The U.S. Food and Drug Administration (FDA) has approved pembrolizumab, the company’s anti-PD-1 (programmed death receptor-1) therapy, for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumours have high PD-L1 expression (tumour proportion score [TPS] of 50 percent or more) as determined by an FDA-approved test, with no EGFR or ALK genomic tumour aberrations.
With this new indication, pembrolizumab is now the only anti-PD-1 therapy to be approved in the first-line treatment setting for these patients.
“The approval of pembrolizumab in the first-line setting adds to the momentum of progress that has been made to treat lung cancer, particularly in the area of immunotherapy,” said Laurie Fenton Ambrose, president and CEO, Lung Cancer Alliance. “Patients now have an option beyond chemotherapy at initial diagnosis. This approval reinforces the need for biomarker testing so care can be personalised and most effective.”
The approval was based on data from KEYNOTE-024, a randomised, open-label, phase 3 study evaluating pembrolizumab monotherapy compared to standard of care (SOC) platinum-containing chemotherapy for the treatment of patients with both squamous (18%) and non-squamous (82%) metastatic NSCLC.
In addition, the FDA approved a labelling update to include data from KEYNOTE-010 in the second-line or greater treatment setting for patients with metastatic NSCLC whose tumours express PD-L1 (TPS of one percent or more) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy.
Patients with EGFR or ALK genomic tumour aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab.
In metastatic NSCLC, pembrolizumab is approved for use at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
KEYNOTE 024 enrolled patients who had not received prior systemic chemotherapy treatment for their metastatic disease and whose tumours had high PD-L1 expression (TPS of 50 percent or more) and with no EGFR or ALK aberrations.
The study randomized 305 patients to receive pembrolizumab (200 mg every three weeks) or investigator-choice SOC platinum-based chemotherapy (pemetrexed carboplatin, pemetrexed cisplatin, gemcitabine cisplatin, gemcitabine carboplatin, or paclitaxel carboplatin).
Pemetrexed maintenance therapy was permitted for patients with non-squamous histologies.
The primary endpoint was progression-free survival (PFS); additional efficacy outcome measures were overall survival (OS) and overall response rate (ORR).
Based on an interim analysis demonstrating pembrolizumab was superior compared to chemotherapy for both the primary endpoint of PFS and the secondary endpoint of OS, the trial was stopped early in June 2016 to give patients still on chemotherapy the opportunity to receive pembrolizumab.
Findings demonstrated that pembrolizumab reduced the risk of progression or death by 50 percent compared to chemotherapy (HR, 0.50 [95% CI, 0.37, 0.68]; p<0.001).
Additionally, pembrolizumab resulted in a 40 percent reduction in the risk of death compared to chemotherapy (HR, 0.60 [95% CI, 0.41, 0.89]; p=0.005).
KEYNOTE-010 is a randomised, open-label, phase 2/3 trial evaluating pembrolizumab (2 mg/kg [n=344] or 10 mg/kg [n=346] every three weeks) compared to SOC chemotherapy (docetaxel, 75 mg/m2 every three weeks [n=343]) in 1,033 patients with squamous (21%) and non-squamous (70%) metastatic NSCLC with all levels of PD-L1 expression (TPS of one percent or more) who had progressed following platinum-containing chemotherapy and, if appropriate, targeted therapy for EGFR or ALK genomic tumour aberrations.
Additionally, results were reported in a subset of patients who had high PD-L1 expression (TPS of 50 percent or more) in the pembrolizumab 2 mg/kg (n=139), pembrolizumab 10 mg/kg (n=151), and chemotherapy cohorts (n=152). The primary endpoints were OS and PFS. Additional efficacy measures included ORR and response duration.
Pembrolizumab demonstrated superior OS versus docetaxel in patients with all levels of PD-L1 expression. Based on exploratory analyses, higher OS was associated with higher PD-L1 expression level.
“Pembrolizumab improved survival, compared to traditional chemotherapy, in patients with non-small cell lung cancer whose tumours express high levels of PD-L1,” said Roger M. Perlmutter, M.D., Ph.D., president, Merck Research Laboratories. “The approval of pembrolizumab for the first-line treatment of metastatic non-small cell lung cancer has the potential to change the treatment landscape for these patients.”
“With this new indication, pembrolizumab can now be a first treatment option instead of chemotherapy for patients with metastatic non-small cell lung cancer whose tumours express high levels of PD-L1,” said Roy S. Herbst, M.D., Ph.D., professor of medicine and chief of medical oncology, Yale Cancer Center and Smilow Cancer Hospital at Yale New Haven. “These data reaffirm the importance of testing for PD-L1 expression in non-small cell lung cancer in order to identify those patients who are most likely to benefit from treatment with pembrolizumab.”
Immune-mediated adverse reactions occurred with pembrolizumab including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.
Based on the severity of the adverse reaction, pembrolizumab should be withheld or discontinued and corticosteroids administered when appropriate. pembrolizumab can also cause severe or life-threatening infusion-related reactions.
Monitor patients for signs and symptoms of infusion-related reactions and for Grade 3 or 4 reactions, stop infusion and permanently discontinue pembrolizumab.
Based on its mechanism of action, pembrolizumab can cause foetal harm when administered to a pregnant woman.
Female patients of reproductive potential should be advised of the potential hazard to a foetus.
For more information regarding immune-mediated and infusion-related adverse reactions and use in pregnancy, see “Selected Important Safety Information” available from the FDA.
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