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Regulatory updates for NSCLC
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The FDA took regulatory action on several applications for agents intended to treat non–small cell lung cancer.
Pembrolizumab
The FDA approved pembrolizumab (Keytruda, Merck) in combination with pemetrexed (Alimta, Eli Lilly) and carboplatin as first-line treatment of metastatic nonsquamous NSCLC.
The approval — which allows use regardless of PD-L1 expression — is based on results from a cohort in the KEYNOTE-021 trial.
The open-label, multicenter trial evaluated the addition of first-line pembrolizumab to pemetrexed and carboplatin in 123 treatment-naive patients who had no EGFR or ALK aberrations.
Sixty patients received 200 mg pembrolizumab, 500 mg/m2 pemetrexed and carboplatin area under the curve 5 mg/mL/min every 3 weeks for four cycles, followed by pembrolizumab every 3 weeks. The other 63 patients received pemetrexed and carboplatin alone.
The pembrolizumab regimen extended median PFS (13 months vs. 8.9 months; HR = 0.53; 95% CI, 0.31-0.91) and improved objective response rate (55% vs. 29%). More patients assigned pembrolizumab achieved a response of at least 6 months (93% vs. 81%).
The most common adverse reactions among pembrolizumab-treated patients included fatigue (8%), decreased neutrophil count (8%), anemia (5%), dyspnea (3.4%) and pneumonitis (3.4%).
Osimertinib
The FDA also approved osimertinib (Tagrisso, AstraZeneca) for patients whose tumors harbor EGFR T790M mutations detected by an FDA–cleared test, and whose disease progressed on or after EGFR tyrosine kinase inhibitor therapy.
The agency had granted accelerated approval to osimertinib for this indication in November 2015 based on results of two single-arm clinical trials, which showed the agent induced a 59% ORR.
The FDA based the regular approval on results of the randomized AURA3 trial, which included 419 patients with metastatic EGFR T790M mutation–positive NSCLC as identified by the cobas EGFR mutation test (Roche Molecular Systems). All patients had progressed after first-line therapy with an EGFR TKI.
Researchers randomly assigned 279 patients to osimertinib 80 mg orally once daily. The other 140 patients received platinum-based doublet chemotherapy with either pemetrexed 500 mg/m2 and carboplatin area under the curve 5, or pemetrexed 500 mg/m2 and cisplatin 75 mg/m2, on day 1 of every 21-day cycle for up to six cycles, followed by pemetrexed maintenance.
Patients assigned chemotherapy who experienced radiological progression could cross over to osimertinib.
Results showed osimertinib significantly extended median PFS (10.1 months vs. 4.4 months; HR = 0.3; 95% CI, 0.23-0.41). Researchers also reported a higher ORR (65% vs. 29%; P < .0001) and longer median duration of response (11 months vs. 4.2 months) among osimertinib-treated patients.
Among patients whose baseline brain scans showed measurable central nervous system lesions, osimertinib appeared associated with a higher ORR (57% vs. 25%) and longer median CNS response duration (not reached vs. 5.7 months).
The most serious adverse events reported in osimertinib-treated patients included interstitial lung disease/pneumonitis (3.5%), cardiomyopathy (1.9%), QT interval prolongation (0.7%) and keratitis (0.7%).
Lorlatinib
The FDA granted breakthrough therapy designation to lorlatinib (PF-06463922, Pfizer) — an investigational next-generation ALK/ROS1 TKI — for the treatment of patients with ALK–positive metastatic NSCLC. The designation is intended for patients previously treated with ALK inhibitors.
The agency based its decision on results of a phase 1/phase 2 trial.
The open-label, randomized phase 3 CROWN study — designed to compare lorlatinib with crizotinib (Xalkori, Pfizer) as first-line treatment for patients with metastatic ALK–positive NSCLC — is ongoing.