Effect of KRAS mutations and PD-L1 expression on therapy response in non-small cell lung cancer

A pooled analysis performed by the FDA showed that chemotherapy plus immunotherapy resulted in a small numerical, but non-significant, overall survival benefit over immunotherapy alone in patients with advanced non-small cell lung cancer (NSCLC) with PD-L1 expression levels ≥50%. Progression-free survival data and overall response rates suggested a more pronounced benefit of the combination therapy in this population. Another pooled analysis displayed that patients with KRAS-mutated NSCLC and KRAS wildtype NSCLC have similar responses to the combination of chemotherapy and immunotherapy and that patients appear to benefit from the addition of chemotherapy to immunotherapy, irrespective of KRAS mutation status or PD-L1 expression levels.

“Both chemotherapy plus immunotherapy and immunotherapy alone regimens have been approved for the treatment of patients with advanced NSCLC,” said Dr Oladimeji Akinboro (US Food and Drug Administration, MD, USA). To date, it is unknown whether patients with PD-L1 expression levels ≥50% benefit more from immunotherapy alone or immunotherapy in combination with chemotherapy. The FDA performed an exploratory-pooled analysis to address this issue [1]. Included were 1,753 patients from 12 different clinical trials with previously untreated advanced NSCLC and PD-L1 expression levels ≥50% who underwent either chemotherapy plus immunotherapy (n=455) or immunotherapy alone (n=1,298). Overall survival (OS) was the primary endpoint.

The median OS data favoured the chemotherapy plus immunotherapy arm numerically, but not statistically significantly, over the immunotherapy alone arm (25.0 vs 20.9 months; HR 0.82; 95% CI 0.62–1.08). The median progression-free survival (9.6 vs 7.1 months; HR 0.69; 95% CI 0.55–0.87) and overall response rates (61% vs 43%; OR 1.2; 95% CI 1.1–1.3) suggested a more pronounced advantage of combination therapies over monotherapies in this population. In contrast, subgroup analysis indicated that patients ≥75 years may benefit more from immunotherapy alone.

A second pooled analysis investigated the outcomes of immunotherapy with or without chemotherapy in patients with advanced NSCLC according to KRAS mutation status [2]. Previous studies have suggested that patients with KRAS-mutated tumours may benefit more from immunotherapy than monotherapy than patients with KRAS wildtype tumours but that patients with KRAS mutations and KRAS wildtype disease respond equally well to immunotherapy plus chemotherapy [3,4]. However, larger assessments are needed to confirm these results. For this purpose, included were 1,430 patients with advanced NSCLC and reported KRAS mutation status who received first-line immunotherapy, chemotherapy, or a combination of those therapies from 12 clinical trials (KRAS wildtype n=875; KRAS-mutated n=555 of whom KRAS-G12C n=157). Dr Erica Nakajima (US Food and Drug Administration, MD, USA) presented the findings of this study.

The overall response rates (ORR) to therapies were similar for patients with KRAS wildtype and KRAS-mutated tumours across treatment regimens: immunotherapy 33% versus 37%; chemotherapy 32% versus 33%; combination 51% versus 46%. These results indicate that patients may respond better to the combination of chemotherapy and immunotherapy than to either one of these therapies alone, irrespective of KRAS mutation status. Additionally, responses to therapies appeared not to diverge in patients with KRAS-G12C mutations. However, this result should be interpreted with caution since the sample size of patients with KRAS-G12C mutations was limited.

Importantly, Dr Akinboro and Dr Nakajima emphasised that these were retrospective exploratory analyses and that the results are only hypothesis-generating. Dr Nakjima added that the data of these pooled analyses indicate that chemotherapy plus immunotherapy may be the optimal control arm in trials evaluating first-line therapies in patients with NSCLC.

1. Akinboro O, et al. Outcomes of anti–PD-(L)1 therapy with or without chemotherapy (chemo) for first-line (1L) treatment of advanced non–small cell lung cancer (NSCLC) with PD-L1 score ≥ 50%: FDA pooled analysis. Abstract 9000, ASCO 2022 Annual Meeting, 3–7 June, Chicago, IL, USA.
2. Nakajima E, et al. Outcomes of first-line immune checkpoint inhibitors with or without chemotherapy according to KRAS mutational status and PD-L1 expression in patients with advanced NSCLC: FDA pooled analysis. Abstract 9001, ASCO 2022 Annual Meeting, 3–7 June, Chicago, IL, USA.
3. Herbst RS, et al. Ann Oncol. 2019;30(2):281–289.
4. Gadgeel S, et al. Ann Oncol. 2019;30(supp_11):xi64–xi65.

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Posted on 5 August 202215 February 2024