The European Commission has approved the combination of pembrolizumab (Keytruda, Merck), pemetrexed (Alimta, Lilly), and platinum chemotherapy for the first-line treatment of metastatic non–small cell lung cancer (NSCLC), according to Merck.
The approval is for nonsquamous NSCLC, which is the most common form of lung cancer. The drug is restricted to patients whose tumors have no EGFR or ALK mutations.
This approval is also the first in Europe for an anti–programmed cell death protein–1 therapy in combination with chemotherapy, the company said.
The new decision was based on efficacy and safety data from the phase 3 KEYNOTE-189 trial in patients with advanced disease.
The trial demonstrated an improvement in overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) across all groups of patients, irrespective of programmed cell death–ligand-1 tumor expression status.
The KEYNOTE-189 results were presented earlier this year at the annual meeting of the American Association for Cancer Research and were simultaneously published online in the New England Journal of Medicine.
“This randomized trial is positive for all the endpoints and sets a new standard for first-line metastatic NSCLC,” said Roy S. Herbst, MD, PhD, director of the Thoracic Oncology Program at the Yale Cancer Center, New Haven, Connecticut, who acted as meeting discussant of the data.
KEYNOTE-189 enrolled 616 patients with stage IV NSCLC with no ALK or EGFR mutations who had received no prior therapy for metastatic disease. Patients were randomly assigned in a 2:1 ratio to receive the combination of pembrolizumab plus chemotherapy (n = 410) or chemotherapy alone (n = 206).
Patients who received pembrolizumab plus chemotherapy had a 51% reduced risk for death (hazard ratio [HR], 0.49; P < .00001) compared with patients who received chemotherapy. Similarly, patients who received pembrolizumab plus chemotherapy had a 48% reduced risk for disease progression (HR, 0.52; P < .00001).
Median OS was not reached for patients who received the combination of pembrolizumab plus chemotherapy; it was 11.3 months for patients who received chemotherapy alone. Median PFS was 8.8 and 4.9 months, respectively.
These results were achieved despite the fact that 67 patients from the chemotherapy group crossed over to the pembrolizumab group.
The ORR was 47.6% for patients who received pembrolizumab plus chemotherapy and 18.9% for patients who received chemotherapy alone (P < .0001).
With median follow-up of 10.5 months, twice as many patients in the pembrolizumab-plus-chemotherapy group remained on therapy as in the chemotherapy group, at 34% vs 18%.
The combination of pembrolizumab plus chemotherapy was associated with more adverse events (AEs) than was chemotherapy alone; 27.7% of the patients who received the combination therapy discontinued that treatment because of AEs, vs 14.9% of the patients who received chemotherapy alone. AEs leading to discontinuation of all treatment occurred in 13.8% of the patients who received the combination therapy, vs 7.9% of the patients who received chemotherapy alone. Of the patients who received the combination therapy, 6.7% died, vs 5.9% of the patients who received chemotherapy alone.
Immune-related AEs occurred in twice as many patients in the pembrolizumab group as in the chemotherapy group, at 22.7% vs 11.9%. Three patients in the pembrolizumab group died of immune-mediated AEs.
Also of note was acute kidney injury, which was seen in 5.2% of patients in the pembrolizumab-plus-chemotherapy group, vs 0.5% of patients in the chemotherapy-only group.
All patients received pemetrexed 500 mg/m2 and carboplatin with area under the curve of 5 or cisplatin 75 mg/m2 for four cycles every 3 weeks, and then received maintenance pemetrexed every 3 weeks.
Patients randomly assigned to receive immunotherapy also received four cycles of pembrolizumab 200 mg every 3 weeks followed by maintenance pembrolizumab for up to 31 cycles.
The combination of pembrolizumab with pemetrexed and carboplatin chemotherapy is already fully approved by the US Food and Drug Administration for first-line treatment in this patient population. The approval was based on these results and results from a small phase 2 trial (KEYNOTE-021).