Nivolumab Disappoints, Pembrolizumab May Replace Chemotherapy in Advanced NSCLC

At the European Society for Medical Oncology (ESMO) meeting in Copenhagen, Denmark, contrasting results were presented for 2 closely competing programmed death-1 (PD-1) inhibitors. While nivolumab (Opdivo) failed to surpass the outcomes of chemotherapy as a first-line treatment in programmed death ligand-1 (PD-L1)—expressing patients with non-small cell lung cancer (NSCLC), pembrolizumab (Keytruda) bettered chemotherapy in improving survival in a similar cohort.

Lung cancer is the leading cause of cancer-related deaths in the United States and is expected to result in more than 158,000 deaths in 2016, alone. Currently, chemotherapy is the first option for patients whose disease is already at an advanced stage when diagnosed. While both PD-1 inhibitors have been successful as second-line treatment in NSCLC, trials over the past year were evaluating the 2 drugs for use in treatment-naïve patients with advanced disease.

The results for pembrolizumab presented at ESMO were expected, based on updates released by Merck over the past few months. The phase 3 study of KEYNOTE-024 was stopped early in June of this year, after recommendations by an independent Data Monitoring Committee, following which the company filed a supplemental Biologics License Application for pembrolizumab.

The global KEYNOTE-024 trial enrolled 305 patients newly diagnosed with advanced NSCLC whose tumor expressed high levels of PD-1. Patients were randomized to receive pembrolizumab or chemotherapy and 44% of those who progressed while on chemotherapy were crossed over to the pembrolizumab arm. Both the primary (progression-free survival, PFS) and secondary (overall survival) endpoints improved with pembrolizumab. PFS was extended by about 4 months compared with chemotherapy (10.3 months vs 6 months, respectively; hazard ratio, [HR], 0.50). Additionally, 80% of patients on pembrolizumab were alive 6 months following initiation of treatment, compared with 72% on chemotherapy (HR, 0.60). The PD-1 inhibitor also led to a higher overall response rate and duration of response compared with chemotherapy, according to the study presented at ESMO.

“This data will completely change the management of patients with advanced NSCLC," said study presenter Martin Reck, MD, PhD, chief oncology physician at the Lung Clinic Grosshansdorf, Germany. "All endpoints of efficacy and tolerability favored treatment with pembrolizumab, suggesting it should become one standard of care for first-line treatment of patients with advanced NSCLC and high PD-L1 expression. This is primarily an opportunity for patients without oncogenic alterations. More information is needed for those with alterations.”

Meanwhile, nivolumab treatment in high PD-1—expressing treatment-naïve patients with advanced NSCLC was not superior to chemotherapy. The drug had failed to improve PFS in patients whose tumors expressed at least 5% of PD-L1, compared with chemotherapy, which meant that the strategy to reach a wider range of patients—irrespective of a biomarker expression—had failed.

“The CheckMate-026 trial results strengthen our belief that the majority of previously untreated NSCLC patients may require combination therapy in order to experience an improved benefit versus chemotherapy,” Fouad Namouni, MD, head of development for oncology at Bristol-Myers Squibb, which has developed nivolumab, said in an associated press release.