The EMPOWER-Lung 1 trial, recently reported in The Lancet and reviewed in this issue of The ASCO Post, showed an improvement in progression-free and overall survival with cemiplimab-rwlc in patients with advanced non–small cell lung cancer (NSCLC) and high PD-L1 expression (tumor proportion score [TPS] ≥ 50% using the 22C3 assay).1 The median overall survival among patients who received cemiplimab was 22.1 months compared with 14.3 months for those given chemotherapy (hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.53–0.87) in the intention-to-treat population of 710 patients. In a prespecified population of 563 patients with PD-L1 expression in ≥ 50% of tumor cells on the 22C3 assay (performed according to the manufacturer’s instructions for use, per U.S. Food and Drug Administration [FDA] request), median overall survival was not reached with cemiplimab vs 14.2 months with chemotherapy (HR = 0.57, 95% CI = 0.42–0.77).
Apar Kishor Ganti, MD, MS
Current Clinical Context
The results of this study must be taken in the context of the various other studies that have evaluated the role of immunotherapy in this patient population. Three studies, including EMPOWER-Lung 1, have compared single-agent immune checkpoint inhibitors against platinum-based therapy in patients with high PD-L1 expression (as defined by the antibody used). The KEYNOTE-024 study showed that pembrolizumab had a superior overall survival compared with chemotherapy, with a median duration of 30.0 months vs 14.2 months (HR = 0.63, 95% CI = 0.47–0.86).2 In the IMpower110 study, the median overall survival was longer with atezolizumab than chemotherapy (20.2 months vs 13.1 months, HR = 0.59, 95% CI = 0.40–0.89). The CheckMate 227 study compared a combination of nivolumab and ipilimumab against chemotherapy and found a survival benefit with combination immunotherapy, regardless of PD-L1 expression.3 In this study, among patients with PD-L1 expression level ≥ 1%, the median overall survival was 17.1 months with nivolumab plus ipilimumab vs 14.9 months with chemotherapy (HR = 0.79, 97.72% CI = 0.65–0.96). The striking similarity among the results of these studies confirms the efficacy of immune checkpoint inhibitors in patients with high PD-L1 expression.
In the EMPOWER-Lung 1 trial, the incidence of grade ≥ 3 adverse events was 14% in the cemiplimab group compared with 39% in the chemotherapy group. In comparison, in the KEYNOTE-024 trial, the incidence of grade ≥ 3 adverse events was 26.6% with pembrolizumab and 53.3% with chemotherapy, and the corresponding figures in the IMpower110 trial were 33.9% with atezolizumab and 56.7% with chemotherapy.4 Thus, in all three studies, the immune checkpoint inhibitor had reduced side effects compared with chemotherapy, although the absolute numbers were lower in both arms of EMPOWER-Lung 1. This probably reflects a better understanding of the side-effect profile and therefore more prompt management than a true difference in the safety profile among the three checkpoint inhibitors.
Big Question Remains: What About Chemotherapy?
A bigger question that still remains unanswered is the role of chemotherapy in the first-line treatment of these patients whose tumors have high PD-L1 expression. The KEYNOTE-189 and KEYNOTE-407 studies showed the superiority of pembrolizumab in combination with platinum-based chemotherapy compared with chemotherapy alone in nonsquamous NSCLC and squamous cell lung cancer, respectively.5,6
In the KEYNOTE-189 trial, the median overall survival in the pembrolizumab arm for the subset of patients with a TPS ≥ 50% was not reached, compared with 10.7 months in the chemotherapy arm (HR = 0.59, 95% CI = 0.39–0.88).6 In the KEYNOTE-407 study of squamous cell lung cancer, the hazard ratio for overall survival was 0.79 (95% CI = 0.52–1.21) among those with a PD-L1 TPS ≥ 50%.
The positive results of the EMPOWER-Lung 1 study add another drug to our armamentarium for patients with advanced NSCLC whose tumors have a high PD-L1 expression.— Apar Kishor Ganti, MD, MS
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Similarly, the IMpower150 study evaluating carboplatin, paclitaxel, and bevacizumab with or without atezolizumab in patients with advanced nonsquamous NSCLC found better overall survival with the addition of atezolizumab.7 However, the final overall survival results for the study have not been published so far, and the magnitude of benefit in the high PD-L1 expression population is unclear.
The CheckMate 9LA study randomly assigned patients to four cycles of chemotherapy or a combination of ipilimumab and nivolumab until disease progression, with chemotherapy given during the first two cycles.8 In the subgroup of patients with high PD-L1 expression in this trial (n = 174), the chemoimmunotherapy group had a better median overall survival than did those given chemotherapy alone (18 months vs 12.6 months, HR = 0.66, 95% CI = 0.44–0.99).
The positive results of the EMPOWER-Lung 1 study add another drug to our armamentarium for patients with advanced NSCLC whose tumors have a high PD-L1 expression. Indeed, the FDA approved cemiplimab for the treatment of advanced NSCLC and high PD-L1 expression. However, these results do not necessarily change the therapeutic paradigm for this cohort, nor do they provide any insights into unanswered questions in the treatment of these patients.
Dr. Ganti is the Associate Director of Clinical Research at the Fred & Pamela Buffett Cancer Center at the University of Nebraska Medical Center, Omaha.
DISCLOSURE: Dr. Ganti has served as a consultant or advisor to AstraZeneca, Blueprint Medicines, Cardinal Health, G1 Therapeutics, Genentech/Roche, Flagship Biosciences, and Jazz Pharmaceuticals; has received research funding from Takeda; and has received institutional research funding from Amgen, Apexigen, Bristol Myers Squibb, Janssen Biotech, Merck, Nektar Therapeutics, Novartis, and Pfizer.
REFERENCES
1. Sezer A, Kilickap S, Gümüş M, et al: Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: A multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet 397:592-604, 2021.
2. Reck M, Rodríguez-Abreu D, Robinson AG, et al: Updated analysis of KEYNOTE-024: Pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol 37:537-546, 2019.
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4. Herbst RS, Giaccone G, de Marinis F, et al: Atezolizumab for first-line treatment of PD-L1–selected patients with NSCLC. N Engl J Med 383:1328-1339, 2020.
5. Gadgeel S, Rodríguez-Abreu D, Speranza G, et al: Updated analysis from KEYNOTE-189: Pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer. J Clin Oncol 38:1505-1517, 2020.
6. Paz-Ares L, Vicente D, Tafreshi A, et al: A randomized, placebo-controlled trial of pembrolizumab plus chemotherapy in patients with metastatic squamous NSCLC: Protocol-specified final analysis of KEYNOTE-407. J Thorac Oncol 15:1657-1669, 2020.
7. Socinski MA, Jotte RM, Cappuzzo F, et al: Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 378:2288-2301, 2018.
8. Paz-Ares L, Ciuleanu TE, Cobo M, et al: First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): An international, randomised, open-label, phase 3 trial. Lancet Oncol 22:198-211, 2021.
