Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer
University of Las Palmas de Gran Canaria1, Sunnybrook Health Sciences Centre2, Autonomous University of Barcelona3, Sanford Health4, Tel Aviv University5, University of Turin6, University of California, Los Angeles7, Kansai Medical University8, Epworth Hospital9, University of Sydney10, University of South Florida11, Merck & Co.12
16 Apr 2018-The New England Journal of Medicine (Massachusetts Medical Society)-Vol. 378, Iss: 22, pp 2078-2092
TL;DR: In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum‐based drug resulted in significantly longer overall survival and progression‐free survival than chemotherapy alone.
Abstract: Background First-line therapy for advanced non–small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial. Methods In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy...
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TL;DR: Atezolizumab plus nab‐paclitaxel prolonged progression‐free survival among patients with metastatic triple‐negative breast cancer in both the intention‐to‐treat population and the PD‐L1–positive subgroup.
Abstract: Background Unresectable locally advanced or metastatic triple-negative (hormone-receptor–negative and human epidermal growth factor receptor 2 [HER2]–negative) breast cancer is an aggressive disease with poor outcomes. Nanoparticle albumin-bound (nab)–paclitaxel may enhance the anticancer activity of atezolizumab. Methods In this phase 3 trial, we randomly assigned (in a 1:1 ratio) patients with untreated metastatic triple-negative breast cancer to receive atezolizumab plus nab-paclitaxel or placebo plus nab-paclitaxel; patients continued the intervention until disease progression or an unacceptable level of toxic effects occurred. Stratification factors were the receipt or nonreceipt of neoadjuvant or adjuvant taxane therapy, the presence or absence of liver metastases at baseline, and programmed death ligand 1 (PD-L1) expression at baseline (positive vs. negative). The two primary end points were progression-free survival (in the intention-to-treat population and PD-L1–positive subgroup) and ov...
2,604 citations
TL;DR: The addition of atezolizumab to bevacIZumab plus chemotherapy significantly improved progression‐free survival and overall survival among patients with metastatic nonsquamous NSCLC, regardless of PD‐L1 expression and EGFR or ALK genetic alteration status.
Abstract: Background The cancer-cell–killing property of atezolizumab may be enhanced by the blockade of vascular endothelial growth factor–mediated immunosuppression with bevacizumab. This open-label, phase 3 study evaluated atezolizumab plus bevacizumab plus chemotherapy in patients with metastatic nonsquamous non–small-cell lung cancer (NSCLC) who had not previously received chemotherapy. Methods We randomly assigned patients to receive atezolizumab plus carboplatin plus paclitaxel (ACP), bevacizumab plus carboplatin plus paclitaxel (BCP), or atezolizumab plus BCP (ABCP) every 3 weeks for four or six cycles, followed by maintenance therapy with atezolizumab, bevacizumab, or both. The two primary end points were investigator-assessed progression-free survival both among patients in the intention-to-treat population who had a wild-type genotype (WT population; patients with EGFR or ALK genetic alterations were excluded) and among patients in the WT population who had high expression of an effector T-cell (Teff) gene signature in the tumor (Teff-high WT population) and overall survival in the WT population. The ABCP group was compared with the BCP group before the ACP group was compared with the BCP group. Results In the WT population, 356 patients were assigned to the ABCP group, and 336 to the BCP group. The median progression-free survival was longer in the ABCP group than in the BCP group (8.3 months vs. 6.8 months; hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.52 to 0.74; P<0.001); the corresponding values in the Teff-high WT population were 11.3 months and 6.8 months (hazard ratio, 0.51 [95% CI, 0.38 to 0.68]; P<0.001). Progression-free survival was also longer in the ABCP group than in the BCP group in the entire intention-to-treat population (including those with EGFR or ALK genetic alterations) and among patients with low or negative programmed death ligand 1 (PD-L1) expression, those with low Teff gene-signature expression, and those with liver metastases. Median overall survival among the patients in the WT population was longer in the ABCP group than in the BCP group (19.2 months vs. 14.7 months; hazard ratio for death, 0.78; 95% CI, 0.64 to 0.96; P=0.02). The safety profile of ABCP was consistent with previously reported safety risks of the individual medicines. Conclusions The addition of atezolizumab to bevacizumab plus chemotherapy significantly improved progression-free survival and overall survival among patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression and EGFR or ALK genetic alteration status. (Funded by F. Hoffmann–La Roche/Genentech; IMpower150 ClinicalTrials.gov number, NCT02366143.)
2,464 citations
University of Turin1, Aix-Marseille University2, National Health Service3, University Hospital of South Manchester NHS Foundation Trust4, University of Ljubljana5, Karolinska University Hospital6, Centre Hospitalier Universitaire de Grenoble7, University of Aberdeen8, The Royal Marsden NHS Foundation Trust9, VU University Medical Center10, University of Salamanca11, Katholieke Universiteit Leuven12, University Hospital of Lausanne13
TL;DR: The ESMO Guidelines Committee concluded that current state-of-the-art oncology practices in France, Belgium, and the Netherlands are suitable for frontline use and recommend further research into these practices.
2,349 citations
Cites methods from "Pembrolizumab plus Chemotherapy in ..."
...In KEYNOTE-189, patients with metastatic non-squamous NSCLC, PS 0–1, without sensitising EGFR or ALK mutations, were randomised to receive pemetrexed and a platinum-based ChT plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy [96]....
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TL;DR: In patients with previously untreated metastatic, squamous NSCLC, the addition of pembrolizumab to chemotherapy with carboplatin plus pac litaxel or nab‐paclitaxel resulted in significantly longer overall survival and progression‐free survival than chemotherapy alone.
Abstract: Background Standard first-line therapy for metastatic, squamous non–small-cell lung cancer (NSCLC) is platinum-based chemotherapy or pembrolizumab (for patients with programmed death ligand 1 [PD-L1] expression on ≥50% of tumor cells). More recently, pembrolizumab plus chemotherapy was shown to significantly prolong overall survival among patients with nonsquamous NSCLC. Methods In this double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, 559 patients with untreated metastatic, squamous NSCLC to receive 200 mg of pembrolizumab or saline placebo for up to 35 cycles; all the patients also received carboplatin and either paclitaxel or nanoparticle albumin-bound [nab]–paclitaxel for the first 4 cycles. Primary end points were overall survival and progression-free survival. Results After a median follow-up of 7.8 months, the median overall survival was 15.9 months (95% confidence interval [CI], 13.2 to not reached) in the pembrolizumab-combination group and 11.3 months (95% CI, 9.5 to 14...
2,307 citations
TL;DR: Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations, and the benefit-to-risk profile suggests that first-line pembrology monotherapy can be extended as first line therapy for locally advanced or metastatic non-small-cell lung cancer patients with sensitising EGFR or ALK translocation.
1,999 citations
References
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TL;DR: The Eastern Cooperative Oncology Group criteria for toxicity and response are presented to facilitate future reference and to encourage further standardization among those conducting clinical trials.
Abstract: STANDARD CRITERIA FOR TOXICITY and for response to treatment are important prerequisites to the conduct of cancer trials. The Eastern Cooperative Oncology Group criteria for toxicity and response are presented to facilitate future reference and to encourage further standardization among those conduc
9,661 citations
"Pembrolizumab plus Chemotherapy in ..." refers background in this paper
...‡ Eastern Cooperative Oncology Group (ECOG) performance-status scores range from 0 to 5, with 0 indicating no symptoms and higher scores indicating greater disability.(8) Data regarding the ECOG status were missing for 2 patients (0....
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TL;DR: Nivolumab was associated with even greater efficacy than docetaxel across all end points in subgroups defined according to prespecified levels of tumor-membrane expression (≥1, ≥5%, and ≥10%) of the PD-1 ligand.
Abstract: BackgroundNivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint–inhibitor antibody, disrupts PD-1–mediated signaling and may restore antitumor immunity. MethodsIn this randomized, open-label, international phase 3 study, we assigned patients with nonsquamous non–small-cell lung cancer (NSCLC) that had progressed during or after platinum-based doublet chemotherapy to receive nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks or docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. ResultsOverall survival was longer with nivolumab than with docetaxel. The median overall survival was 12.2 months (95% confidence interval [CI], 9.7 to 15.0) among 292 patients in the nivolumab group and 9.4 months (95% CI, 8.1 to 10.7) among 290 patients in the docetaxel group (hazard ratio for death, 0.73; 96% CI, 0.59 to 0.89; P=0.002). At 1 year, the overall survival rate was 51% (95% CI, 45 to 56) with nivolumab ve...
7,474 citations
TL;DR: Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non-small-cell lung cancer (NSCLC), with increased activity in tumors that express PD-L1 as mentioned in this paper.
Abstract: BackgroundPembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non–small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1). MethodsIn this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator’s choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety. ResultsMedi...
7,053 citations
Johns Hopkins University1, City of Hope National Medical Center2, Netherlands Cancer Institute3, University of Duisburg-Essen4, Russian Academy5, University of South Florida6, University of Chicago7, Duke University8, Harvard University9, Charles University in Prague10, Bristol-Myers Squibb11, Sarah Cannon Research Institute12, Erasmus University Rotterdam13, Autonomous University of Madrid14
TL;DR: Among patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level.
Abstract: BackgroundPatients with advanced squamous-cell non–small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint–inhibitor antibody, as compared with docetaxel in this patient population. MethodsWe randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. ResultsThe median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42% (95% CI, 3...
6,869 citations
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TL;DR: This paper is an overview of the new response evaluation criteria in solid tumours: revised RECIST guideline (version 1. 1), with a focus on updated contents.
Abstract: This paper is an overview of the new response evaluation criteria in solid tumours: revised RECIST guideline (version 1. 1), with a focus on updated contents.
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