Can KRAS Mutation Status Guide Nivolumab Therapy in NSCLC?

The immune checkpoint inhibitor nivolumab was found to be effective and safe in patients with previously treated advanced nonsquamous non–small-cell lung cancer (NSCLC), regardless of KRAS mutation status, according to a new study.

Though immune checkpoint inhibitors have already changed the treatment landscape for this malignancy, many patients still do not gain benefit from these therapies. “Thus, identifying predictive biomarkers of clinical response/resistance to immune checkpoint inhibitors is crucial for the selection of an appropriate candidate to immunotherapy,” wrote study authors led by Francesco Passiglia, MD, of the University of Palermo in Italy. KRAS mutations are the most common oncogene driver in nonsquamous NSCLC, occurring in approximately 30% of patients.

The new trial compared the efficacy of nivolumab in a cohort of 530 patients who were evaluated for KRAS mutation status; of those, 206 patients (39%) were mutation positive, while 324 (61%) had wild-type KRAS. The median age of these two groups was similar (66 years and 65 years, respectively), and approximately two-thirds of the patients were male. As has been shown previously, KRAS mutations were associated with current or former smokers; these comprised 86% of KRAS-positive patients and 76% of those without mutations (P = .01). Results of the analysis were published in the British Journal of Cancer.

The presence of KRAS mutations did not appear to substantially affect treatment outcomes. The objective response rate to nivolumab in KRAS-positive patients was 20%, compared with 17% in KRAS-negative patients (P = .39). The disease control rate in the two groups was 47% and 41%, respectively (P = .23). There were few complete responses, with only two in patients with mutations and one in those without.

The median progression-free survival (PFS) in the KRAS-positive group was 4 months, compared with 3 months in the KRAS-negative group (P = .56). However, the 3-month PFS rate was higher in those with mutations, at 53% compared with 42% (P = .01). At 6 and 12 months, though, the PFS rates were not significantly different between the two groups.

There were also no differences with regard to overall survival (OS). The median OS was 11.2 months in those with KRAS mutations, and 10 months in those without (P = .86). There were no significant differences in OS rate at 3, 6, or 12 months, and no differences were observed in various predefined subgroups.

Treatment-related adverse events of any grade occurred in 45% of KRAS-positive patients and in 33% of KRAS-negative patients (P = .003). Grade 3 or higher events were also more frequent in those with mutations, at 11% compared with 6% (P = .03). No treatment-related deaths have been reported.

“Our results demonstrated that KRAS status is not a reliable predictor of nivolumab efficacy in terms of response rate, PFS, and OS,” the authors wrote, and thus these mutations will likely not be useful in helping select patients for this therapy. Still, the results showed that nivolumab is a safe and effective treatment in previously treated advanced NSCLC patients, they concluded, regardless of KRAS status.