Frontline Keytruda Gains Priority Review for Lung Cancer

Keytruda (pembrolizumab) in combination with pemetrexed plus carboplatin was granted a priority review to a supplemental biologics license application (sBLA) by the FDA to treat patients with metastatic or advanced non-small cell lung cancer (NSCLC) without EGFR or ALK mutations and regardless of PD-L1 expression.

The sBLA 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 13.0 months with the addition of Keytruda versus 8.9 months for chemotherapy alone.

Under the priority review program, the FDA will decide on the sBLA for the Keytruda combination within six months compared with the standard 10-month review. The target action date for the application is May 10, 2017, according to a statement from Merck, the developer of the PD-1 inhibitor.

“Keytruda in combination with chemotherapy has shown promise versus chemotherapy alone in the first-line treatment of non-squamous metastatic non—small cell lung cancer, regardless of PD-L1 levels," Roger Dansey, M.D., senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories, said in a statement. "If approved, this could be the first regimen combining chemotherapy with an immuno-oncology agent for patients with advanced non–small cell lung cancer.”

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). In both groups, carboplatin was given at AUC 5 mg/mL per min and pemetrexed was given at 500 mg/m² every three weeks for four cycles followed by indefinite pemetrexed maintenance. In the investigational arm, Keytruda was continued for 24 months.

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 0 (40 percent vs 46 percent) and 1 (58 percent and 54 percent) for those in the Keytruda and control arms, respectively. Eighteen percent of those in the Keytruda arm were of non-white ethnic origin compared with 8 percent in the control arm. Additionally, 25 percent of those in the Keytruda arm were never smokers 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 six-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 six-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.

In assessments of PD-L1 staining, those with expression of less than 1 percent had an ORR of 57 percent with the Keytruda combination (12 of 21) compared with 13 percent in the chemotherapy arm (three of 23). In those with expression on greater than 1 percent of cells, the ORR was 54 percent with Keytruda and chemotherapy (21 of 39). The ORRs were 80 percent and 35 percent in those with at least 50 percent expression for the Keytruda (16 of 20) and chemotherapy arms (six of 17), respectively.

The most frequently observed all-grade treatment-related adverse events (AEs) in the Keytruda and chemotherapy arms, respectively, were fatigue (64 percent vs 40 percent), nausea (58 percent vs 44 percent), anemia (32 percent vs 53 percent), vomiting (25 percent vs 18 percent), rash (27 percent vs 15 percent), decreased appetite (19 percent vs 18 percent) and diarrhea (20 percent vs 10 percent). AEs led to treatment discontinuations for 10 percent of those in the Keytruda arm versus 13 percent in the control group.

There were more grade 3/4 treatment-related AEs in the Keytruda arm (39 percent vs 26 percent). The most common grade 3 or higher treatment-related AEs were anemia (12 percent vs 15 percent, respectively), decreased neutrophil count (5 percent vs 3 percent), thrombocytopenia (3 percent vs 3 percent), decreased lymphocyte count (3 percent vs 2 percent), neutropenia (3 percent vs 2 percent) and sepsis (3 percent vs 2 percent).

“Pembrolizumab, in combination with carboplatin and pemetrexed, is superior to carboplatin and pemetrexed alone as first-line therapy for advanced, nonsquamous non—small cell lung cancer,” lead investigator Corey J. Langer, M.D., director of Thoracic Oncology at University of Pennsylvania, said when he reported the findings at the 2016 ESMO Congress. “The combination is tolerable and has a manageable safety profile, and could be an effective treatment option for patients with chemotherapy-naïve, advanced, nonsquamous non–small cell lung cancer."

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 (NCT02578680).