Efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer patients with rare KRAS mutations: a real-world retrospective study

Abstract

Background: Kirsten rat sarcoma homolog (KRAS) mutations are one of the key drivers in non-small cell lung cancer (NSCLC) and FDA-approved specific inhibitors of KRAS-G12C mutation are available clinically. However, inhibitors of certain KRAS mutation subtypes remain unavailable, especially rare KRAS mutations including G13C, G13D, and Q61H. In this study, we retrospectively investigated the outcomes of NSCLC patients with rare KRAS-mutation to determine if they may benefit from immune checkpoint inhibitors (ICIs).

Methods: Our retrospective study involved 240 advanced NSCLC patients with KRAS mutations, who visited Shanghai Chest Hospital from July 2018 to July 2021. Complete clinical and pathological data were recorded and progression-free survival (PFS) and overall survival (OS) were adopted as primary endpoints.

Results: The median follow-up time was 36.5 months (range, 30.8-42.1 months) and the median OS was 9.7 months (range, 7.6-11.8 months). Of the 240 patients evaluated, 130 (54.2%) received chemotherapy and 110 (45.8%) received ICI-based treatment. Among the patients who received chemotherapy, patients with rare KRAS-mutations presented worse survival outcomes (median PFS, 3.4 vs. 4.1 months, P=0.047; median OS, 5.2 vs. 7.1 months, P=0.02) than conventional KRAS-mutant patients. PFS and OS of rare KRAS-mutation patients were prolonged after immunotherapy (median PFS 7.3 vs. 3.4 months, P<0.001; median OS, 13.3 vs. 5.2 months, P<0.001) and had no significant difference compared with conventional KRAS-mutant patients, in part of them whose programmed death-ligand 1 (PD-L1) expression data before immunotherapy were available (n=72), patients with a higher rate of PD-L1 positive tumor cells (≥50%) presented elevated PFS and OS.

Conclusions: Despite having potential survival disadvantage compared with other NSCLC patients, rare KRAS-mutant patients (other than G12A, C, D, V) could benefit specifically from ICI-based therapy and survival outcomes are correlated with PD-L1 expression.

Keywords: Advanced non-small cell lung cancer (advanced NSCLC); Kirsten rat sarcoma homolog mutations (KRAS mutations); immune checkpoint inhibitor (ICI); rare KRAS mutations; survival benefit.

Figure 1

The enrolling process (A), distribution of KRAS mutation subtypes (B), and specific composition of rare KRAS mutations (C), the others included G12L (n=1), G12F (n=3), A146T (n=1), A59G (n=1), Q61K (n=1), G13Y (n=1), A59T (n=1) and G12I (n=1). KRAS, Kirsten rat sarcoma homolog; ICI, immune checkpoint inhibitor.

Figure 2

Comparison of progression-free survival (A) and overall survival (B) between all conventional mutation patients (G12ACDV) and other rare mutation patients; and comparison of progression-free survival (C) and overall survival (D) between conventional mutation patients and other rare mutation patients who were treated with chemotherapy.

Figure 3

Comparison of progression-free survival (A) and overall survival (B) between all immunotherapy and non-immune patients; and comparison of progression-free survival (C) and overall survival (D) between rare mutation patients who received ICIs or not. ICI, immune checkpoint inhibitor.

Figure 4

For all immunotherapy patients (PD-L1 expressions were available in 72 of them), their PFS (A) and OS (B) elevated with their expression of PD-L1 rate (P=0.01, P<0.001). For rare mutation patients receiving ICIs (17 with available PD-L1 expressions), their PFS (C) and OS (D) also elevated with their expression of PD-L1 rate (P=0.07, P=0.02). PD-L1, programmed death-ligand 1; PFS, progression-free survival; OS, overall survival; ICI, immune checkpoint inhibitor.

Figure 5

STK11/KRAS co-mutation have brought patients worse PFS (4.7 vs. 5.5 months, P=0.06, A) and OS (6.6 vs. 10.6 months, P=0.03, B), such differences were also observed in patients received immunotherapy (PFS: 5.8 vs. 8.8 months, P=0.002, C; OS: 13.3 vs. 20.9 months, P=0.02, D). KRAS, Kirsten rat sarcoma homolog; PFS, progression-free survival; OS, overall survival.