Pembrolizumab added to etoposide and platinum significantly improved progression-free survival compared with placebo and etoposide/platinum as first-line therapy in patients with newly diagnosed, extensive-stage small cell lung cancer (SCLC).1 These results from the randomized, double-blind, phase III KEYNOTE-604 study were presented during the ASCO20 Virtual Scientific Program and published simultaneously in the Journal of Clinical Oncology.2
“Results of KEYNOTE-604 show that adding pembrolizumab to standard first-line therapy significantly improved progression-free survival in patients with extensive-stage SCLC and is associated with durable responses in a subset of patients. There was a trend toward improved overall survival as well, but this did not meet the threshold for statistical significance. Overall, these results add to the growing body of evidence in support of the value of immune checkpoint inhibitor in this historically difficult-to-treat cancer,” said lead author Charles M. Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York.
Charles M. Rudin, MD, PhD
SCLC accounts for about 15% of all lung cancers, and it is strongly associated with tobacco use. SCLC is an aggressive cancer type, with a 5-year overall survival rate of about 6% to 7%. Although a number of combinations have been studied, until the recent advent of immune checkpoint inhibitors, standard first-line therapy for extensive-stage SCLC had remained etoposide/platinum for the preceding 30 years, Dr. Rudin noted. Although patients respond to etoposide/platinum, the median overall survival on this regimen is less than 1 year.
Pembrolizumab is currently U.S. Food and Drug Administration–approved for use as third-line or later therapy for metastatic SCLC. This study sought to explore its use in the first-line setting for SCLC.
Study Details
KEYNOTE-604 was conducted at 133 sites in 18 countries and randomly assigned 453 patients with previously untreated disease in a 1:1 ratio to pembrolizumab/etoposide/platinum or placebo/etoposide/platinum. Pembrolizumab was given as 200 mg once every 3 weeks for up to 35 cycles plus 4 cycles of etoposide/platinum. In the control arm, matching saline placebo was given with the same chemotherapy regimen. Platinum therapy was the investigator’s choice of cisplatin or carboplatin. Treated and stable brain metastases were allowed at enrollment.
Baseline characteristics generally were well balanced between the two treatment arms, with the exception of more brain metastases in the pembrolizumab arm (14.5% vs 9.8%). The median age of study patients was 65 years. About 75% of participants had an Eastern Cooperative Oncology Group performance status of 1, more than 50% had an elevated level of lactate dehydrogenase, and 40% had liver metastases. About 41% tested positive for PD-L1 (ie, Combined Positive Score ≥ 1%).
At the final analysis, treatment was ongoing for 20 patients in the pembrolizumab arm vs 3 in the placebo arm. Disease progression was the most common reason for treatment discontinuation on both arms.
Survival Outcomes
At the second interim analysis, progression-free survival was significantly prolonged in the pembrolizumab group (hazard ratio = 0.75; P = .0023). The 12-month progression-free survival estimates were 13.6% and 3.1%, respectively.
“The progression-free survival curves overlapped during chemotherapy and then diverged in favor of pembrolizumab,” Dr. Rudin said. “At the final analysis, the separation of curves was maintained, suggesting a long-term benefit in subsets of patients.”
At the time of the final analysis, death was reported in 169 patients in the pembrolizumab group and in 188 patients in the control group. The hazard ratio for overall survival was 0.80 (95% confidence interval = 0.64–0.98; P = .0164). The estimated overall survival rates at 24 months were 22.5% and 11.2%, respectively.
“Pembrolizumab appeared to prolong overall survival, but the threshold for statistical significance was narrowly missed,” Dr. Rudin noted.
Subgroup analysis for progression-free and overall survival favored the addition of pembrolizumab to etoposide/platinum, with the exception of patients with baseline brain metastases and those with fewer than three metastatic sites. “Outcomes were similar regardless of PD-L1 positivity,” added Dr. Rudin.
At the final analysis, the objective response rate was 70.6% with pembrolizumab/etoposide/platinum vs 61.8% with placebo/etoposide/platinum. “More important to me is the duration of response, which is longer with pembrolizumab. The curves diverged in favor of pembrolizumab, and at 12 months, ongoing responses were observed in 19% vs 3%, respectively,” he said.
Toxicity
About 75% of patients in both arms experienced grade 3 or 4 adverse events. Discontinuation of treatment because of adverse events was reported in 14.8% of the pembrolizumab group and 6.3% of controls. Adverse events were generally similar in participants who received pembrolizumab or placebo. Adverse events leading to death occurred in 6.3% and 5.4%, respectively. The rate of death attributed to study treatment was identical in both arms (2.7%).
“The most common adverse events were hematologic, typical of platinum/etoposide, and this does not appear to be exacerbated by the addition of pembrolizumab,” Dr. Rudin said.
“Consistent with prior studies, about 25% of patients in the pembrolizumab arm had immune-mediated adverse events. However, no patient died of an immune-related event. Most events were grades 1 and 2,” he noted.
DISCLOSURE: The study was funded by Merck & Co. Dr. Rudin has served as a consultant or advisor to AbbVie, Amgen, Ascentage Pharma, AstraZeneca, Bicycle Therapeutics, Bridge Medicines, Celgene, Daiichi Sankyo, Genentech/Roche, Harpoon Therapeutics, Ipsen, Loxo, and PharmaMar and has received research funding from AbbVie/Stemcentrx, Daiichi Sankyo, Merck, and Viralytics.
REFERENCES
1. Rudin CM, Awad MM, Navarro A, et al: KEYNOTE-604: Pembrolizumab or placebo plus etoposide and platinum as first-line therapy for extensive-stage small-cell lung cancer. ASCO20 Virtual Scientific Program. Abstract 9001. Presented May 29, 2020.
2. Rudin CM, Awad MM, Navarro A, et al: Pembrolizumab or placebo plus etoposide and platinum as first-line therapy for extensive-stage small-cell lung cancer: Randomized, double-blind, phase III KEYNOTE-604 study. J Clin Oncol. May 29, 2020 (early release online).
