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Immunotherapy and chemo drug combo increases lung cancer survival rates

The immunotherapy drug pembrolizumab, when combined with chemotherapy, doubles survival in patients with non-squamous non-small cell lung cancer (NSNSCLC) lacking genetic changes in the EGFR or ALK genes, when compared to chemotherapy alone, according to an international, Phase III clinical trial.

Principal investigator Dr Leena Gandhi, director of the thoracic medical oncology programme at Perlmutter Cancer Centre at NYU Langone Health and associate professor of medicine in the division of medical oncology at NYU School of Medicine, presented these findings 16 April at the American Association for Cancer Research (AACR) Annual Meeting 2018 in Chicago.

A total of 616 patients with untreated, metastatic NSNSCLC without EGFR or ALK alterations, from 118 international sites, were randomly allocated for the trial – 405 patients were treated with both pembrolizumab and platinum + pemetrexed, and 202 received platinum + pemetrexed with a saline placebo.

Response rates, overall survival and progression-free survival rates were superior in the pembrolizumab and chemotherapy combination-treatment group.

Of those treated with pembrolizumab and platinum + pemetrexed, the risk of death was reduced by 51%, compared to those treated with platinum + pemetrexed alone. Among patients treated with the combination therapy, the chance of progression or death was reduced by 48%. In other words, chance of overall and progression free survival doubled.

"The data show that treatment with pembrolizumab and chemotherapy together is more effective than chemotherapy alone," says Gandhi. "Using this combination therapy to treat patients with such an aggressive disease could be an important advance in keeping patients alive and well for longer."

The risk of severe side effects was similar in both groups (67.2% in the combination group and 65.8% in the standard treatment group), although there was an increased risk of acute kidney injury with the combination treatment (5.2% vs. 0.5%). The most common side effects experienced by both groups were nausea, anaemia and fatigue.
Non-small cell lung cancer is the leading cause of all cancer death, in part because in the majority of cases, the cancer has already spread at the time of diagnosis.

Pembrolizumab in combination with chemotherapy is US Food and Drug Administration-approved to treat these patients, based on a previous phase II trial on which Gandhi was one of the lead investigators.

"Although some non-small cell lung cancer patients have increased benefit of targeted therapy or immunotherapy instead of chemotherapy, for some groups of patients with NSNSCLC, chemotherapy has been the standard treatment for more than 30 years," Gandhi notes. "But for patients with NSNSLC without EGFR or ALK alterations, this study may suggest a new standard of care."

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 was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review.
Results: After a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebo-combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group.
Conclusions: 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.

Authors
Leena Gandhi, Delvys Rodríguez-Abreu, Shirish Gadgeel, Emilio Esteban, Enriqueta Felip, Flávia De Angelis, Manuel Domine, Philip Clingan, Maximilian J Hochmair, Steven F Powell, Susanna Y-S Cheng, Helge G Bischoff, Nir Peled, Francesco Grossi, Ross R Jennens, Martin Reck, Rina Hui, Edward B Garon, Michael Boyer, Belén Rubio-Viqueira, Silvia Novello, Takayasu Kurata, Jhanelle E Gray, John Vida, Ziwen Wei, Jing Yang, Harry Raftopoulos, M Catherine Pietanza, Marina C Garassino

[link url="https://nyulangone.org/press-releases/combination-of-pembrolizumab-and-chemotherapy-doubles-survival-in-patients-with-metastatic-lung-cancer"]NYU Langone Health/NYU School of Medicine material[/link]
[link url="http://www.nejm.org/doi/10.1056/NEJMoa1801005"]New England Journal of Medicine abstract[/link]

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