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Single-agent pembrolizumab (Keytruda) proved to be an effective first-line therapy for patients with PD-L1-positive, advanced nonsquamous non-small cell lung cancer (NSCLC) harboring KRAS mutations, though perhaps less so for those without these aberrations, an exploratory analysis of KEYNOTE-042 showed.

Among those with KRAS mutations in the phase III trial, median overall survival (OS) was 28 months for the 30 patients who received first-line pembrolizumab, as compared with 11 months for the 39 patients treated with chemotherapy (HR 0.42, 95% CI 0.22-0.81), reported Gilberto de Lima Lopes, Jr., MD, of the Sylvester Comprehensive Cancer Center at the University of Miami, and colleagues.

And for the subset with a KRAS G12C mutation, median OS was not reached among 12 patients on pembrolizumab and 8 months for the 17 on chemotherapy (HR 0.28, 95% CI 0.09-0.86), according to findings presented at the 2019 European Society for Medical Oncology Immuno-Oncology congress.

By contrast, however, the significant OS benefit disappeared for the largest group in the analysis, those without KRAS mutations. Here, the 127-patient pembrolizumab group had a median OS of 15 months versus 12 months for the 105 patients in the chemotherapy group (HR 0.86, 95% CI 0.63-1.18).

"The results extend our findings from the main analysis of KEYNOTE-042 in which patients with PD-L1 expression of 1% or higher benefited from pembrolizumab versus chemotherapy," Lopes told 番茄社区app. "In this study, we also showed that patients with KRAS mutations and with the G12C mutation did better with pembrolizumab."

Somatic KRAS mutations, detected in approximately 15-30% of lung adenocarcinomas, are associated with poor prognosis, Lopes noted.

"We still don't know if the benefit [with pembrolizumab monotherapy] is intrinsic to the presence of KRAS mutations or if it is due to the higher PD-L1 expression and tumor mutational burden we see in patients with KRAS mutations," he said.

When asked about recent reports on investigational agents showing activity in lung cancer patients with KRAS G12C mutations, Lopes said the "data on [a] G12C inhibitor is emerging fast and it seems most patients benefit." In the KEYNOTE-042 analysis, he pointed out, "responses were very high for patients with G12C mutations, around 66%, suggesting that we need to use pembrolizumab-containing options in comparator arms."

The current analysis focused on a subgroup of 301 patients enrolled in KEYNOTE-042. All had nonsquamous histology and available tumor and matched-normal tissue, and underwent whole-exome sequencing to assess KRAS mutational status and tumor mutational burden.

"I applaud the authors for examining outcomes within the KEYNOTE-042 study by molecular subtyping," commented Lecia Sequist, MD, MPH, of of Massachusetts General Hospital in Boston. "This is a key goal for all large randomized studies in lung cancer," said Sequist, who was not affiliated with the study. "Exciting emerging data about KRAS G12C inhibitors will likely shape our approach to this specific type of KRAS mutation in the near future," she agreed.

However, Sequist also emphasized that it would be difficult to draw conclusions from this analysis since only a quarter of the 1,274 patients with metastatic nonsquamous NSCLC enrolled in KEYNOTE-042 had sufficient samples for KRAS mutation analysis. In addition, co-mutations occurring with KRAS, which can predict response to immunotherapy (IO), were not evaluated, she pointed out.

"In my opinion, at the current time, KRAS mutational status should not influence a choice between chemo, IO, and chemo plus IO in the clinic," Sequist told 番茄社区app. "In contrast, EGFR, ALK, ROS1, and RET-driven cancers should consider targeted therapy before IO."

In the analysis from Lopes and colleagues, 232 patients had no KRAS mutations, 69 had any KRAS mutations, and 29 had the KRAS G12C mutation. Patients were randomized 1:1 to receive either pembrolizumab 200 mg intravenously every 3 weeks or chemotherapy with either pemetrexed (Alimta) or paclitaxel (Taxol) until progression of disease or unacceptable toxicity.

Overall response rates with pembrolizumab monotherapy versus chemotherapy, respectively, were:

• Any KRAS mutation: 56.7% vs 18.0%
• KRAS G12C mutation: 66.7% vs 23.5%
• No KRAS mutations: 29.1% vs 21.0%

Median progression-free survival (PFS) was 12 months with pembrolizumab versus 6 months with chemotherapy (HR 0.51, 95% CI 0.29-0.87) in those with any KRAS mutation, and 15 months versus 6 months for those with the KRAS G12C mutation (HR 0.27, 95% CI 0.10-0.71). No PFS difference was seen for those without KRAS mutations, at 6 months in each arm (HR 1.00, 95% CI 0.75-1.34).

Descriptive analyses of the correlation between KRAS mutational status and shifts in the distribution of tumor mutational burden and PD-L1 expression showed that patients with KRAS mutations tended to have higher PD-L1 tumor proportional scores as well as a higher tumor mutational burden than patients without KRAS mutations.

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