Nivolumab May Work as First-Line NSCLC Therapy

Results from the first trial of nivolumab (Opdivo; Bristol-Myers Squibb) as a first-line treatment for non–small cell lung cancer (NSCLC) suggest that the drug extends survival but raise questions about its safety in combination with chemotherapy.

The standard first-line treatment for NSCLC is platinum-doublet chemotherapy. Median overall survival (OS) for patients receiving this regimen, however, is only 10 to 12 months. Nivolumab, a checkpoint inhibitor that blocks PD-1 receptors on T cells, is an approved second-line treatment for patients with advanced NSCLC, and now researchers are testing whether the drug extends survival as a first-line treatment.

The new results come from two arms of the phase I CheckMate 012 trial, which were reported separately. In one arm, 52 patients received nivolumab alone. Objective responses occurred in 23% of the patients, and 8% exhibited complete responses, a rarity with chemotherapy, notes study co-author Scott Gettinger, MD, of Yale School of Medicine in New Haven, CT. The median OS was 19.4 months. “This trial shows that there is clearly activity in the first-line setting” for nivolumab, he says.

The drug triggered side effects such as diarrhea, nausea, and fatigue in 71% of the patients, with 19% suffering grade 3 or 4 adverse effects. As a result, 12% of patients stopped treatment.

In the second arm of the trial, Naiyer Rizvi, MD, of Columbia University Medical Center in New York, NY, and colleagues treated 56 patients with one of two doses of nivolumab (10 mg/kg or 5 mg/kg) and one of three chemotherapy combinations: gemcitabine plus cisplatin, pemetrexed plus cisplatin, or paclitaxel plus carboplatin. The rationale for this strategy is that platinum-doublet chemotherapy promotes the release of tumor antigens and thus might boost nivolumab's potency.

Median OS ranged from 11.6 months to 19.2 months in the patients who received platinum-doublet chemotherapy with the highest dose of nivolumab, 10 mg/kg. However, median OS hasn't been reached in patients who received paclitaxel and carboplatin with the 5 mg/kg dose of nivolumab, indicating that the chemotherapy combination and nivolumab dose may have a bigger impact on survival. Chemotherapy may have increased nivolumab's side effects, because 21% of patients stopped therapy due to adverse events.

Researchers didn't know what to expect from the combination of nivolumab and chemotherapy, says Rizvi, so “it's an important trial showing that we have a lot yet to learn about how to combine checkpoint inhibitors with other agents.”

An unresolved issue with PD-1 checkpoint inhibitors is whether to use levels of PD-L1, the ligand for PD-1, to determine which patients receive treatment. In the nivolumab-only arm, even patients lacking PD-L1 responded to the drug, but overall response rates were higher among those with PD-L1 expression. In the nivolumab-plus-chemotherapy arm, there was no correlation between PD-L1 levels and tumor response.

“The data here are very impressive and support the future use of nivolumab in the first line,” says Roy Herbst, MD, PhD, of Yale School of Medicine, who wasn't connected to either study. Another expert, Daniel Morgensztern, MD, of Washington University Medical School in St. Louis, MO, describes the results as “interesting and hypothesis-generating.” However, both agree that more data are needed before drawing conclusions about nivolumab's effectiveness in the first-line setting for patients with advanced NSCLC.

The phase III CheckMate 227 trial could provide some answers; it is comparing platinum-doublet chemotherapy to nivolumab, nivolumab plus chemotherapy, and nivolumab plus the CTLA4 blocker ipilimumab (Yervoy; Bristol-Meyers Squibb). –Mitch Leslie