Copenhagen, Denmark—Patients with non–small-cell lung cancer (NSCLC) who lack targetable EGFR or ALK mutations typically receive platinum-based doublet chemotherapy as first-line therapy. Two phase 3 clinical trials presented at the 2016 European Society for Medical Oncology (ESMO) Congress compared immunotherapy and platinum-based chemotherapy as first-line treatment for patients with NSCLC. In KEYNOTE-024, pembrolizumab (Keytruda) was superior to chemotherapy in terms of progression-free survival (PFS) and overall survival (OS), whereas in CheckMate-026, nivolumab (Opdivo) failed to improve PFS compared with chemotherapy.
Experts suspect that patient selection according to PD-L1 status may explain these disparate findings.
In KEYNOTE-024, pembrolizumab extended PFS and OS compared with standard chemotherapy in patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells. In addition, patients who received pembrolizumab had fewer adverse events than those who received chemotherapy. These results were hailed as practice-changing at ESMO 2016, and were simultaneously published online (Reck M, et al. N Engl J Med. 2016 Oct 9. Epub ahead of print).
“These data will completely change the management of patients with advanced NSCLC,” said lead investigator Martin Reck, MD, Lung Clinic Grosshansdorf, German Center of Lung Research, Germany. “All end points of efficacy and tolerability favored treatment with pembrolizumab, suggesting it should become one standard of care for the first-line treatment of patients with advanced NSCLC and high PD-L1 expression. This is primarily an opportunity for the 30% of patients without oncogenic alterations who are high expressers of PD-L1. More information is needed for those with genetic alterations,” he added.
In addition, Dr Reck emphasized the importance of upfront testing for PD-L1 expression for selecting patients who would benefit most from pembrolizumab treatment.
KEYNOTE-024 randomized 305 patients with untreated advanced NSCLC and PD-L1 expression on at least 50% of tumor cells. Patients with EGFR or ALK mutations were excluded from the study. Patients received a fixed dose of pembrolizumab 200 mg every 3 weeks or investigator’s choice of chemotherapy. Crossover to pembrolizumab was permitted for patients whose disease progressed during treatment with chemotherapy.
The median PFS was 10.3 months with pembrolizumab versus 6 months with chemotherapy (P <.001). The estimated OS at 6 months was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group (P = .005).
The response rate was 44.8% with pembrolizumab versus 27.8% with chemotherapy. The median duration of response was not yet reached for pembrolizumab and was 6.3 months for chemotherapy.
Treatment-related adverse events of any grade were 73.4% with pembrolizumab versus 90% with chemotherapy. The rate of grades 3 to 5 treatment-related adverse events was 26.6% with pembrolizumab versus 53.3% with chemotherapy.
“This study may change current practice for the treatment of patients with advanced NSCLC. It is the first time a therapy has improved progression-free survival over the current standard first-line treatment with platinum-based doublet chemotherapy,” said Johan Vansteenkiste, MD, Chief Oncology Physician, Unit of Respiratory Oncology, University Hospital Leuven, Belgium,
Dr Vansteenkiste attributed the success of this clinical trial to patient selection, enrolling only patients with high levels of PD-L1 expression. “Additional research should be done to find out whether patients with lower levels of PD-L1 expression also benefit more from pembrolizumab than from chemotherapy.”
Indeed, based on these results, on October 24, 2016, the FDA approved pembrolizumab for first-line treatment of patients with NSCLC (see Keytruda Receives New FDA Indication for First-Line Treatment of Metastatic NSCLC).
The results of the CheckMate-026 clinical trial were negative for the immunotherapy drug nivolumab versus chemotherapy as the first-line treatment of patients with NSCLC without EGFR or ALK mutations. This study enrolled a broader group of patients than KEYNOTE-024 with regard to PD-L1 expression levels.
The CheckMate-026 study evaluated first-line treatment with nivolumab versus platinum-based doublet chemotherapy in 541 patients with advanced NSCLC and PD-L1–positive tumors, defined as PD-L1 expression in ≥1% of tumor cells. Patients with EGFR or ALK mutations were excluded from the study. Patients whose disease progressed during treatment with chemotherapy could cross over to nivolumab as second-line treatment.
In 423 patients with ≥5% PD-L1 expression, PFS was better with chemotherapy than with nivolumab (5.9 months vs 4.2 months, respectively). In addition, OS was 14.4 months with nivolumab versus 13.2 months with chemotherapy. The rate of all-grade adverse events was 71% in the nivolumab group versus 92% in the chemotherapy group. The rate of grade 3 or 4 adverse events was 18% with nivolumab versus 51% with chemotherapy.
“There are a number of possible reasons for the disappointing PFS results,” said lead investigator Mark A. Socinski, MD, Executive Medical Director, Florida Hospital Cancer Institute, Orlando. “Regarding OS, there was a high rate of crossover to immunotherapy in the chemotherapy arm. OS in the chemotherapy arm was better than historical standards, which may be due to the fact that it had a greater proportion of women and Asian patients.”
Dr Vansteenkiste also commented on the results of CheckMate-026. “In my view, the reason nivolumab did not improve PFS over chemotherapy in this study is because the trial included a broad range of patients with a low PD-L1 expression of just 1% or greater. Standard first-line treatment with platinum doublet chemotherapy gives a PFS of 6 months, and to beat that may require being more selective on who receives the drug,” he said. “More research is needed on how to use the PD-L1 biomarker to select patients for treatment with nivolumab,” he added.
