LUGANO-COPENHAGEN - The addition of PD-1 antibody pembrolizumab to standard first-line chemotherapy for treatment-naïve advanced non-small-cell lung cancer significantly improves response rates and progression-free survival, researchers reported at the ESMO 2016 Congress in Copenhagen today.
Pembrolizumab is a class of immunotherapeutic anti-cancer drugs called checkpoint inhibitors, which target the mechanism the tumour uses to shut down the body’s immune response.
“Pembrolizumab enables T cells to ‘reactivate’ and accomplish what they are designed to do – facilitate tumour cell killing,” said principal investigator Dr Corey Langer, director of the Thoracic Oncology Program at the Abramson Cancer Center at the University of Pennsylvania, US.
In the phase II KEYNOTE-021 study, researchers randomized 123 patients with stage IIIB/IV, chemotherapy-naive, nonsquamous non-small-cell lung cancer to receive four cycles of carboplatin and pemetrexed (500 mg/m2 every three weeks), with or without 24 months treatment with pembrolizumab (200mg every three weeks).
After a median follow-up of 10.6 months, researchers observed a significantly greater objective response rate (55% vs. 29%, P = 0.0016) in the patients who received pembrolizumab as well as chemotherapy, compared to those treated with chemotherapy alone. While patients were not selected by the amount of PD-L1 expression in their tumour, researchers did note a higher response rate (around 80%) for the pembrolizumab and chemotherapy combination in tumours with PD-L1 expression greater than or equal to 50%.
Participants in the pembrolizumab arm also experienced an improved progression-free survival (median 13.0 months vs. 8.9 months) although overall survival rates were similar between the two arms (6 month survival rate = 92%), in this early landmark assessment.
There was a higher incidence of adverse events of grade 3 severity or above in the pembrolizumab arm compared to the chemotherapy alone arm (39% vs. 26%), but this had no impact on treatment discontinuation rates (10% for the pembrolizumab arm compared to 13% for the chemotherapy only arm) or treatment-related deaths. The most common treatment-related adverse events were fatigue and nausea, which were more common in patients receiving pembrolizumab, and anemia, which was more common in the chemotherapy alone arm of the study.
“This is the first randomized phase II trial in advanced, treatment-naïve non-squamous non-small-cell lung cancer to assess the benefit of adding a monoclonal antibody targeting PD1 to standard chemotherapy,” said Langer. “If these benefits are confirmed in an ongoing phase III trial, the results may radically alter the treatment paradigm in advanced non-small-cell lung cancer.”
Commenting on the study, Dr Raffaele Califano, Consultant in Medical Oncology at The Christie Hospital and University Hospital of South Manchester in Manchester, UK said: “Data for the combination of chemotherapy plus pembrolizumab in this population is certainly encouraging, and it is reassuring to see that the addition of pembrolizumab to first-line chemotherapy has a manageable toxicity profile and doesn’t increase the incidence of treatment-related adverse events or deaths.”
“Notably, the progression-free survival reported in the standard arm was much longer than expected and nearly doubled when compared to historical data, which could be due to patient selection or other clinical/molecular characteristics of the patients enrolled in this study,” Califano said.
“In order to establish if this strategy should be adopted in clinical practice, these results should be investigated further in a phase III randomized study with a similar design, adequately powered for progression-free survival and with robust assessment of patient’s reported outcomes.”
Notes to Editors
LBA46_PR - Randomized, phase 2 study of carboplatin and pemetrexed with or without pembrolizumab as first-line therapy for advanced NSCLC: KEYNOTE-021 cohort G will be presented by Dr Corey Langer during Presidential Symposium 2 on Sunday 9 October, 16:30 (CEST).
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Abstract for LBA46_PR
Randomized, phase 2 study of carboplatin and pemetrexed with or without pembrolizumab as first-line therapy for advanced NSCLC: KEYNOTE-021 cohort G
Authors: Corey J. Langer,1 Shirish Gadgeel,2 Hossein Borghaei,3 Vassiliki A. Papadimitrakopoulou,4 Amita Patnaik,5 Steven F. Powell,6 Ryan D. Gentzler,7 Renato G. Martins,8 James P. Stevenson,9 Shadia I. Jalal,10 Amit Panwalkar,11 James Chih-Hsin Yang,12 Matthew Gubens,13 Lecia V. Sequist,14 Mark M. Awad,15 Joseph Fiore,16 Yang Joy Ge,16 Harry Raftopoulos,16 Leena Gandhi15,17
Affiliations: 1Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA; 2Karmanos Cancer Institute/Wayne State University, Detroit, MI, USA; 3Fox Chase Cancer Center, Philadelphia, PA, USA; 4The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 5South Texas Accelerated Research Therapeutics, San Antonio, TX, USA; 6Sanford Cancer Center, University of South Dakota Sanford School of Medicine, Sioux Falls, SD, USA; 7Emily Couric Clinical Cancer Center, University of Virginia School of Medicine, Charlottesville, VA, USA; 8Seattle Cancer Care Alliance, Seattle, WA, USA; 9Cleveland Clinic, Cleveland, OH, USA; 10Indiana University School of Medicine, Indianapolis, IN, USA; 11Sanford Roger Maris Cancer Center, Fargo, ND, USA; 12National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan, Republic of China; 13University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; 14Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA; 15Dana-Farber Cancer Institute, Boston, MA, USA; 16Merck & Co., Inc., Kenilworth, NJ, USA; 17Current affiliation: Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York, USA
Background: Pembrolizumab (pembro) monotherapy exhibits robust antitumor activity in PD-L1─expressing advanced NSCLC. Cohort G of the multicenter, open-label, phase 1/2 KEYNOTE-021 study (NCT02039674) evaluated the efficacy and safety of pembro + carboplatin and pemetrexed (CP) vs CP alone as first-line therapy for advanced nonsquamous NSCLC.
Methods: Key eligibility criteria were stage IIIB/IV, chemotherapy-naive, nonsquamous NSCLC, ECOG PS 0-1, and no EGFR mutation or ALK translocation. Patients (pts) were randomized to 4 cycles of carboplatin AUC 5 + pemetrexed 500 mg/m2 Q3W ± 24 mo of pembro 200 mg Q3W; maintenance pemetrexed was allowed in both arms. Randomization was stratified by PD-L1 tumor proportion score ≥1% vs <1%. Eligible pts with radiologic progression on CP could crossover to pembro monotherapy. Primary end point was ORR, with PFS as the key secondary end point; both were assessed per RECIST v1.1 by blinded independent central review. ORR and PFS superiority thresholds were one-sided α = 0.025.
Results: 123 pts were enrolled: 60 in the pembro + CP arm, 63 in the CP arm. Demographics were generally balanced between treatment arms. As of Aug 8, 2016, median follow-up was 10.6 mo (range, 0.8-19.3); median exposure was 8.0 mo for pembro + CP and 4.9 mo for CP. In the CP arm, 43 pts discontinued therapy; 32 received subsequent anti–PD-1 therapy as part of crossover (n = 20) or off study (n = 12). Pembro + CP significantly improved ORR (55% vs 29%; P = 0.0016) and PFS (HR 0.53, 95% CI 0.31-0.91, P = 0.0102; median 13.0 vs 8.9 mo). Overall survival was similar; 6-mo survival rates were 92% in each arm. Without adjusting for exposure, for pembro + CP vs CP, treatment-related AEs led to discontinuation in10% vs 13%, were of grade ≥3 severity in 39% vs 26%, and led to death in 2% (sepsis, n = 1) vs 3% (sepsis and pancytopenia, n = 1 each). The most common any-grade treatment-related AEs were fatigue (64% vs 40%), nausea (58% vs 44%), and anemia (32% vs 53%).
Conclusions: Pembro 200 mg Q3W + CP demonstrated a statistically significant, clinically relevant ORR and PFS benefit over CP alone and had a manageable, safety profile as first-line therapy in patients with advanced nonsquamous NSCLC.