The Food and Drug Administration (FDA) has granted an accelerated approval to Keytruda (pembrolizumab) for use in combination with pemetrexed plus carboplatin as a frontline treatment for patients with metastatic or advanced nonsquamous non–small cell lung cancer (NSCLC), regardless of PD-L1 expression.
The approval was based on part 2 of cohort G in the KEYNOTE-021 trial, in which the Keytruda triplet elicited an objective response rate (ORR) of 55 percent compared with 29 percent with the chemotherapy agents alone. The median progression-free survival (PFS) was 13 months with the addition of Keytruda versus 8.9 months for chemotherapy alone.
“The combination of this immunotherapy with pemetrexed and carboplatin is more good news for patients,” said Bonnie J. Addario, a lung cancer survivor and founder of the Bonnie J. Addario Lung Cancer Foundation. “Congratulations to Merck and the FDA for moving so swiftly on this important addition to our patients’ options for treatment. With this approval, hope for lung cancer patients continues to improve.”
In the open-label phase 2 KEYNOTE-021 cohort study, 123 patients were randomized to receive pemetrexed and carboplatin alone (63 patients) or in combination with Keytruda (60 patients).
The baseline characteristics were balanced between the two arms. The average age of participants was 62.5 years in the Keytruda group versus 63.2 years for the control arm. The ECOG performance status was zero (40 percent versus 46 percent) and 1 (58 percent and 54 percent) for those in the Keytruda and control arms, respectively. Eighteen percent of those in the Keyrruda arm were of non-white ethnic origin compared with 8 percent in the control arm. Additionally, 25 percent of those in the Keytruda arm never smoked versus 14 percent in the control group.
After 10.6 months of follow-up, 88 percent of those in the Keytruda arm remained alive and progression free compared with 78 percent for the chemotherapy agents alone. The median time to response was 1.5 months with Keytruda compared with 2.7 months for the chemotherapy agents alone. Overall, a response of at least six months was seen for 92 percent of patients in the Keytruda group compared with 81 percent of those in the control arm.
The 6-month PFS rate was 77 percent with Keytruda compared with 63 percent for chemotherapy alone. At the time of the analysis, 78 percent of patients remained alive in each arm, with no discernible differences in survival between the two groups. The 6-month overall survival was 92 percent in both arms. However, this analysis was likely confounded by crossover, since 74 percent of patients in the chemotherapy alone arm went on to receive a subsequent PD-1 or PD-L1 inhibitor compared with none in the Keytruda arm.
Frequently observed all-grade treatment-related adverse events (AEs) in the Keytruda and chemotherapy arms, respectively, included fatigue, nausea, constipation, rash, vomiting, fever, diarrhea and decreased appetite. AEs led to treatment discontinuations for 10 percent of those in the Keytruda arm versus 13 percent in the control group.
The most common grade 3 or higher treatment-related AEs were decreased lymphocytes, hemoglobin decreased, decreased neutrophil count and platelets decreased.
The accelerated approval is contingent on results from a confirmatory trial.
A phase 3 study is currently exploring platinum-based chemotherapy plus pemetrexed with or without Keytruda for patients with untreated squamous NSCLC. In this study, investigators will be able to pick between cisplatin or carboplatin as their platinum-based chemotherapy of choice. The primary endpoint of the study is PFS, with an accrual goal of 570 patients and an estimated completion date of March 2019.