health-related quality of life as compared to the control arm, and that’s a very important result, because in the metastatic setting our goal is twofold: We want to prolong survival, and we want patients to have improved quality of life,” Dr. Bardia said.
The Ascent trial is sponsored by Gilead Sciences. Dr. Punie disclosed relationships with multiple companies/organizations, not including Gilead. Dr. Bardia disclosed contracted research for Gilead and others, as well as other relationships.
FROM ESMO 2021
Response to preop immunotherapy predicts survival in early NSCLC
Although major pathological response after neoadjuvant cisplatin-based chemotherapy has been shown to predict survival in patients with early-stage NSCLC, this is the first time a similar association has been demonstrated with neoadjuvant immune checkpoint inhibition, Marie Wislez, MD, PhD, a researcher at Hopital Cochin, Paris, reported at the 2021 European Society of Medical Oncology Congress.
Primary outcomes of the multicenter trial showed 12- and 18-month OS of 89.1%, and 12- and 18-month DFS of 78.3% and 73.7%, respectively, in 46 patients treated with preoperative durvalumab. Median OS and DFS were not reached.
Major pathological response was observed in eight patients (18.6%), with three patients experiencing complete pathological response. No deaths or recurrences were observed in patients in this group. A significant association was observed between major pathological response and DFS. However, the study was stopped early because of excessive 90-day postoperative mortality, which the authors said were most likely related to comorbidities.
The current post hoc analysis of data from the study showed poorer overall survival and disease-free survival with increasing percentage of residual viable tumor (RVT) cells on multivariate prognostic analysis (hazard ratio, 1.05 and 1.06; P = .04 and .02, respectively), Dr. Wislez said in her presentation made on Sept. 18 (abstract 1151MO).
“For each 10% increase of RVT, you have an increased risk of death of 64% and increased risk of recurrence of 71%,” she said.
Study subjects, who were enrolled between April 2017 and August 2019, had a median age of 61 years, 67.4% were men, 98% were smokers or former smokes, and all had Eastern Cooperative Oncology Group performance status scores of 0-1. The median percentage of RVT cells was 36.11.
Of the 50 patients enrolled, 46 were eligible for and received durvalumab and 43 underwent surgery. Those with stages IB and 4 cm or greater tumor size to stage IIIA non-N2 NSCLC received three cycles of durvalumab before surgery. Durvalumab was given intravenously at a dose of 750 mg on days 1, 15, and 29, and surgery was performed 2-14 days after the last infusion.
Tissue specimens from patients who underwent neoadjuvant durvalumab and complete surgical resection were retrospectively evaluated by two pathologists blinded to patient outcomes, Dr. Wislez noted.
Session chair Michael Thomas, MD, of Thoraxklinik-Heidelberg at Heidelberg (Germany) University Hospital, described the study as “hypotheses generating,” and noted that it suggests incremental step-wise assessment of pathological response could be an additional tool for subgrouping of patients in upcoming trials.
Indeed, this novel finding suggests that the extent of pathological response could be considered as a surrogate marker for neoadjuvant treatment trials, although the use of a continuous variable would be challenging in the trial setting, Dr. Wislez agreed.
“But it’s a demonstration that [with] immunotherapy monotherapy ... the extent of pathological response is associated with overall survival,” she said.
This study was funded by AstraZeneca. Dr. Wislez reported honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche, Novartis, Merck, and MSD.
Although major pathological response after neoadjuvant cisplatin-based chemotherapy has been shown to predict survival in patients with early-stage NSCLC, this is the first time a similar association has been demonstrated with neoadjuvant immune checkpoint inhibition, Marie Wislez, MD, PhD, a researcher at Hopital Cochin, Paris, reported at the 2021 European Society of Medical Oncology Congress.
Primary outcomes of the multicenter trial showed 12- and 18-month OS of 89.1%, and 12- and 18-month DFS of 78.3% and 73.7%, respectively, in 46 patients treated with preoperative durvalumab. Median OS and DFS were not reached.
Major pathological response was observed in eight patients (18.6%), with three patients experiencing complete pathological response. No deaths or recurrences were observed in patients in this group. A significant association was observed between major pathological response and DFS. However, the study was stopped early because of excessive 90-day postoperative mortality, which the authors said were most likely related to comorbidities.
The current post hoc analysis of data from the study showed poorer overall survival and disease-free survival with increasing percentage of residual viable tumor (RVT) cells on multivariate prognostic analysis (hazard ratio, 1.05 and 1.06; P = .04 and .02, respectively), Dr. Wislez said in her presentation made on Sept. 18 (abstract 1151MO).
“For each 10% increase of RVT, you have an increased risk of death of 64% and increased risk of recurrence of 71%,” she said.
Study subjects, who were enrolled between April 2017 and August 2019, had a median age of 61 years, 67.4% were men, 98% were smokers or former smokes, and all had Eastern Cooperative Oncology Group performance status scores of 0-1. The median percentage of RVT cells was 36.11.
Of the 50 patients enrolled, 46 were eligible for and received durvalumab and 43 underwent surgery. Those with stages IB and 4 cm or greater tumor size to stage IIIA non-N2 NSCLC received three cycles of durvalumab before surgery. Durvalumab was given intravenously at a dose of 750 mg on days 1, 15, and 29, and surgery was performed 2-14 days after the last infusion.
Tissue specimens from patients who underwent neoadjuvant durvalumab and complete surgical resection were retrospectively evaluated by two pathologists blinded to patient outcomes, Dr. Wislez noted.
Session chair Michael Thomas, MD, of Thoraxklinik-Heidelberg at Heidelberg (Germany) University Hospital, described the study as “hypotheses generating,” and noted that it suggests incremental step-wise assessment of pathological response could be an additional tool for subgrouping of patients in upcoming trials.
Indeed, this novel finding suggests that the extent of pathological response could be considered as a surrogate marker for neoadjuvant treatment trials, although the use of a continuous variable would be challenging in the trial setting, Dr. Wislez agreed.
“But it’s a demonstration that [with] immunotherapy monotherapy ... the extent of pathological response is associated with overall survival,” she said.
This study was funded by AstraZeneca. Dr. Wislez reported honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche, Novartis, Merck, and MSD.
Although major pathological response after neoadjuvant cisplatin-based chemotherapy has been shown to predict survival in patients with early-stage NSCLC, this is the first time a similar association has been demonstrated with neoadjuvant immune checkpoint inhibition, Marie Wislez, MD, PhD, a researcher at Hopital Cochin, Paris, reported at the 2021 European Society of Medical Oncology Congress.
Primary outcomes of the multicenter trial showed 12- and 18-month OS of 89.1%, and 12- and 18-month DFS of 78.3% and 73.7%, respectively, in 46 patients treated with preoperative durvalumab. Median OS and DFS were not reached.
Major pathological response was observed in eight patients (18.6%), with three patients experiencing complete pathological response. No deaths or recurrences were observed in patients in this group. A significant association was observed between major pathological response and DFS. However, the study was stopped early because of excessive 90-day postoperative mortality, which the authors said were most likely related to comorbidities.
The current post hoc analysis of data from the study showed poorer overall survival and disease-free survival with increasing percentage of residual viable tumor (RVT) cells on multivariate prognostic analysis (hazard ratio, 1.05 and 1.06; P = .04 and .02, respectively), Dr. Wislez said in her presentation made on Sept. 18 (abstract 1151MO).
“For each 10% increase of RVT, you have an increased risk of death of 64% and increased risk of recurrence of 71%,” she said.
Study subjects, who were enrolled between April 2017 and August 2019, had a median age of 61 years, 67.4% were men, 98% were smokers or former smokes, and all had Eastern Cooperative Oncology Group performance status scores of 0-1. The median percentage of RVT cells was 36.11.
Of the 50 patients enrolled, 46 were eligible for and received durvalumab and 43 underwent surgery. Those with stages IB and 4 cm or greater tumor size to stage IIIA non-N2 NSCLC received three cycles of durvalumab before surgery. Durvalumab was given intravenously at a dose of 750 mg on days 1, 15, and 29, and surgery was performed 2-14 days after the last infusion.
Tissue specimens from patients who underwent neoadjuvant durvalumab and complete surgical resection were retrospectively evaluated by two pathologists blinded to patient outcomes, Dr. Wislez noted.
Session chair Michael Thomas, MD, of Thoraxklinik-Heidelberg at Heidelberg (Germany) University Hospital, described the study as “hypotheses generating,” and noted that it suggests incremental step-wise assessment of pathological response could be an additional tool for subgrouping of patients in upcoming trials.
Indeed, this novel finding suggests that the extent of pathological response could be considered as a surrogate marker for neoadjuvant treatment trials, although the use of a continuous variable would be challenging in the trial setting, Dr. Wislez agreed.
“But it’s a demonstration that [with] immunotherapy monotherapy ... the extent of pathological response is associated with overall survival,” she said.
This study was funded by AstraZeneca. Dr. Wislez reported honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche, Novartis, Merck, and MSD.
FROM ESMO 2021
Studies confirm survival benefit with postchemoradiotherapy consolidation in NSCLC
Checkpoint inhibition for consolidation after chemoradiotherapy (CRT) showed promising survival benefit in patients with unresectable stage III non–small cell lung cancer (NSCLC) in two recent studies, including one looking at the investigational agent sugemalimab and one assessing durvalumab in a real-world setting.
Statistically significant and clinically meaningful improvement in progression-free survival (PFS) was observed with sugemalimab versus placebo in the randomized, phase 3 GEMSTONE-301 study, and consolidation durvalumab showed effectiveness in a real-world cohort in the PACIFIC-R study.
Findings from both studies were presented at the 2021 European Society for Medical Oncology Congress.
GEMSTONE-301
Median progression-free survival among 381 patients randomized 2:1 to receive 1,200 mg of sugemalimab or placebo every 3 weeks after either concurrent or sequential chemoradiotherapy was 9.0 versus 5.8 months, in the treatment arms, respectively (hazard ratio, 0.64) (Abstract LBA43), reported Yi-Long Wu, MD, of Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Guangzhou, China.
Patients were recruited from 50 sites, and one-third had received sequential CRT. Progression-free survival was assessed at median follow up of 14 months.
“The 12- and 18-month PFS rates were 45% vs. 26% and 39% vs. 23%, respectively,” Dr. Wu said.
Of note, the PFS benefit was observed both for patients who underwent sequential CRT (median PFS, 8.1 vs. 4.1 months with sugemalimab vs. placebo; hazard ratio, 0.59) and for those who received concurrent CRT (median PFS, 10.5 vs. 6.4 months; HR, 0.66).
Overall survival (OS) data were not mature at the time of the presentation, but a trend favoring sugemalimab was observed (HR, 0.44) he noted.
Sugemalimab, an investigational anti–programmed death-ligand 1 (PD-L1 )monoclonal antibody, was well tolerated; grade 3 or higher treatment-emergent adverse events (AEs) occurred in 24.3% of patients in the sugemalimab group and in 23.8% in the placebo group.
Concurrent chemoradiotherapy followed by immunotherapy is the standard of care for patients with unresectable stage III NSCLC, but nearly half undergo sequential CRT because they can’t tolerate concurrent treatment, Dr. Wu explained, describing the rationale for the study – the first phase 3 trial looking at both concurrent and sequential CRT in this patient population.
The results provide evidence for sugemalimab as a consolidation treatment for those who did not progress following either approach to CRT, he concluded.
PACIFIC-R study
The large, international, observational PACIFIC-R study also looked at consolidation in a real-world setting, and confirmed a PFS benefit with durvalumab in stage III NSCLC patients who had completed concurrent or sequential platinum-based CRT within the previous 12 weeks without evidence of disease progression (Abstract 1171MO).
“The median real-world PFS in this cohort was 21.7 months, which is higher than that in the durvalumab arm in the PACIFIC trial, which was 16.9 months,” reported Nicolas Girard, MD, a professor at Institut Curie, Paris.
The PACIFIC trial set the standard for durvalumab-based consolidation after CRT, and ongoing survival benefit was confirmed by 5-year follow-up data, he noted.
The PACIFIC-R trial included 1,399 patients from 11 countries who were treated as part of an expanded-access program following the PACIFIC trial.
Median time to durvalumab initiation after the end of radiotherapy in the cohort was 56 days. Overall median durvalumab treatment duration was 11 months, and the median number of infusions was 22, Dr. Girard said.
Pneumonitis was the most common adverse event leading to discontinuation: 214 (18.5%) patients experienced any-grade pneumonitis and/or interstitial lung disease, and 9.5 discontinued the study as a result. Most cases were mild or moderate, he said.
Subgroup analyses showed that real-world PFS was higher among patients with stage IIIa disease and those with PD-L1–positive tumors, those with nonsquamous disease histology, and those who received concurrent CRT.
“For example, in those with stage IIIa disease, the median real-world PFS was 23.7 months versus 19.2 months in patients with stage IIIb and c disease,” he said.
“PACIFIC-R demonstrated the efficacy of durvalumab consolidation in patients with unresectable stage III non–small cell lung cancer after completion of chemoradiotherapy,” said Dr. Girard. “The effectiveness of durvalumab was consistent among key subgroups, as was safety, when comparing the data with that of PACIFIC.
“The future read-outs of OS will further provide insight into the effectiveness of this regimen.”
Session chair Lizza E. Hendriks, MD, PhD, of Maastricht (the Netherlands) University, applauded the inclusion of patients undergoing sequential CRT in the GEMSTONE-301 and PACIFIC-R studies, noting that it is “very important to have data in sequential radiochemotherapy populations” given the substantial number of patients who require a sequential approach because of poor performance status, difficulty tolerating concurrent CRT, or logistical reasons, such as an inability to travel to receive concurrent CRT.
The GEMSTONE-301 study was funded by CStone Pharmaceuticals. Dr. Wu reported having no disclosures. The PACIFIC-R study was funded by AstraZeneca. Dr. Girard reported financial relationships with AstraZeneca, Bristol Myers Squibb, and Merck Sharp & Dohme. Dr. Hendriks reported financial relationships with numerous companies.
Checkpoint inhibition for consolidation after chemoradiotherapy (CRT) showed promising survival benefit in patients with unresectable stage III non–small cell lung cancer (NSCLC) in two recent studies, including one looking at the investigational agent sugemalimab and one assessing durvalumab in a real-world setting.
Statistically significant and clinically meaningful improvement in progression-free survival (PFS) was observed with sugemalimab versus placebo in the randomized, phase 3 GEMSTONE-301 study, and consolidation durvalumab showed effectiveness in a real-world cohort in the PACIFIC-R study.
Findings from both studies were presented at the 2021 European Society for Medical Oncology Congress.
GEMSTONE-301
Median progression-free survival among 381 patients randomized 2:1 to receive 1,200 mg of sugemalimab or placebo every 3 weeks after either concurrent or sequential chemoradiotherapy was 9.0 versus 5.8 months, in the treatment arms, respectively (hazard ratio, 0.64) (Abstract LBA43), reported Yi-Long Wu, MD, of Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Guangzhou, China.
Patients were recruited from 50 sites, and one-third had received sequential CRT. Progression-free survival was assessed at median follow up of 14 months.
“The 12- and 18-month PFS rates were 45% vs. 26% and 39% vs. 23%, respectively,” Dr. Wu said.
Of note, the PFS benefit was observed both for patients who underwent sequential CRT (median PFS, 8.1 vs. 4.1 months with sugemalimab vs. placebo; hazard ratio, 0.59) and for those who received concurrent CRT (median PFS, 10.5 vs. 6.4 months; HR, 0.66).
Overall survival (OS) data were not mature at the time of the presentation, but a trend favoring sugemalimab was observed (HR, 0.44) he noted.
Sugemalimab, an investigational anti–programmed death-ligand 1 (PD-L1 )monoclonal antibody, was well tolerated; grade 3 or higher treatment-emergent adverse events (AEs) occurred in 24.3% of patients in the sugemalimab group and in 23.8% in the placebo group.
Concurrent chemoradiotherapy followed by immunotherapy is the standard of care for patients with unresectable stage III NSCLC, but nearly half undergo sequential CRT because they can’t tolerate concurrent treatment, Dr. Wu explained, describing the rationale for the study – the first phase 3 trial looking at both concurrent and sequential CRT in this patient population.
The results provide evidence for sugemalimab as a consolidation treatment for those who did not progress following either approach to CRT, he concluded.
PACIFIC-R study
The large, international, observational PACIFIC-R study also looked at consolidation in a real-world setting, and confirmed a PFS benefit with durvalumab in stage III NSCLC patients who had completed concurrent or sequential platinum-based CRT within the previous 12 weeks without evidence of disease progression (Abstract 1171MO).
“The median real-world PFS in this cohort was 21.7 months, which is higher than that in the durvalumab arm in the PACIFIC trial, which was 16.9 months,” reported Nicolas Girard, MD, a professor at Institut Curie, Paris.
The PACIFIC trial set the standard for durvalumab-based consolidation after CRT, and ongoing survival benefit was confirmed by 5-year follow-up data, he noted.
The PACIFIC-R trial included 1,399 patients from 11 countries who were treated as part of an expanded-access program following the PACIFIC trial.
Median time to durvalumab initiation after the end of radiotherapy in the cohort was 56 days. Overall median durvalumab treatment duration was 11 months, and the median number of infusions was 22, Dr. Girard said.
Pneumonitis was the most common adverse event leading to discontinuation: 214 (18.5%) patients experienced any-grade pneumonitis and/or interstitial lung disease, and 9.5 discontinued the study as a result. Most cases were mild or moderate, he said.
Subgroup analyses showed that real-world PFS was higher among patients with stage IIIa disease and those with PD-L1–positive tumors, those with nonsquamous disease histology, and those who received concurrent CRT.
“For example, in those with stage IIIa disease, the median real-world PFS was 23.7 months versus 19.2 months in patients with stage IIIb and c disease,” he said.
“PACIFIC-R demonstrated the efficacy of durvalumab consolidation in patients with unresectable stage III non–small cell lung cancer after completion of chemoradiotherapy,” said Dr. Girard. “The effectiveness of durvalumab was consistent among key subgroups, as was safety, when comparing the data with that of PACIFIC.
“The future read-outs of OS will further provide insight into the effectiveness of this regimen.”
Session chair Lizza E. Hendriks, MD, PhD, of Maastricht (the Netherlands) University, applauded the inclusion of patients undergoing sequential CRT in the GEMSTONE-301 and PACIFIC-R studies, noting that it is “very important to have data in sequential radiochemotherapy populations” given the substantial number of patients who require a sequential approach because of poor performance status, difficulty tolerating concurrent CRT, or logistical reasons, such as an inability to travel to receive concurrent CRT.
The GEMSTONE-301 study was funded by CStone Pharmaceuticals. Dr. Wu reported having no disclosures. The PACIFIC-R study was funded by AstraZeneca. Dr. Girard reported financial relationships with AstraZeneca, Bristol Myers Squibb, and Merck Sharp & Dohme. Dr. Hendriks reported financial relationships with numerous companies.
Checkpoint inhibition for consolidation after chemoradiotherapy (CRT) showed promising survival benefit in patients with unresectable stage III non–small cell lung cancer (NSCLC) in two recent studies, including one looking at the investigational agent sugemalimab and one assessing durvalumab in a real-world setting.
Statistically significant and clinically meaningful improvement in progression-free survival (PFS) was observed with sugemalimab versus placebo in the randomized, phase 3 GEMSTONE-301 study, and consolidation durvalumab showed effectiveness in a real-world cohort in the PACIFIC-R study.
Findings from both studies were presented at the 2021 European Society for Medical Oncology Congress.
GEMSTONE-301
Median progression-free survival among 381 patients randomized 2:1 to receive 1,200 mg of sugemalimab or placebo every 3 weeks after either concurrent or sequential chemoradiotherapy was 9.0 versus 5.8 months, in the treatment arms, respectively (hazard ratio, 0.64) (Abstract LBA43), reported Yi-Long Wu, MD, of Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Guangzhou, China.
Patients were recruited from 50 sites, and one-third had received sequential CRT. Progression-free survival was assessed at median follow up of 14 months.
“The 12- and 18-month PFS rates were 45% vs. 26% and 39% vs. 23%, respectively,” Dr. Wu said.
Of note, the PFS benefit was observed both for patients who underwent sequential CRT (median PFS, 8.1 vs. 4.1 months with sugemalimab vs. placebo; hazard ratio, 0.59) and for those who received concurrent CRT (median PFS, 10.5 vs. 6.4 months; HR, 0.66).
Overall survival (OS) data were not mature at the time of the presentation, but a trend favoring sugemalimab was observed (HR, 0.44) he noted.
Sugemalimab, an investigational anti–programmed death-ligand 1 (PD-L1 )monoclonal antibody, was well tolerated; grade 3 or higher treatment-emergent adverse events (AEs) occurred in 24.3% of patients in the sugemalimab group and in 23.8% in the placebo group.
Concurrent chemoradiotherapy followed by immunotherapy is the standard of care for patients with unresectable stage III NSCLC, but nearly half undergo sequential CRT because they can’t tolerate concurrent treatment, Dr. Wu explained, describing the rationale for the study – the first phase 3 trial looking at both concurrent and sequential CRT in this patient population.
The results provide evidence for sugemalimab as a consolidation treatment for those who did not progress following either approach to CRT, he concluded.
PACIFIC-R study
The large, international, observational PACIFIC-R study also looked at consolidation in a real-world setting, and confirmed a PFS benefit with durvalumab in stage III NSCLC patients who had completed concurrent or sequential platinum-based CRT within the previous 12 weeks without evidence of disease progression (Abstract 1171MO).
“The median real-world PFS in this cohort was 21.7 months, which is higher than that in the durvalumab arm in the PACIFIC trial, which was 16.9 months,” reported Nicolas Girard, MD, a professor at Institut Curie, Paris.
The PACIFIC trial set the standard for durvalumab-based consolidation after CRT, and ongoing survival benefit was confirmed by 5-year follow-up data, he noted.
The PACIFIC-R trial included 1,399 patients from 11 countries who were treated as part of an expanded-access program following the PACIFIC trial.
Median time to durvalumab initiation after the end of radiotherapy in the cohort was 56 days. Overall median durvalumab treatment duration was 11 months, and the median number of infusions was 22, Dr. Girard said.
Pneumonitis was the most common adverse event leading to discontinuation: 214 (18.5%) patients experienced any-grade pneumonitis and/or interstitial lung disease, and 9.5 discontinued the study as a result. Most cases were mild or moderate, he said.
Subgroup analyses showed that real-world PFS was higher among patients with stage IIIa disease and those with PD-L1–positive tumors, those with nonsquamous disease histology, and those who received concurrent CRT.
“For example, in those with stage IIIa disease, the median real-world PFS was 23.7 months versus 19.2 months in patients with stage IIIb and c disease,” he said.
“PACIFIC-R demonstrated the efficacy of durvalumab consolidation in patients with unresectable stage III non–small cell lung cancer after completion of chemoradiotherapy,” said Dr. Girard. “The effectiveness of durvalumab was consistent among key subgroups, as was safety, when comparing the data with that of PACIFIC.
“The future read-outs of OS will further provide insight into the effectiveness of this regimen.”
Session chair Lizza E. Hendriks, MD, PhD, of Maastricht (the Netherlands) University, applauded the inclusion of patients undergoing sequential CRT in the GEMSTONE-301 and PACIFIC-R studies, noting that it is “very important to have data in sequential radiochemotherapy populations” given the substantial number of patients who require a sequential approach because of poor performance status, difficulty tolerating concurrent CRT, or logistical reasons, such as an inability to travel to receive concurrent CRT.
The GEMSTONE-301 study was funded by CStone Pharmaceuticals. Dr. Wu reported having no disclosures. The PACIFIC-R study was funded by AstraZeneca. Dr. Girard reported financial relationships with AstraZeneca, Bristol Myers Squibb, and Merck Sharp & Dohme. Dr. Hendriks reported financial relationships with numerous companies.
FROM ESMO 2021
Once daily poziotinib shows efficacy in non–small cell lung cancer
Tumor reductions, stated lead author Robin Cornelissen, PhD, MD, Erasmus University, Rotterdam, the Netherlands, were seen in 88% of patients.
EGFR and HER2 exon 20 insertion mutations are rare subsets accounting for about 10% each of all mutations and 2%-4% each in NSCLC. “There is no approved therapy for either treatment-naive or previously treated NSCLC with HER2 exon 20 mutations,” Dr. Cornelissen said in a virtual oral presentation (abstract LBA46) on Sept. 18. While chemotherapy agents with or without checkpoint inhibitors and tyrosine kinase inhibitors (TKIs) are currently utilized, none are specific to exon 20 mutations, and historical response rates from mostly small uncontrolled studies vary widely from about 6.9%-35%, with median progression-free survival (PFS) ranging from 3 to 7 months. Poziotinib is a potent oral pan-HER TKI with activity in patients with EGFR or HER2 exon 20–mutated NSCLC.
Dr. Cornelissen presented preliminary safety and efficacy data from the phase 2 ZENITH20, a seven-cohort global clinical trial, specifically from cohort 4 (daily dosing) which included 48 HER2 exon 20 insertion NSCLC patients (median age, 60.5 years; female/male, 26/22) treated first-line with oral daily poziotinib (16 mg). The majority were White (75%), female (54%), and nonsmokers (69%) with an Eastern Cooperative Oncology Group performance status of 1 (65%).The primary endpoint was objective response rate evaluated centrally by an independent image review committee using RECIST 1.1 criteria.
All patients have experienced treatment-related adverse events (TRAEs) with 10% considered serious, and permanent discontinuation in 13%. About 83% of patients had dose interruptions and 76% had dose reductions. The most common adverse events were diarrhea (any grade, 83%; grade 3, 15%), rash (any grade, 69%; grade 3, 35%), stomatitis/mucosal inflammation (any grade, 81%; grade 3, 21%), and paronychia (any grade, 46%; grade 3 8%). Pneumonitis occurred in two patients (4%), with one grade 3 (2%). No grade 4/5 TRAEs were reported.
Discontinuations in 44 patients (92%), Dr. Cornelissen said, are attributed to death (5/10%), disease progression (30/63%), adverse events (1/2%), and other (8/17%), with treatment ongoing in 4 patients (8%).
The rate for the primary endpoint of ORR was 43.8% (n = 21) (95% confidence interval, 29.5%-58.8%).Tumor reductions have been observed in 42/48 patients (88%) with a median reduction of 35%. One complete response was reported (2.1%), with partial responses in 20 (41.7%), stable disease in 15 (31.3%), progressive disease in 7 (14.6%), and 5 (10.4%) not evaluable. The disease control rate was 75.0%.
Among secondary endpoints, median duration of response (DoR) was 5.4 months (range, 2.8 to >19.1), with 42% of patients having response duration greater than6 months and 24% greater than 12 months. Median PFS was 5.6 months (range, 0 to >20.2), with progression-free survival duration greater than6 months in 42% and duration greater than12 months in 26%.
Dr. Cornelissen concluded: “Poziotinib shows clinically meaningful efficacy for treatment-naive NSCLC HER2 exon 20 mutations with [daily] dosing.” The toxicity profile, he added, is manageable and in line with previous poziotinib studies and other second-generation EGFR TKIs.
Noting that improved tolerability and antitumor activity have been observed in the cohort 5 (8 mg b.i.d.) interim analysis, Dr. Cornelissen said that cohort 4 is ongoing with patients enrolling at 8-mg b.i.d. dosing.
HER2 mutations represents 1.7%-2.2% of NSCLC, with high-sequence homology with EGFR mutation, observed ESMO-appointed discussant Daniel S.W. Tan, PhD, National Cancer Center in Singapore. He pointed out that, while HER2 antibody drug conjugates and TKIs have gained approval in other cancer types (e.g., breast, gastric), currently no HER2 therapies are approved in NSCLC. Reviewing ZENITH20 findings (risk ratio, 43.8%; DoR, 5.4 months; PFS, 5.6 months), Dr. Tan stated that poziotinib is an active agent in HER2 mutated NSCLC. “One concern that remains for me is the safety profile that will require further evaluation in order to determine optimal dosing,” he said.
Potential combinations, he added, need to be explored to improve the durability of response. “Until we can properly characterize this and other important aspects such as CNS activity, we need to be cautious about transitioning to a frontline setting. Also, we do need to give due consideration to strategies to improve HER2 testing rates in order to expand on clinical experience. This argues for the importance of broad upfront next generation sequencing testing in NSCLC.”
The study was funded by Spectrum Pharmaceuticals. Other authors associated with the research disclosed full or part-time employment with Spectrum.
Tumor reductions, stated lead author Robin Cornelissen, PhD, MD, Erasmus University, Rotterdam, the Netherlands, were seen in 88% of patients.
EGFR and HER2 exon 20 insertion mutations are rare subsets accounting for about 10% each of all mutations and 2%-4% each in NSCLC. “There is no approved therapy for either treatment-naive or previously treated NSCLC with HER2 exon 20 mutations,” Dr. Cornelissen said in a virtual oral presentation (abstract LBA46) on Sept. 18. While chemotherapy agents with or without checkpoint inhibitors and tyrosine kinase inhibitors (TKIs) are currently utilized, none are specific to exon 20 mutations, and historical response rates from mostly small uncontrolled studies vary widely from about 6.9%-35%, with median progression-free survival (PFS) ranging from 3 to 7 months. Poziotinib is a potent oral pan-HER TKI with activity in patients with EGFR or HER2 exon 20–mutated NSCLC.
Dr. Cornelissen presented preliminary safety and efficacy data from the phase 2 ZENITH20, a seven-cohort global clinical trial, specifically from cohort 4 (daily dosing) which included 48 HER2 exon 20 insertion NSCLC patients (median age, 60.5 years; female/male, 26/22) treated first-line with oral daily poziotinib (16 mg). The majority were White (75%), female (54%), and nonsmokers (69%) with an Eastern Cooperative Oncology Group performance status of 1 (65%).The primary endpoint was objective response rate evaluated centrally by an independent image review committee using RECIST 1.1 criteria.
All patients have experienced treatment-related adverse events (TRAEs) with 10% considered serious, and permanent discontinuation in 13%. About 83% of patients had dose interruptions and 76% had dose reductions. The most common adverse events were diarrhea (any grade, 83%; grade 3, 15%), rash (any grade, 69%; grade 3, 35%), stomatitis/mucosal inflammation (any grade, 81%; grade 3, 21%), and paronychia (any grade, 46%; grade 3 8%). Pneumonitis occurred in two patients (4%), with one grade 3 (2%). No grade 4/5 TRAEs were reported.
Discontinuations in 44 patients (92%), Dr. Cornelissen said, are attributed to death (5/10%), disease progression (30/63%), adverse events (1/2%), and other (8/17%), with treatment ongoing in 4 patients (8%).
The rate for the primary endpoint of ORR was 43.8% (n = 21) (95% confidence interval, 29.5%-58.8%).Tumor reductions have been observed in 42/48 patients (88%) with a median reduction of 35%. One complete response was reported (2.1%), with partial responses in 20 (41.7%), stable disease in 15 (31.3%), progressive disease in 7 (14.6%), and 5 (10.4%) not evaluable. The disease control rate was 75.0%.
Among secondary endpoints, median duration of response (DoR) was 5.4 months (range, 2.8 to >19.1), with 42% of patients having response duration greater than6 months and 24% greater than 12 months. Median PFS was 5.6 months (range, 0 to >20.2), with progression-free survival duration greater than6 months in 42% and duration greater than12 months in 26%.
Dr. Cornelissen concluded: “Poziotinib shows clinically meaningful efficacy for treatment-naive NSCLC HER2 exon 20 mutations with [daily] dosing.” The toxicity profile, he added, is manageable and in line with previous poziotinib studies and other second-generation EGFR TKIs.
Noting that improved tolerability and antitumor activity have been observed in the cohort 5 (8 mg b.i.d.) interim analysis, Dr. Cornelissen said that cohort 4 is ongoing with patients enrolling at 8-mg b.i.d. dosing.
HER2 mutations represents 1.7%-2.2% of NSCLC, with high-sequence homology with EGFR mutation, observed ESMO-appointed discussant Daniel S.W. Tan, PhD, National Cancer Center in Singapore. He pointed out that, while HER2 antibody drug conjugates and TKIs have gained approval in other cancer types (e.g., breast, gastric), currently no HER2 therapies are approved in NSCLC. Reviewing ZENITH20 findings (risk ratio, 43.8%; DoR, 5.4 months; PFS, 5.6 months), Dr. Tan stated that poziotinib is an active agent in HER2 mutated NSCLC. “One concern that remains for me is the safety profile that will require further evaluation in order to determine optimal dosing,” he said.
Potential combinations, he added, need to be explored to improve the durability of response. “Until we can properly characterize this and other important aspects such as CNS activity, we need to be cautious about transitioning to a frontline setting. Also, we do need to give due consideration to strategies to improve HER2 testing rates in order to expand on clinical experience. This argues for the importance of broad upfront next generation sequencing testing in NSCLC.”
The study was funded by Spectrum Pharmaceuticals. Other authors associated with the research disclosed full or part-time employment with Spectrum.
Tumor reductions, stated lead author Robin Cornelissen, PhD, MD, Erasmus University, Rotterdam, the Netherlands, were seen in 88% of patients.
EGFR and HER2 exon 20 insertion mutations are rare subsets accounting for about 10% each of all mutations and 2%-4% each in NSCLC. “There is no approved therapy for either treatment-naive or previously treated NSCLC with HER2 exon 20 mutations,” Dr. Cornelissen said in a virtual oral presentation (abstract LBA46) on Sept. 18. While chemotherapy agents with or without checkpoint inhibitors and tyrosine kinase inhibitors (TKIs) are currently utilized, none are specific to exon 20 mutations, and historical response rates from mostly small uncontrolled studies vary widely from about 6.9%-35%, with median progression-free survival (PFS) ranging from 3 to 7 months. Poziotinib is a potent oral pan-HER TKI with activity in patients with EGFR or HER2 exon 20–mutated NSCLC.
Dr. Cornelissen presented preliminary safety and efficacy data from the phase 2 ZENITH20, a seven-cohort global clinical trial, specifically from cohort 4 (daily dosing) which included 48 HER2 exon 20 insertion NSCLC patients (median age, 60.5 years; female/male, 26/22) treated first-line with oral daily poziotinib (16 mg). The majority were White (75%), female (54%), and nonsmokers (69%) with an Eastern Cooperative Oncology Group performance status of 1 (65%).The primary endpoint was objective response rate evaluated centrally by an independent image review committee using RECIST 1.1 criteria.
All patients have experienced treatment-related adverse events (TRAEs) with 10% considered serious, and permanent discontinuation in 13%. About 83% of patients had dose interruptions and 76% had dose reductions. The most common adverse events were diarrhea (any grade, 83%; grade 3, 15%), rash (any grade, 69%; grade 3, 35%), stomatitis/mucosal inflammation (any grade, 81%; grade 3, 21%), and paronychia (any grade, 46%; grade 3 8%). Pneumonitis occurred in two patients (4%), with one grade 3 (2%). No grade 4/5 TRAEs were reported.
Discontinuations in 44 patients (92%), Dr. Cornelissen said, are attributed to death (5/10%), disease progression (30/63%), adverse events (1/2%), and other (8/17%), with treatment ongoing in 4 patients (8%).
The rate for the primary endpoint of ORR was 43.8% (n = 21) (95% confidence interval, 29.5%-58.8%).Tumor reductions have been observed in 42/48 patients (88%) with a median reduction of 35%. One complete response was reported (2.1%), with partial responses in 20 (41.7%), stable disease in 15 (31.3%), progressive disease in 7 (14.6%), and 5 (10.4%) not evaluable. The disease control rate was 75.0%.
Among secondary endpoints, median duration of response (DoR) was 5.4 months (range, 2.8 to >19.1), with 42% of patients having response duration greater than6 months and 24% greater than 12 months. Median PFS was 5.6 months (range, 0 to >20.2), with progression-free survival duration greater than6 months in 42% and duration greater than12 months in 26%.
Dr. Cornelissen concluded: “Poziotinib shows clinically meaningful efficacy for treatment-naive NSCLC HER2 exon 20 mutations with [daily] dosing.” The toxicity profile, he added, is manageable and in line with previous poziotinib studies and other second-generation EGFR TKIs.
Noting that improved tolerability and antitumor activity have been observed in the cohort 5 (8 mg b.i.d.) interim analysis, Dr. Cornelissen said that cohort 4 is ongoing with patients enrolling at 8-mg b.i.d. dosing.
HER2 mutations represents 1.7%-2.2% of NSCLC, with high-sequence homology with EGFR mutation, observed ESMO-appointed discussant Daniel S.W. Tan, PhD, National Cancer Center in Singapore. He pointed out that, while HER2 antibody drug conjugates and TKIs have gained approval in other cancer types (e.g., breast, gastric), currently no HER2 therapies are approved in NSCLC. Reviewing ZENITH20 findings (risk ratio, 43.8%; DoR, 5.4 months; PFS, 5.6 months), Dr. Tan stated that poziotinib is an active agent in HER2 mutated NSCLC. “One concern that remains for me is the safety profile that will require further evaluation in order to determine optimal dosing,” he said.
Potential combinations, he added, need to be explored to improve the durability of response. “Until we can properly characterize this and other important aspects such as CNS activity, we need to be cautious about transitioning to a frontline setting. Also, we do need to give due consideration to strategies to improve HER2 testing rates in order to expand on clinical experience. This argues for the importance of broad upfront next generation sequencing testing in NSCLC.”
The study was funded by Spectrum Pharmaceuticals. Other authors associated with the research disclosed full or part-time employment with Spectrum.
FROM ESMO 2021
Atezolizumab plus chemotherapy superior to best supportive care in early lung cancer
according to Enriqueta Felip, MD, the head of thoracic and head and neck cancer unit at Vall d’Hebron Institute of Oncology, Hospital, Barcelona.
IMpower010 is the first positive randomized phase 3 study to show significant disease-free survival (DFS) improvement with adjuvant cancer immunotherapy (atezolizumab, anti–programmed death–ligand 1, and platinum-based chemotherapy) in this population, Dr. Felip said in a presentation at the 2021 European Society for Medical Oncology Congress on Sept. 20 (abstract LBA9).
High unmet need
Up to 60% of patients with stage I-III NSCLC still experience disease relapse despite having received treatment, Dr. Felip said. IMpower010 included 1,280 patients who received up to four cycles of chemotherapy (cisplatin with pemetrexed, gemcitabine, docetaxel, or vinorelbine) after completely resected stage IB-IIIA NSCLC. Patients were randomized to open label to atezolizumab (1,200 mg every 21 days for 16 cycles or best supportive care (BSC). The primary endpoint of investigator-assessed DFS in the stage II-IIIA population (n = 1,005) was stratified according to three groups: PD-L1 tumor cells of at least 1% (stage II-IIIA), all-randomized (stage II-IIIA) and intention-to-treat (stage IB-IIIA).
Median disease-free survival in PD-L1 tumor cells of at least 1% was not estimated in the atezolizumab group and was 35.3 months in the BSC group (95% CI, 29.0 to NE). In the all-randomized group, median DFS was 42.3 months in the atezolizumab group (95% CI, 36.0 to NE) and 35.3 months in the BSC group (95% CI, 30.4-46.4) with a stratified hazard ratio of 0.79 (95% CI, 0.64-0.96; P = .02). In the intent-to-treat population, median DFS was not evaluable in the atezolizumab group and 37.2 months in the BSC group (95% CI, 31.6 to NE) with a hazard ratio of 0.81 (95% CI, 0.67-0.99; P = .04).
DFS hazard ratio 0.43 in TC ≥50% group
Looking at DFS by PD-L1 status in the population with and without known EGFR/ALK+ disease, Dr. Felip said that the hazard ratio for the tumor cells of at least 50% group (n = 229) was 0.43 (95% CI, 0.27-0.68), as compared with 0.87 (95% CI, 0.60-1.26) for the tumor cells 1%-49% group. With EGFR/ALK+ patients excluded, the respective HRs were similar (0.43/0.82). Considering DFS events including only disease recurrence, disease incidence was 29.4%/44.7% in the atezolizumab and BSC groups, respectively for those with PD-L1 tumor cells of at least 1%. The same pattern of atezolizumab benefit persisted in the all-randomized and intent-to-treat groups.
An assessment according to regions of relapse (locoregional only, distant only, locoregional and distant, CNS only, second primary lung) revealed no differences in the three groups. Analysis of time from randomization to relapse revealed regional differences in the PD-L1 tumor cells of at least 1% group with a median time to any relapse of 17.6 months in the atezolizumab group and 10.9 months in the BSC group. Time from randomization to relapse was generally similar for atezolizumab and best supportive care in the all randomized and intent-to-treat groups (about 11-12 months).
“The greatest magnitude of disease-free survival benefit was observed in the PD-L1 tumor cell of at least 50% population with a hazard ratio of 0.43,” Dr. Felip said. In a post hoc analysis excluding patients with known EFGR/ALK with NSCLC, she said that hazard ratios were numerically improved in most PD-L1 subgroups. Postrelapse cancer immunotherapies were used at a higher rate in the BSC arm of the trial. “Longer-term follow-up is warranted and may reveal differences in relapse patterns and treatment options.
Playing with the immune system
Benjamin Besse, MD, director of oncology and chair of the EORTC Lung Group at Paris-Saclay University, acknowledged the disease-free survival benefit with atezolizumab in IMpower010 and underscored that adjuvant immunotherapy has been changing treatment in resected cancers across tumor types (i.e., melanoma, renal cell carcinoma, NSCLC). He voiced some concerns, including the absence of benefit in PD-L1 less than 1%, pneumonectomy and EGFRmut/ALK+ patients, and generally the potential “when you play with the immune system for there to be a dark side too.” Dr. Besse said delayed side effects in 43.2% of patients , citing a recent report of chronic, mostly grade 1-2 immune-related adverse events following (>12 weeks after discontinuation) adjuvant anti–PD-1 therapy for high-risk resected melanoma. He mentioned, however, that the rate of second primary lung tumors in the atezolizumab group (1.4%) was lower than in the BSC group (2.6%), with generally similar rates between immuno- and nonimmunotherapies in melanoma and breast cancer trials.
“IMpower 010 is the first adjuvant study establishing immune checkpoint blockade as a new standard of care. We need to cure more, not to delay relapse,” he said. The optimal population for treatment is still yet to be defined, as is the best perioperative strategy, Dr. Besse added. “If approved I would prescribe adjuvant atezolizumab ... until I see the overall survival curves.”
IMpower010 was funded by–F. Hoffmann-La Roche. Dr. Felip disclosed numerous financial interests, including having received financial support from F. Hoffmann–La Roche, AstraZeneca, Amgen, and Merck, among other pharmaceutical companies.
according to Enriqueta Felip, MD, the head of thoracic and head and neck cancer unit at Vall d’Hebron Institute of Oncology, Hospital, Barcelona.
IMpower010 is the first positive randomized phase 3 study to show significant disease-free survival (DFS) improvement with adjuvant cancer immunotherapy (atezolizumab, anti–programmed death–ligand 1, and platinum-based chemotherapy) in this population, Dr. Felip said in a presentation at the 2021 European Society for Medical Oncology Congress on Sept. 20 (abstract LBA9).
High unmet need
Up to 60% of patients with stage I-III NSCLC still experience disease relapse despite having received treatment, Dr. Felip said. IMpower010 included 1,280 patients who received up to four cycles of chemotherapy (cisplatin with pemetrexed, gemcitabine, docetaxel, or vinorelbine) after completely resected stage IB-IIIA NSCLC. Patients were randomized to open label to atezolizumab (1,200 mg every 21 days for 16 cycles or best supportive care (BSC). The primary endpoint of investigator-assessed DFS in the stage II-IIIA population (n = 1,005) was stratified according to three groups: PD-L1 tumor cells of at least 1% (stage II-IIIA), all-randomized (stage II-IIIA) and intention-to-treat (stage IB-IIIA).
Median disease-free survival in PD-L1 tumor cells of at least 1% was not estimated in the atezolizumab group and was 35.3 months in the BSC group (95% CI, 29.0 to NE). In the all-randomized group, median DFS was 42.3 months in the atezolizumab group (95% CI, 36.0 to NE) and 35.3 months in the BSC group (95% CI, 30.4-46.4) with a stratified hazard ratio of 0.79 (95% CI, 0.64-0.96; P = .02). In the intent-to-treat population, median DFS was not evaluable in the atezolizumab group and 37.2 months in the BSC group (95% CI, 31.6 to NE) with a hazard ratio of 0.81 (95% CI, 0.67-0.99; P = .04).
DFS hazard ratio 0.43 in TC ≥50% group
Looking at DFS by PD-L1 status in the population with and without known EGFR/ALK+ disease, Dr. Felip said that the hazard ratio for the tumor cells of at least 50% group (n = 229) was 0.43 (95% CI, 0.27-0.68), as compared with 0.87 (95% CI, 0.60-1.26) for the tumor cells 1%-49% group. With EGFR/ALK+ patients excluded, the respective HRs were similar (0.43/0.82). Considering DFS events including only disease recurrence, disease incidence was 29.4%/44.7% in the atezolizumab and BSC groups, respectively for those with PD-L1 tumor cells of at least 1%. The same pattern of atezolizumab benefit persisted in the all-randomized and intent-to-treat groups.
An assessment according to regions of relapse (locoregional only, distant only, locoregional and distant, CNS only, second primary lung) revealed no differences in the three groups. Analysis of time from randomization to relapse revealed regional differences in the PD-L1 tumor cells of at least 1% group with a median time to any relapse of 17.6 months in the atezolizumab group and 10.9 months in the BSC group. Time from randomization to relapse was generally similar for atezolizumab and best supportive care in the all randomized and intent-to-treat groups (about 11-12 months).
“The greatest magnitude of disease-free survival benefit was observed in the PD-L1 tumor cell of at least 50% population with a hazard ratio of 0.43,” Dr. Felip said. In a post hoc analysis excluding patients with known EFGR/ALK with NSCLC, she said that hazard ratios were numerically improved in most PD-L1 subgroups. Postrelapse cancer immunotherapies were used at a higher rate in the BSC arm of the trial. “Longer-term follow-up is warranted and may reveal differences in relapse patterns and treatment options.
Playing with the immune system
Benjamin Besse, MD, director of oncology and chair of the EORTC Lung Group at Paris-Saclay University, acknowledged the disease-free survival benefit with atezolizumab in IMpower010 and underscored that adjuvant immunotherapy has been changing treatment in resected cancers across tumor types (i.e., melanoma, renal cell carcinoma, NSCLC). He voiced some concerns, including the absence of benefit in PD-L1 less than 1%, pneumonectomy and EGFRmut/ALK+ patients, and generally the potential “when you play with the immune system for there to be a dark side too.” Dr. Besse said delayed side effects in 43.2% of patients , citing a recent report of chronic, mostly grade 1-2 immune-related adverse events following (>12 weeks after discontinuation) adjuvant anti–PD-1 therapy for high-risk resected melanoma. He mentioned, however, that the rate of second primary lung tumors in the atezolizumab group (1.4%) was lower than in the BSC group (2.6%), with generally similar rates between immuno- and nonimmunotherapies in melanoma and breast cancer trials.
“IMpower 010 is the first adjuvant study establishing immune checkpoint blockade as a new standard of care. We need to cure more, not to delay relapse,” he said. The optimal population for treatment is still yet to be defined, as is the best perioperative strategy, Dr. Besse added. “If approved I would prescribe adjuvant atezolizumab ... until I see the overall survival curves.”
IMpower010 was funded by–F. Hoffmann-La Roche. Dr. Felip disclosed numerous financial interests, including having received financial support from F. Hoffmann–La Roche, AstraZeneca, Amgen, and Merck, among other pharmaceutical companies.
according to Enriqueta Felip, MD, the head of thoracic and head and neck cancer unit at Vall d’Hebron Institute of Oncology, Hospital, Barcelona.
IMpower010 is the first positive randomized phase 3 study to show significant disease-free survival (DFS) improvement with adjuvant cancer immunotherapy (atezolizumab, anti–programmed death–ligand 1, and platinum-based chemotherapy) in this population, Dr. Felip said in a presentation at the 2021 European Society for Medical Oncology Congress on Sept. 20 (abstract LBA9).
High unmet need
Up to 60% of patients with stage I-III NSCLC still experience disease relapse despite having received treatment, Dr. Felip said. IMpower010 included 1,280 patients who received up to four cycles of chemotherapy (cisplatin with pemetrexed, gemcitabine, docetaxel, or vinorelbine) after completely resected stage IB-IIIA NSCLC. Patients were randomized to open label to atezolizumab (1,200 mg every 21 days for 16 cycles or best supportive care (BSC). The primary endpoint of investigator-assessed DFS in the stage II-IIIA population (n = 1,005) was stratified according to three groups: PD-L1 tumor cells of at least 1% (stage II-IIIA), all-randomized (stage II-IIIA) and intention-to-treat (stage IB-IIIA).
Median disease-free survival in PD-L1 tumor cells of at least 1% was not estimated in the atezolizumab group and was 35.3 months in the BSC group (95% CI, 29.0 to NE). In the all-randomized group, median DFS was 42.3 months in the atezolizumab group (95% CI, 36.0 to NE) and 35.3 months in the BSC group (95% CI, 30.4-46.4) with a stratified hazard ratio of 0.79 (95% CI, 0.64-0.96; P = .02). In the intent-to-treat population, median DFS was not evaluable in the atezolizumab group and 37.2 months in the BSC group (95% CI, 31.6 to NE) with a hazard ratio of 0.81 (95% CI, 0.67-0.99; P = .04).
DFS hazard ratio 0.43 in TC ≥50% group
Looking at DFS by PD-L1 status in the population with and without known EGFR/ALK+ disease, Dr. Felip said that the hazard ratio for the tumor cells of at least 50% group (n = 229) was 0.43 (95% CI, 0.27-0.68), as compared with 0.87 (95% CI, 0.60-1.26) for the tumor cells 1%-49% group. With EGFR/ALK+ patients excluded, the respective HRs were similar (0.43/0.82). Considering DFS events including only disease recurrence, disease incidence was 29.4%/44.7% in the atezolizumab and BSC groups, respectively for those with PD-L1 tumor cells of at least 1%. The same pattern of atezolizumab benefit persisted in the all-randomized and intent-to-treat groups.
An assessment according to regions of relapse (locoregional only, distant only, locoregional and distant, CNS only, second primary lung) revealed no differences in the three groups. Analysis of time from randomization to relapse revealed regional differences in the PD-L1 tumor cells of at least 1% group with a median time to any relapse of 17.6 months in the atezolizumab group and 10.9 months in the BSC group. Time from randomization to relapse was generally similar for atezolizumab and best supportive care in the all randomized and intent-to-treat groups (about 11-12 months).
“The greatest magnitude of disease-free survival benefit was observed in the PD-L1 tumor cell of at least 50% population with a hazard ratio of 0.43,” Dr. Felip said. In a post hoc analysis excluding patients with known EFGR/ALK with NSCLC, she said that hazard ratios were numerically improved in most PD-L1 subgroups. Postrelapse cancer immunotherapies were used at a higher rate in the BSC arm of the trial. “Longer-term follow-up is warranted and may reveal differences in relapse patterns and treatment options.
Playing with the immune system
Benjamin Besse, MD, director of oncology and chair of the EORTC Lung Group at Paris-Saclay University, acknowledged the disease-free survival benefit with atezolizumab in IMpower010 and underscored that adjuvant immunotherapy has been changing treatment in resected cancers across tumor types (i.e., melanoma, renal cell carcinoma, NSCLC). He voiced some concerns, including the absence of benefit in PD-L1 less than 1%, pneumonectomy and EGFRmut/ALK+ patients, and generally the potential “when you play with the immune system for there to be a dark side too.” Dr. Besse said delayed side effects in 43.2% of patients , citing a recent report of chronic, mostly grade 1-2 immune-related adverse events following (>12 weeks after discontinuation) adjuvant anti–PD-1 therapy for high-risk resected melanoma. He mentioned, however, that the rate of second primary lung tumors in the atezolizumab group (1.4%) was lower than in the BSC group (2.6%), with generally similar rates between immuno- and nonimmunotherapies in melanoma and breast cancer trials.
“IMpower 010 is the first adjuvant study establishing immune checkpoint blockade as a new standard of care. We need to cure more, not to delay relapse,” he said. The optimal population for treatment is still yet to be defined, as is the best perioperative strategy, Dr. Besse added. “If approved I would prescribe adjuvant atezolizumab ... until I see the overall survival curves.”
IMpower010 was funded by–F. Hoffmann-La Roche. Dr. Felip disclosed numerous financial interests, including having received financial support from F. Hoffmann–La Roche, AstraZeneca, Amgen, and Merck, among other pharmaceutical companies.
FROM ESMO 2021
Study supports chemotherapy with immunotherapy for some never-smokers with lung cancer
Median overall survival was similar at 21.0 months and 22.1 months in 169 patients who received cancer immunotherapy plus chemotherapy and 351 who received cancer immunotherapy monotherapy, respectively (adjusted hazard ratio, 1.03). Median real-world progression-free survival (PFS) was also similar in the two groups (10.8 vs. 11.5 months; aHR, 1.04), Solange Peters, MD, reported at the 2021 European Society for Medical Oncology Congress on Sept. 17 (abstract VP2_2021).
However, in a small subgroup of 50 never-smokers, CIT plus chemotherapy showed significant and meaningful improvement in both overall survival and real-world progression-free survival, compared with CIT monotherapy, said Dr. Peters, ESMO president and professor and chair of medical oncology at the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
The hazard ratios for overall survival and progression-free survival, after adjusting for baseline characteristics, were 0.50 and 0.40 in this subgroup, Dr. Peters said.
She and her colleagues reviewed data from the nationwide Flatiron Health Electronic Health Record–derived deidentified database for patients with metastatic nonsquamous NSCLC with a PD-L1 tumor proportion score at least 50% expression who initiated first-line CIT monotherapy or CIT plus chemotherapy between Oct. 24, 2016, and Feb. 28, 2019.
Median follow-up was 23.5 and 19.9 months in the monotherapy and combination therapy groups, respectively.
The findings are notable because “this is a very important scientific question, which by the way, is a daily question we have,” Dr. Peters said during a plenary debate session at the conference.
“One in four patients [with metastatic nonsquamous NSCLC has] this high PDL expression,” she explained, noting that both treatment approaches are commonly used in the first-line setting in this patient population.
The findings highlight the value of “well-conducted real-world evidence trials” in the absence of randomized trial results, she said.
Invited discussant Marina Chiara Garassino, MBBS, professor of medicine at the University of Chicago, also acknowledged the importance of the findings, noting the “multiple possibilities” for treatment selection in the metastatic nonsquamous NSCLC patient population.
Although patients with PD-L1 expression below 50% derive clear benefit from combination versus single-agent therapy, treatment selection for those with high PD-L1 expression is “very tricky and debatable,” she said.
For those with high PD-L1 expression, the choice is less clear and wrought with uncertainties – particularly for certain subgroups like never-smokers and those with PD-L1 expression over 90%, she said.
The findings reinforce those seen in prior meta-analyses and other clinical trials, particularly with respect to the role of smoking history when making treatment decisions.
“After these results and previous subgroup analyses, in my opinion, in [patients with] PD-L1 expression over 50%, we should consider the combination of chemotherapy and immunotherapy,” she said.
Conversely, findings from this study showing no difference in outcomes between the treatment approaches in patients with brain or liver metastases are based on small numbers and lack power for drawing any conclusions, she said. It also remains unclear whether there is a differential effect for women and those with PD-L1 expression over 90%, high tumor mutation burden, performance score greater than 2, and age over 75 years.
Both Dr. Garassino and Dr. Peters said they are looking to the INSIGNA trial, which is currently recruiting patients in the United States to evaluate the timing of pembrolizumab alone or with chemotherapy as first-line treatment and maintenance in NSCLC, to provide more clarification regarding the best treatment approaches.
This study was funded by F. Hoffmann–La Roche. Dr. Peters and Dr. Garassino each disclosed personal and/or institutional financial relationships with numerous pharmaceutical companies.
Median overall survival was similar at 21.0 months and 22.1 months in 169 patients who received cancer immunotherapy plus chemotherapy and 351 who received cancer immunotherapy monotherapy, respectively (adjusted hazard ratio, 1.03). Median real-world progression-free survival (PFS) was also similar in the two groups (10.8 vs. 11.5 months; aHR, 1.04), Solange Peters, MD, reported at the 2021 European Society for Medical Oncology Congress on Sept. 17 (abstract VP2_2021).
However, in a small subgroup of 50 never-smokers, CIT plus chemotherapy showed significant and meaningful improvement in both overall survival and real-world progression-free survival, compared with CIT monotherapy, said Dr. Peters, ESMO president and professor and chair of medical oncology at the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
The hazard ratios for overall survival and progression-free survival, after adjusting for baseline characteristics, were 0.50 and 0.40 in this subgroup, Dr. Peters said.
She and her colleagues reviewed data from the nationwide Flatiron Health Electronic Health Record–derived deidentified database for patients with metastatic nonsquamous NSCLC with a PD-L1 tumor proportion score at least 50% expression who initiated first-line CIT monotherapy or CIT plus chemotherapy between Oct. 24, 2016, and Feb. 28, 2019.
Median follow-up was 23.5 and 19.9 months in the monotherapy and combination therapy groups, respectively.
The findings are notable because “this is a very important scientific question, which by the way, is a daily question we have,” Dr. Peters said during a plenary debate session at the conference.
“One in four patients [with metastatic nonsquamous NSCLC has] this high PDL expression,” she explained, noting that both treatment approaches are commonly used in the first-line setting in this patient population.
The findings highlight the value of “well-conducted real-world evidence trials” in the absence of randomized trial results, she said.
Invited discussant Marina Chiara Garassino, MBBS, professor of medicine at the University of Chicago, also acknowledged the importance of the findings, noting the “multiple possibilities” for treatment selection in the metastatic nonsquamous NSCLC patient population.
Although patients with PD-L1 expression below 50% derive clear benefit from combination versus single-agent therapy, treatment selection for those with high PD-L1 expression is “very tricky and debatable,” she said.
For those with high PD-L1 expression, the choice is less clear and wrought with uncertainties – particularly for certain subgroups like never-smokers and those with PD-L1 expression over 90%, she said.
The findings reinforce those seen in prior meta-analyses and other clinical trials, particularly with respect to the role of smoking history when making treatment decisions.
“After these results and previous subgroup analyses, in my opinion, in [patients with] PD-L1 expression over 50%, we should consider the combination of chemotherapy and immunotherapy,” she said.
Conversely, findings from this study showing no difference in outcomes between the treatment approaches in patients with brain or liver metastases are based on small numbers and lack power for drawing any conclusions, she said. It also remains unclear whether there is a differential effect for women and those with PD-L1 expression over 90%, high tumor mutation burden, performance score greater than 2, and age over 75 years.
Both Dr. Garassino and Dr. Peters said they are looking to the INSIGNA trial, which is currently recruiting patients in the United States to evaluate the timing of pembrolizumab alone or with chemotherapy as first-line treatment and maintenance in NSCLC, to provide more clarification regarding the best treatment approaches.
This study was funded by F. Hoffmann–La Roche. Dr. Peters and Dr. Garassino each disclosed personal and/or institutional financial relationships with numerous pharmaceutical companies.
Median overall survival was similar at 21.0 months and 22.1 months in 169 patients who received cancer immunotherapy plus chemotherapy and 351 who received cancer immunotherapy monotherapy, respectively (adjusted hazard ratio, 1.03). Median real-world progression-free survival (PFS) was also similar in the two groups (10.8 vs. 11.5 months; aHR, 1.04), Solange Peters, MD, reported at the 2021 European Society for Medical Oncology Congress on Sept. 17 (abstract VP2_2021).
However, in a small subgroup of 50 never-smokers, CIT plus chemotherapy showed significant and meaningful improvement in both overall survival and real-world progression-free survival, compared with CIT monotherapy, said Dr. Peters, ESMO president and professor and chair of medical oncology at the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
The hazard ratios for overall survival and progression-free survival, after adjusting for baseline characteristics, were 0.50 and 0.40 in this subgroup, Dr. Peters said.
She and her colleagues reviewed data from the nationwide Flatiron Health Electronic Health Record–derived deidentified database for patients with metastatic nonsquamous NSCLC with a PD-L1 tumor proportion score at least 50% expression who initiated first-line CIT monotherapy or CIT plus chemotherapy between Oct. 24, 2016, and Feb. 28, 2019.
Median follow-up was 23.5 and 19.9 months in the monotherapy and combination therapy groups, respectively.
The findings are notable because “this is a very important scientific question, which by the way, is a daily question we have,” Dr. Peters said during a plenary debate session at the conference.
“One in four patients [with metastatic nonsquamous NSCLC has] this high PDL expression,” she explained, noting that both treatment approaches are commonly used in the first-line setting in this patient population.
The findings highlight the value of “well-conducted real-world evidence trials” in the absence of randomized trial results, she said.
Invited discussant Marina Chiara Garassino, MBBS, professor of medicine at the University of Chicago, also acknowledged the importance of the findings, noting the “multiple possibilities” for treatment selection in the metastatic nonsquamous NSCLC patient population.
Although patients with PD-L1 expression below 50% derive clear benefit from combination versus single-agent therapy, treatment selection for those with high PD-L1 expression is “very tricky and debatable,” she said.
For those with high PD-L1 expression, the choice is less clear and wrought with uncertainties – particularly for certain subgroups like never-smokers and those with PD-L1 expression over 90%, she said.
The findings reinforce those seen in prior meta-analyses and other clinical trials, particularly with respect to the role of smoking history when making treatment decisions.
“After these results and previous subgroup analyses, in my opinion, in [patients with] PD-L1 expression over 50%, we should consider the combination of chemotherapy and immunotherapy,” she said.
Conversely, findings from this study showing no difference in outcomes between the treatment approaches in patients with brain or liver metastases are based on small numbers and lack power for drawing any conclusions, she said. It also remains unclear whether there is a differential effect for women and those with PD-L1 expression over 90%, high tumor mutation burden, performance score greater than 2, and age over 75 years.
Both Dr. Garassino and Dr. Peters said they are looking to the INSIGNA trial, which is currently recruiting patients in the United States to evaluate the timing of pembrolizumab alone or with chemotherapy as first-line treatment and maintenance in NSCLC, to provide more clarification regarding the best treatment approaches.
This study was funded by F. Hoffmann–La Roche. Dr. Peters and Dr. Garassino each disclosed personal and/or institutional financial relationships with numerous pharmaceutical companies.
FROM ESMO 2021
First-line bevacizumab-osimertinib disappoint in EGFR-mutant NSCLC
Median progression-free survival (PFS) was 20.2 months in 61 patients in the osimertinib monotherapy arm and 22.1 months in 61 patients in the combination treatment arm (hazard ratio, 0.862), Hirotsugu Kenmotsu, MD, PhD, reported at the 2021 Congress of the European Society for Medical Oncology Sept. 18 (abstract LBA44).
“The study did not meet the primary endpoint,” said Dr. Kenmotsu of Shizuoka Cancer Center, Nagaizumi, Japan. “One-year progression-free survival was 63.7% and 73.8%, respectively.
However, subgroup analyses showed a trend toward improved PFS with combination bevacizumab and osimertinib in ever-smokers (HR, 0.481) and patients with Del19 mutations (HR, 0.622), he said.
Bevacizumab was also associated with a significant reduction in the risk of pneumonitis, an interstitial lung disease (ILD): Pneumonitis occurred in 18.3% of patients in the combination therapy arm, compared with 3.3% in the osimertinib monotherapy arm.
Study participants were untreated patients with advanced nonsquamous NSCLC harboring an EGFR-sensitizing mutation – either Del19 or L858R – without symptomatic brain metastases. They were enrolled between January 2018 and September 2018 and randomized to receive 80 mg of osimertinib daily, either alone or with 15 mg/kg of bevacizumab every 3 weeks.
The objective response rate was 82% in the combination therapy arm and 86% in osimertinib monotherapy arm, Dr. Kenmotsu said, adding that overall survival data are not yet mature.
Grade 3-4 adverse events occurred in 34 patients (56%) in the combination therapy arm and in 29 patients (48%) in the osimertinib monotherapy arm, he noted.
Osimertinib, a third-generation EGFR tyrosine kinase inhibitor has been a standard first-line treatment for NSCLC harboring activating EGFR mutations, he explained, noting that prior studies have shown promise for improved PFS with the addition of antivascular endothelial growth factor inhibitors to first-generation EGFR TKIs in this population.
Although the current study failed to show efficacy of the combination therapy versus osimertinib monotherapy for improving PFS in nonsquamous NSCLC harboring EGFR mutation, ever-smokers and patients with exon 19 deletions might benefit from the combination therapy as first-line treatment, and the combination might also reduce the risk of osimertinib-related pneumonitis, Dr. Kenmotsu said.
The study is among those that address “really important questions in lung cancer today,” said invited discussant Natasha B. Leighl, MD, professor of medicine at the University of Toronto’s Princess Margaret Cancer Center.
“I certainly agree with the authors that this study is a negative trial and bevacizumab does not improve PFS over the standard of osimertinib alone,” she said, acknowledging that the study is the first randomized comparison of the two treatment approaches in the first-line setting. She also agreed with the authors that the subgroup findings are intriguing.
“But ... what is the biomarker?” she asked, referring to the “very interesting” finding of a possible bevacizumab benefit among ever-smokers. “I’m looking forward to more correlative studies to help define this further.”
The novel finding of a significantly reduced risk of pneumonitis with the addition of bevacizumab, on the other hand, is “extremely exciting,” she said, explaining that the combination therapy approach could “perhaps [be used] as a potential therapy for patients with TKI-induced ILD and no other options, or those at very high risk of ILD, for example, perhaps, post immunotherapy or in high-risk populations.”
This study was funded by AstraZeneca. Dr. Kenmotsu and Dr. Leigh each disclosed financial relationships with numerous pharmaceutical companies.
This article was updated Sept. 24, 2021.
Median progression-free survival (PFS) was 20.2 months in 61 patients in the osimertinib monotherapy arm and 22.1 months in 61 patients in the combination treatment arm (hazard ratio, 0.862), Hirotsugu Kenmotsu, MD, PhD, reported at the 2021 Congress of the European Society for Medical Oncology Sept. 18 (abstract LBA44).
“The study did not meet the primary endpoint,” said Dr. Kenmotsu of Shizuoka Cancer Center, Nagaizumi, Japan. “One-year progression-free survival was 63.7% and 73.8%, respectively.
However, subgroup analyses showed a trend toward improved PFS with combination bevacizumab and osimertinib in ever-smokers (HR, 0.481) and patients with Del19 mutations (HR, 0.622), he said.
Bevacizumab was also associated with a significant reduction in the risk of pneumonitis, an interstitial lung disease (ILD): Pneumonitis occurred in 18.3% of patients in the combination therapy arm, compared with 3.3% in the osimertinib monotherapy arm.
Study participants were untreated patients with advanced nonsquamous NSCLC harboring an EGFR-sensitizing mutation – either Del19 or L858R – without symptomatic brain metastases. They were enrolled between January 2018 and September 2018 and randomized to receive 80 mg of osimertinib daily, either alone or with 15 mg/kg of bevacizumab every 3 weeks.
The objective response rate was 82% in the combination therapy arm and 86% in osimertinib monotherapy arm, Dr. Kenmotsu said, adding that overall survival data are not yet mature.
Grade 3-4 adverse events occurred in 34 patients (56%) in the combination therapy arm and in 29 patients (48%) in the osimertinib monotherapy arm, he noted.
Osimertinib, a third-generation EGFR tyrosine kinase inhibitor has been a standard first-line treatment for NSCLC harboring activating EGFR mutations, he explained, noting that prior studies have shown promise for improved PFS with the addition of antivascular endothelial growth factor inhibitors to first-generation EGFR TKIs in this population.
Although the current study failed to show efficacy of the combination therapy versus osimertinib monotherapy for improving PFS in nonsquamous NSCLC harboring EGFR mutation, ever-smokers and patients with exon 19 deletions might benefit from the combination therapy as first-line treatment, and the combination might also reduce the risk of osimertinib-related pneumonitis, Dr. Kenmotsu said.
The study is among those that address “really important questions in lung cancer today,” said invited discussant Natasha B. Leighl, MD, professor of medicine at the University of Toronto’s Princess Margaret Cancer Center.
“I certainly agree with the authors that this study is a negative trial and bevacizumab does not improve PFS over the standard of osimertinib alone,” she said, acknowledging that the study is the first randomized comparison of the two treatment approaches in the first-line setting. She also agreed with the authors that the subgroup findings are intriguing.
“But ... what is the biomarker?” she asked, referring to the “very interesting” finding of a possible bevacizumab benefit among ever-smokers. “I’m looking forward to more correlative studies to help define this further.”
The novel finding of a significantly reduced risk of pneumonitis with the addition of bevacizumab, on the other hand, is “extremely exciting,” she said, explaining that the combination therapy approach could “perhaps [be used] as a potential therapy for patients with TKI-induced ILD and no other options, or those at very high risk of ILD, for example, perhaps, post immunotherapy or in high-risk populations.”
This study was funded by AstraZeneca. Dr. Kenmotsu and Dr. Leigh each disclosed financial relationships with numerous pharmaceutical companies.
This article was updated Sept. 24, 2021.
Median progression-free survival (PFS) was 20.2 months in 61 patients in the osimertinib monotherapy arm and 22.1 months in 61 patients in the combination treatment arm (hazard ratio, 0.862), Hirotsugu Kenmotsu, MD, PhD, reported at the 2021 Congress of the European Society for Medical Oncology Sept. 18 (abstract LBA44).
“The study did not meet the primary endpoint,” said Dr. Kenmotsu of Shizuoka Cancer Center, Nagaizumi, Japan. “One-year progression-free survival was 63.7% and 73.8%, respectively.
However, subgroup analyses showed a trend toward improved PFS with combination bevacizumab and osimertinib in ever-smokers (HR, 0.481) and patients with Del19 mutations (HR, 0.622), he said.
Bevacizumab was also associated with a significant reduction in the risk of pneumonitis, an interstitial lung disease (ILD): Pneumonitis occurred in 18.3% of patients in the combination therapy arm, compared with 3.3% in the osimertinib monotherapy arm.
Study participants were untreated patients with advanced nonsquamous NSCLC harboring an EGFR-sensitizing mutation – either Del19 or L858R – without symptomatic brain metastases. They were enrolled between January 2018 and September 2018 and randomized to receive 80 mg of osimertinib daily, either alone or with 15 mg/kg of bevacizumab every 3 weeks.
The objective response rate was 82% in the combination therapy arm and 86% in osimertinib monotherapy arm, Dr. Kenmotsu said, adding that overall survival data are not yet mature.
Grade 3-4 adverse events occurred in 34 patients (56%) in the combination therapy arm and in 29 patients (48%) in the osimertinib monotherapy arm, he noted.
Osimertinib, a third-generation EGFR tyrosine kinase inhibitor has been a standard first-line treatment for NSCLC harboring activating EGFR mutations, he explained, noting that prior studies have shown promise for improved PFS with the addition of antivascular endothelial growth factor inhibitors to first-generation EGFR TKIs in this population.
Although the current study failed to show efficacy of the combination therapy versus osimertinib monotherapy for improving PFS in nonsquamous NSCLC harboring EGFR mutation, ever-smokers and patients with exon 19 deletions might benefit from the combination therapy as first-line treatment, and the combination might also reduce the risk of osimertinib-related pneumonitis, Dr. Kenmotsu said.
The study is among those that address “really important questions in lung cancer today,” said invited discussant Natasha B. Leighl, MD, professor of medicine at the University of Toronto’s Princess Margaret Cancer Center.
“I certainly agree with the authors that this study is a negative trial and bevacizumab does not improve PFS over the standard of osimertinib alone,” she said, acknowledging that the study is the first randomized comparison of the two treatment approaches in the first-line setting. She also agreed with the authors that the subgroup findings are intriguing.
“But ... what is the biomarker?” she asked, referring to the “very interesting” finding of a possible bevacizumab benefit among ever-smokers. “I’m looking forward to more correlative studies to help define this further.”
The novel finding of a significantly reduced risk of pneumonitis with the addition of bevacizumab, on the other hand, is “extremely exciting,” she said, explaining that the combination therapy approach could “perhaps [be used] as a potential therapy for patients with TKI-induced ILD and no other options, or those at very high risk of ILD, for example, perhaps, post immunotherapy or in high-risk populations.”
This study was funded by AstraZeneca. Dr. Kenmotsu and Dr. Leigh each disclosed financial relationships with numerous pharmaceutical companies.
This article was updated Sept. 24, 2021.
FROM ESMO 2021
Combination treatment shows promise for men with advanced prostate cancer
The findings were specific to patients not yet been treated with chemotherapy and whose tumors were positive for homologous recombination deficiency (HRD). However, for patients whose tumors were negative for HRD, the clinical activity was limited, said Daniel P. Petrylak, MD, Yale University, New Haven, Conn., and lead investigator for the study called CheckMate 9KD (NCT03338790) .
The patients who were included in all CheckMate 9KD cohorts had no prior treatment with targeted T-cell co-stimulation or immune checkpoint pathways. They had metastatic castrate resistant prostate cancer with documented disease progression, ECOG performance status of 0-1, and tissue available for HRD testing.
Dr. Petrylak offered an updated analysis of cohort A2 with 71 patients (median age 73 years), all of whom had received 1-2 prior new hormonal therapies in the pre-chemotherapy setting. Patients who had received prior PARP inhibitors were ineligible, as were those who refused chemotherapy treatment.
ORR/PSA RR primary endpoints
Patients received nivolumab and rucaparib, nivolumab at 480 mg (q4 weeks up to 2 years) and rucaparib at 600 mg b.i.d., until disease progression or unacceptable toxicity. Objective response rate and PSA response rate (PSA-RR) were the primary endpoint, with overall survival as a secondary endpoint, along with time to objective response, duration of objective response, time to PSA progression, safety, and radiographic progression-free survival.
Median follow-up was 17.5 months with median treatment duration of 4.6 months in the nivolumab group and 5.5 months for rucaparib. At the time of the final database lock in March 2021, 65 patients (91.5%) had discontinued treatment, most often for disease progression (n = 43; 60.6%) or study drug toxicity (n = 8; 11.3%). Four patients (5.6%) remained on treatment.
Better responses for HRD and BRCA 1/2 positive
Stratifying response outcomes showed higher rates for patients who were HRD positive and BRCA1/2 positive for confirmed objective response rate (HRD+ 25.0%, BRCA 1/2+ 33.3%, HRD-/not evaluable 5.3%, all patients 15.4%) and for PSA response (HRD+ 41.9%, BRCA 1/2+ 84.6%, HRD-/not evaluable 14.3%, all patients 27.3%). Partial response rates were 33.3% for BRCA 1/2, 25.0% for HRD positive, 5.3% for HRD- and 15.4% for all patients. Radiographic progression-free survival was longer in the HRD positive group at a median of 10.9 months (95% CI 6.7-12.0), compared with 5.6 months (3.7-9.1) in the HRD-/not evaluable group. Overall survival was similar in the HRD negative group/not evaluable group at 19.0 months (8.2-22.1) and the HRD positive group at 22.7 months (14.1-NE).
Safety profile as expected
Treatment-related adverse events were reported for most patients (64/71, 90.1%), with grade 3-4 events in about half (50.7%). The most common event was grade 1-2 nausea (40.8%), with anemia at 32.4% and alanine aminotransferase (ALT) increases and fatigue both at 28.2%. Adverse events led to discontinuation in 23.9% of patients, with anemia and increased ALT leading both at 4.2%. Grade 3-4 adverse events led to discontinuation in 15.5% of patients. Investigators reported no treatment-related deaths. “The safety profile of nivolumab plus rucaparib was as expected based on the individual components with no new safety signals,” Dr. Petrylak said.
Longer follow-up is needed, Dr. Petrylak added, to better characterize the clinical benefits of adding nivolumab to rucaparib for this population.
Discussion moderator Guilia Baciarello, MD, Milan, asked how much nivolumab added to the rucaparib benefit. Dr. Petrylak responded, “We really can’t determine how much it’s adding because the single-agent data, particularly with the checkpoints, is generally very low. I can’t recall any published data with nivolumab as a single agent, but for example with pembrolizumab or atezolizumab in unselected patients it’s 5%-10%. So, we really can’t tell how much nivolumab added in the BRCA positive patients.”
Dr. Baciarello asked, “Will there be a nivolumab versus rucaparib trial in HRD positive patients?”
“I think that’s something that needs to be considered. I think we may also want to consider doing a broader phase II in that group of patients to really nail down the signal. That’s under discussion,” Dr. Petrylak said.
The study was funded by Bristol Myers Squibb. Dr. Petrylak disclosed numerous financial interests including personal and consulting fees.
This article was updated Sept. 24, 2021.
The findings were specific to patients not yet been treated with chemotherapy and whose tumors were positive for homologous recombination deficiency (HRD). However, for patients whose tumors were negative for HRD, the clinical activity was limited, said Daniel P. Petrylak, MD, Yale University, New Haven, Conn., and lead investigator for the study called CheckMate 9KD (NCT03338790) .
The patients who were included in all CheckMate 9KD cohorts had no prior treatment with targeted T-cell co-stimulation or immune checkpoint pathways. They had metastatic castrate resistant prostate cancer with documented disease progression, ECOG performance status of 0-1, and tissue available for HRD testing.
Dr. Petrylak offered an updated analysis of cohort A2 with 71 patients (median age 73 years), all of whom had received 1-2 prior new hormonal therapies in the pre-chemotherapy setting. Patients who had received prior PARP inhibitors were ineligible, as were those who refused chemotherapy treatment.
ORR/PSA RR primary endpoints
Patients received nivolumab and rucaparib, nivolumab at 480 mg (q4 weeks up to 2 years) and rucaparib at 600 mg b.i.d., until disease progression or unacceptable toxicity. Objective response rate and PSA response rate (PSA-RR) were the primary endpoint, with overall survival as a secondary endpoint, along with time to objective response, duration of objective response, time to PSA progression, safety, and radiographic progression-free survival.
Median follow-up was 17.5 months with median treatment duration of 4.6 months in the nivolumab group and 5.5 months for rucaparib. At the time of the final database lock in March 2021, 65 patients (91.5%) had discontinued treatment, most often for disease progression (n = 43; 60.6%) or study drug toxicity (n = 8; 11.3%). Four patients (5.6%) remained on treatment.
Better responses for HRD and BRCA 1/2 positive
Stratifying response outcomes showed higher rates for patients who were HRD positive and BRCA1/2 positive for confirmed objective response rate (HRD+ 25.0%, BRCA 1/2+ 33.3%, HRD-/not evaluable 5.3%, all patients 15.4%) and for PSA response (HRD+ 41.9%, BRCA 1/2+ 84.6%, HRD-/not evaluable 14.3%, all patients 27.3%). Partial response rates were 33.3% for BRCA 1/2, 25.0% for HRD positive, 5.3% for HRD- and 15.4% for all patients. Radiographic progression-free survival was longer in the HRD positive group at a median of 10.9 months (95% CI 6.7-12.0), compared with 5.6 months (3.7-9.1) in the HRD-/not evaluable group. Overall survival was similar in the HRD negative group/not evaluable group at 19.0 months (8.2-22.1) and the HRD positive group at 22.7 months (14.1-NE).
Safety profile as expected
Treatment-related adverse events were reported for most patients (64/71, 90.1%), with grade 3-4 events in about half (50.7%). The most common event was grade 1-2 nausea (40.8%), with anemia at 32.4% and alanine aminotransferase (ALT) increases and fatigue both at 28.2%. Adverse events led to discontinuation in 23.9% of patients, with anemia and increased ALT leading both at 4.2%. Grade 3-4 adverse events led to discontinuation in 15.5% of patients. Investigators reported no treatment-related deaths. “The safety profile of nivolumab plus rucaparib was as expected based on the individual components with no new safety signals,” Dr. Petrylak said.
Longer follow-up is needed, Dr. Petrylak added, to better characterize the clinical benefits of adding nivolumab to rucaparib for this population.
Discussion moderator Guilia Baciarello, MD, Milan, asked how much nivolumab added to the rucaparib benefit. Dr. Petrylak responded, “We really can’t determine how much it’s adding because the single-agent data, particularly with the checkpoints, is generally very low. I can’t recall any published data with nivolumab as a single agent, but for example with pembrolizumab or atezolizumab in unselected patients it’s 5%-10%. So, we really can’t tell how much nivolumab added in the BRCA positive patients.”
Dr. Baciarello asked, “Will there be a nivolumab versus rucaparib trial in HRD positive patients?”
“I think that’s something that needs to be considered. I think we may also want to consider doing a broader phase II in that group of patients to really nail down the signal. That’s under discussion,” Dr. Petrylak said.
The study was funded by Bristol Myers Squibb. Dr. Petrylak disclosed numerous financial interests including personal and consulting fees.
This article was updated Sept. 24, 2021.
The findings were specific to patients not yet been treated with chemotherapy and whose tumors were positive for homologous recombination deficiency (HRD). However, for patients whose tumors were negative for HRD, the clinical activity was limited, said Daniel P. Petrylak, MD, Yale University, New Haven, Conn., and lead investigator for the study called CheckMate 9KD (NCT03338790) .
The patients who were included in all CheckMate 9KD cohorts had no prior treatment with targeted T-cell co-stimulation or immune checkpoint pathways. They had metastatic castrate resistant prostate cancer with documented disease progression, ECOG performance status of 0-1, and tissue available for HRD testing.
Dr. Petrylak offered an updated analysis of cohort A2 with 71 patients (median age 73 years), all of whom had received 1-2 prior new hormonal therapies in the pre-chemotherapy setting. Patients who had received prior PARP inhibitors were ineligible, as were those who refused chemotherapy treatment.
ORR/PSA RR primary endpoints
Patients received nivolumab and rucaparib, nivolumab at 480 mg (q4 weeks up to 2 years) and rucaparib at 600 mg b.i.d., until disease progression or unacceptable toxicity. Objective response rate and PSA response rate (PSA-RR) were the primary endpoint, with overall survival as a secondary endpoint, along with time to objective response, duration of objective response, time to PSA progression, safety, and radiographic progression-free survival.
Median follow-up was 17.5 months with median treatment duration of 4.6 months in the nivolumab group and 5.5 months for rucaparib. At the time of the final database lock in March 2021, 65 patients (91.5%) had discontinued treatment, most often for disease progression (n = 43; 60.6%) or study drug toxicity (n = 8; 11.3%). Four patients (5.6%) remained on treatment.
Better responses for HRD and BRCA 1/2 positive
Stratifying response outcomes showed higher rates for patients who were HRD positive and BRCA1/2 positive for confirmed objective response rate (HRD+ 25.0%, BRCA 1/2+ 33.3%, HRD-/not evaluable 5.3%, all patients 15.4%) and for PSA response (HRD+ 41.9%, BRCA 1/2+ 84.6%, HRD-/not evaluable 14.3%, all patients 27.3%). Partial response rates were 33.3% for BRCA 1/2, 25.0% for HRD positive, 5.3% for HRD- and 15.4% for all patients. Radiographic progression-free survival was longer in the HRD positive group at a median of 10.9 months (95% CI 6.7-12.0), compared with 5.6 months (3.7-9.1) in the HRD-/not evaluable group. Overall survival was similar in the HRD negative group/not evaluable group at 19.0 months (8.2-22.1) and the HRD positive group at 22.7 months (14.1-NE).
Safety profile as expected
Treatment-related adverse events were reported for most patients (64/71, 90.1%), with grade 3-4 events in about half (50.7%). The most common event was grade 1-2 nausea (40.8%), with anemia at 32.4% and alanine aminotransferase (ALT) increases and fatigue both at 28.2%. Adverse events led to discontinuation in 23.9% of patients, with anemia and increased ALT leading both at 4.2%. Grade 3-4 adverse events led to discontinuation in 15.5% of patients. Investigators reported no treatment-related deaths. “The safety profile of nivolumab plus rucaparib was as expected based on the individual components with no new safety signals,” Dr. Petrylak said.
Longer follow-up is needed, Dr. Petrylak added, to better characterize the clinical benefits of adding nivolumab to rucaparib for this population.
Discussion moderator Guilia Baciarello, MD, Milan, asked how much nivolumab added to the rucaparib benefit. Dr. Petrylak responded, “We really can’t determine how much it’s adding because the single-agent data, particularly with the checkpoints, is generally very low. I can’t recall any published data with nivolumab as a single agent, but for example with pembrolizumab or atezolizumab in unselected patients it’s 5%-10%. So, we really can’t tell how much nivolumab added in the BRCA positive patients.”
Dr. Baciarello asked, “Will there be a nivolumab versus rucaparib trial in HRD positive patients?”
“I think that’s something that needs to be considered. I think we may also want to consider doing a broader phase II in that group of patients to really nail down the signal. That’s under discussion,” Dr. Petrylak said.
The study was funded by Bristol Myers Squibb. Dr. Petrylak disclosed numerous financial interests including personal and consulting fees.
This article was updated Sept. 24, 2021.
FROM ESMO 2021