Immunotherapy Agent Falls Short Versus Chemotherapy in Lung Cancer

Progression-free survival (PFS) was not improved with frontline Opdivo (nivolumab) compared to standard chemotherapy in patients with PD-L1—positive non-small cell lung cancer (NSCLC), according to the results of a recent randomized trial

Opdivo-treated patients had a median PFS of 4.2 months compared with 5.9 months for patients treated with a chemotherapy doublet chosen by the treating physician. Overall survival (OS) and response rate also did not differ significantly between treatment groups.

More than 60.4 percent of patients in the chemotherapy arm crossed over to Opdivo at progression, as compared with 43.6 percent of patients in the Opdivo arm who crossed over to chemotherapy. Whether that difference influenced the results has yet to be determined, as reported at the 2016 Europpean Society for Medical Oncology (ESMO) Congress.

“Nivolumab did not meet the primary endpoint of superior PFS compared with chemotherapy,” said Mark Socinski, M.D., executive medical director of Florida Hospital Cancer Institute in Orlando. “Safety results were consistent with the known safety profile of nivolumab: there were fewer treatment-related grade 3/4 adverse events in the nivolumab versus chemotherapy arm. Exploratory subgroup analyses were consistent with the overall study.”

The randomized CheckMate-026 trial failed to live up to expectations created by the phase 1 CheckMate-012 trial of first-line Opdivo (ASCO 2016, Abstract 3001). The CheckMate-012 results suggested first-line Opdivo had clinical activity with increasing levels of PD-L1 expression, although investigators also observed activity in patients with low-level or no PD-L1 expression, said Socinski.

Already approved for use in patients with previously treated advanced NSCLC, Opdivo underwent evaluation of its first-line potential in CheckMate-026. The international, multicenter, open-label trial examined the safety and efficacy of the PD-1 inhibitor as front-line treatment of patients with advanced NSCLC.

Eligible patients had stage 4 or recurrent NSCLC and had received no prior systemic therapy for advanced disease and had no EGFR or ALK mutations sensitive to available targeted therapies. The trial was limited to patients whose tumors had less than 1 percent PD-L1 expression.

Investigators randomized 541 patients to receive Opdivo 3 mg/kg every two weeks or a platinum-based chemotherapy doublet determined by the treating physician’s preference. Treatment continued until disease progression. Assessment of tumor status occurred every six weeks for 48 weeks and then every 12 weeks. At progression, patients could cross over to treatment with Opdivo.

The primary endpoint was PFS, as determined by independent review, in the subgroup of patients who had tumors with 5 percent or more PD-L1 expression (415 patients). Secondary endpoints included PFS in the entire study population, OS, and objective response rate.

The chemotherapy arm had more women (45 percent vs 32 percent). Otherwise, the two treatment groups had no significant differences in key baseline characteristics. About 40 percent of patients in both arms had received prior radiation therapy.

More than half of the patients in each group remained on assigned therapy for more than three months. Thereafter, substantially more patients remained on Opdivo, including 20.6 percent who remained on therapy for more than 12 months, as compared with 10.6 percent in the chemotherapy arm.

The two most commonly used chemotherapy doublets were pemetrexed/carboplatin (43.7 percent) and pemetrexed/cisplatin (32.7 percent). About 40 percent of patients received maintenance pemetrexed.

The primary analysis showed no evidence of Opdivo superiority. In addition to the median PFS, the one-year PFS also did not differ between groups, 23.6 percent with Opdivo and 23.2 percent with chemotherapy.

Median OS in patients with 5 percent or more PD-L1 expression was 14.4 months with Opdivo and 13.2 months with chemotherapy. The one-year survival was 56.3 percent and 53.6 percent with Opdivo and chemotherapy, respectively.

Objective responses occurred in 26.1 percent of Opdivo patients and 33.5 percent of chemotherapy-treated patients. Substantially more patients in the Opdivo arm had progressive disease as best response: 27.5 percent compared with 9.9 percent.

Outcomes remained similar in subgroup analyses. In those with non-squamous histology (412 patients), the unstratified HRs for OS and PFS were 1.17 and 1.29, respectively, for Opdivo versus chemotherapy. Additionally, a benefit was not observed for Opdivo versus chemotherapy in those with PD-L1 expression on 50 percent or more of cells, with a HR for PFS of 1.07 and an HR of 0.90 for OS. Opdivo was superior compared with chemotherapy in those with squamous histology (129 patients), with an HR of 0.83 for PFS and 0.82 for OS.

Safety and adverse events in both treatment groups were consistent with known effects of the therapies. The most common adverse events (any grade) in the Opdivo arm were fatigue (21.0 percent vs 35.4 percent with chemotherapy), diarrhea (13.9 percent vs 12.9 percent), decreased appetite (12.0 percent vs 27.8 percent) and nausea (11.6 percent vs 48.3 percent). Grade 3/4 adverse events were uncommon with Opdivo. The most common grade 3/4 adverse events in the chemotherapy arm were anemia (17.5 percent), neutropenia (11.0 percent), thrombocytopenia (8.4 percent) and fatigue (5.3 percent).

The total rate of crossover at progression was 43.6 percent in the Opdivo arm and 64.2 percent in the chemotherapy arm. In the Opdivo arm, 1.4 percent of patients crossed over to other immunotherapy, as compared with 60.4 percent. At the end of the trial, 18.7 percent of treated patients remained on randomized therapy in the Opdivo group versus 5.3 percent of the chemotherapy arm.

Despite the negative results, evaluation of Opdivo in the first-line setting of advanced NSCLC will continue, said Socinski. The CheckMate-227 trial will compare Opdivo alone, Opdivo plus Yervoy (ipilimumab), and chemotherapy. Additionally, the trial will enroll patients into separate groups according to PD-L1 expression (1 percent or more or less than 1 percent, and both groups will be randomized to all three treatments).