Corey J. Langer, MD
Less than 2 years after checkpoint blockade immunotherapy first became available for patients with non–small cell lung cancer (NSCLC), the PD-1 inhibitor pembrolizumab (Keytruda) is poised to reshape the treatment paradigm for previously untreated individuals without molecular mutations.
On May 10, the FDA granted an accelerated approval to pembrolizumab for use in combination with pemetrexed plus carboplatin as a frontline treatment for patients with metastatic or advanced nonsquamous NSCLC, regardless of PD-L1 expression, based on a cohort from the KEYNOTE-021 study.1
The decision amplifies the frontline role for the drug following the FDA’s October 2016 approval for pembrolizumab monotherapy in patients with metastatic NSCLC with greater than 50% PD-L1 expression as a result of the KEYNOTE-024 trial.2
The expanded indications make pembrolizumab part of the first-line treatment considerations for the estimated 80% of patients with NSCLC whose tumors do not harbor EGFR
mutations or ALK
rearrangements, and cap a rapid rise for antibodies that target the PD-1/ PD-L1 pathway in NSCLC (Timeline). Looking forward, researchers are anticipating results from randomized phase III combination trials involving checkpoint blockade agents.
“This approval marks an important milestone in the treatment of lung cancer. Now, pembrolizumab in combination with pemetrexed and carboplatin can be prescribed in the first-line setting for patients with metastatic nonsquamous non–small cell lung cancer, irrespective of PD-L1 expression,” Corey J. Langer, MD, principal investigator on the pivotal KEYNOTE-021 trial, said in a statement. “Physicians should continue to use each patient’s individual characteristics—including biomarker status, histology, and other clinical factors—to determine the best treatment plan for each person.” The evolving role of checkpoint blockade immunotherapy has been evident since the approval of pembrolizumab monotherapy. “As of October 2016, we saw a major shift in the therapeutic landscape in advanced NSCLC,” Langer, director of thoracic oncology and professor of medicine at the Hospital of the University of Pennsylvania in Philadelphia, said in an interview with OncologyLive® that took place before the latest approval. “KEYNOTE-024, at least in individuals with 50% or higher expression, documented a clear-cut outcome advantage for pembrolizumab versus standard platinum-based chemotherapy combinations.”
Timeline. FDA Checkpoint Immunotherapy Approvals in NSCLC
Pivotal Clinical Trial Findings
Findings from the phase II KEYNOTE-021 cohort study are scheduled to be updated at the 2017 American Society of Clinical Oncology Annual Meeting (Abstract 9094). In the trial, 123 patients were randomized to receive pemetrexed and carboplatin alone (n = 63) or in combination with pembrolizumab (n = 60). In the investigational arm, pembrolizumab was continued for 24 months.
In data submitted for the FDA’s approval, the pembrolizumab triplet elicited an objective response rate (ORR) of 55% compared with 29% with the chemotherapy agents alone (P = .0032). The median progression-free survival (PFS) was 13.0 months with the addition of pembrolizumab versus 8.9 months for chemotherapy alone (HR, 0.53; 95% CI, 0.31-0.91; P
After 10.6 months of follow-up, 88% of those in the pembrolizumab arm remained alive and progression free compared with 78% for the chemotherapy agents alone. The median time to response was 1.5 months with pembrolizumab compared with 2.7 months for the chemotherapy agents alone. Overall, a response of at least 6 months was seen for 92% of patients in the pembrolizumab group compared with 81% of those in the control arm.
The 6-month PFS rate was 77% with pembrolizumab (95% CI, 64-86) compared with 63% for chemotherapy alone (95% CI, 49-74). At the time of the analysis, 78% of patients remained alive in each arm, with no discernible differences in survival between the 2 groups (HR, 0.90; 95% CI, 0.42-1.91; P
= .39). The 6-month overall survival (OS) was 92% in both arms. However, this analysis was likely confounded by crossover, since 74% of patients in the chemotherapy alone arm went on to receive a subsequent PD-1 or PD-L1 inhibitor compared with none in the pembrolizumab arm.