KEYNOTE-407: Pembrolizumab Plus Chemotherapy Benefits Response, Survival in Squamous NSCLC


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THE COMBINATION of pembrolizumab (Keytruda) plus platinum-based chemotherapy improved overall survival, response rates, and duration of response in patients with advanced squamous cell non–small cell lung cancer (NSCLC) compared with chemotherapy alone irrespective of programmed cell death ligand 1 (PD-L1) status, according to the results of the phase III KEYNOTE-407 trial, reported at the 2018 ASCO Annual Meeting.1 In addition, progression-free survival and objective response rates were more favorable and durable with the combination therapy than with chemotherapy alone, the investigators reported. The frequency and severity of adverse events were mostly similar between the two treatments.

Luis Paz-Ares, MD

Luis Paz-Ares, MD

“The data suggest that pembrolizumab plus carboplatin and paclitaxel or nab-paclitaxel [Abraxane] should become a new standard of care for squamous NSCLC,” stated lead author Luis Paz-Ares, MD, of the University Hospital 12 de Octubre and National Oncology Research Center, Madrid. 

These results extend the positive findings with pembrolizumab plus chemotherapy as first-line treatment in metastatic nonsquamous NSCLC in the KEYNOTE-189 trial, presented at the 2018 American Association for Cancer Research meeting and published in The New England Journal of Medicine.2 “Our study was the next logical step, to see how the combination works in squamous cell lung cancer, which is a challenge to treat,” Dr. Paz-Ares told listeners. 

It can be difficult to keep all the checkpoint inhibitor trials straight, experts agreed. For context, pembrolizumab plus chemotherapy has improved overall survival in both squamous and nonsquamous metastatic NSCLCs and is approved for the treatment of nonsquamous NSCLC. Pembrolizumab monotherapy is approved for both squamous and nonsquamous metastatic NSCLCs. 

“The data suggest that pembrolizumab plus carboplatin and paclitaxel or nab-paclitaxel should become a new standard of care for squamous NSCLC.”
— Luis Paz-Ares, MD

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Study Details 

AT THE ASCO meeting, Dr. Paz-Ares reported on the results of the second interim analysis of KEYNOTE-407 based on 559 patients with untreated stage IV squamous cell NSCLC. They were randomized 1:1 to receive pembrolizumab at 200 mg/week plus carboplatin AUC 6 every 3 weeks and paclitaxel at 200 mg/ m2 every 3 weeks or nanoparticle albumin-bound (nab)-paclitaxel at 100 mg/ m2 every week for 4 cycles vs the same chemotherapy plus placebo. The experimental arm received further pembrolizumab for up to 31 cycles, whereas the control arm received placebo. Crossover from the control arm to pembrolizumab for up to 35 cycles was optional (42.5% crossed over). Patients were stratified according to PD-L1 total proportion score (TPS) < 1% vs ≥ 1%, choice of taxane, and geographic region. 

At baseline both arms had similar demographic and disease characteristics. At the time the results were presented, 121 patients in the experimental arm were still on treatment compared with 72 patients in the chemotherapy arm. 

Updated Results 

AT THE SECOND interim analysis, with a median follow-up of 7.8 months, overall survival was significantly improved in the pembrolizumab-containing arm: median overall survival of 15.9 months vs 11.3 months in the chemotherapy arm (P = .0008). All predefined subgroups had superior overall survival on the pembrolizumab/ chemotherapy arm. The magnitude of the survival benefit from pembrolizumab added to chemotherapy was similar among all PD-L1 TPS strata. (The study results were broken down according to PD-L1 TPS < 1%, TPS 1% to 49%, and TPS ≥ 50%.) 

Progression-free survival also favored pembrolizumab/chemotherapy: median of 6.4 months vs 4.8 months with chemotherapy (P < .0001). Progression-free survival was better with the addition of pembrolizumab in all three PD-L1 TPS categories, but the reduction on the rate of disease progression was proportional to PD-L1 expression in tumor. 

FINDINGS OF KEYNOTE-407 IN SQUAMOUS LUNG CANCER

  • Pembrolizumab plus chemotherapy improved overall survival, progression-free survival, response rate, and duration of response versus chemotherapy in untreated patients with metastatic squamous NSCLC.
  • The combination improved survival irrespective of the level of PD-L1 expression.
  • Pembrolizumab plus chemotherapy represents a new standard of care for squamous NSCLC.

The objective response rate was significantly higher in the pembrolizumab/chemotherapy arm: 59.4% vs 38%, respectively (P = .0004). The median duration of response was 7.7 months vs 4.8 months, respectively. 

No new safety concerns were evident when pembrolizumab was added to chemotherapy. The frequency and severity of adverse events were similar between the two arms, with about 98% of patients reporting an adverse event and 69% experiencing grades 3 to 5 adverse events. Adverse events leading to treatment discontinuation were more frequent in the pembrolizumab/chemotherapy arm (13.3% vs 6.4%, respectively). 

Immune-related adverse events of any grade were more frequent in the pembrolizumab/chemotherapy arm as well: hypothyroidism occurred in 7.9% vs 1.8%; hyperthyroidism occurred in 7.2% and 0.7%; and pneumonitis occurred in 6.5% and 2.1%, respectively. 

Additional Commentary 

John Heymach, MD, PhD

John Heymach, MD, PhD

AGREEING THAT treatment of NSCLC is becoming increasingly complex, ASCO expert John Heymach, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston, said the KEYNOTE-407 results in squamous NSCLC were eagerly awaited. 

“This study showed that even patients with squamous NSCLC and PD-L1 TPS < 1% benefited from the combination of pembrolizumab plus chemotherapy. Over the past few months, treatment of NSCLC has been turned upside down. All patients now get tested for driver mutation and those with a mutation get targeted therapy. If there is no driver mutation, they all can be treated with an immune checkpoint inhibitor. Now virtually all patients can be treated with targeted therapy or pembrolizumab by itself or with chemotherapy,” declared Dr. Heymach. ■

DISCLOSURE: Dr. Paz-Ares has served as a consultant or advisor to Astellas Oncology, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, and Roche. Dr. Heymach has served on the advisory boards for Merck, BMS, Genentech, and AstraZeneca. 

REFERENCES 

1. Paz-Ares LG, et al: Phase 3 study of carboplatin-paclitaxel/nab-paclitaxel with or without pembrolizumab for patients with metastatic squamous non-small cell lung cancer. 2018 ASCO Annual Meeting. Abstract 105. Presented June 3, 2018. 

2. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al: Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 378:2078-2092, 2018


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