P2.01-67 Are KRAS Mutations Predictive of Response to Immunotherapy in Non Small-Cell Lung Cancer? A Single Center Experience

Abstract

Lung cancer is the leading cause of cancer-related mortality. In the last decade, the treatment landscape has evolved for non-small-cell lung cancer (NSCLC), in large part thanks to two therapeutic advances: targeted therapy for oncogene driven tumours and immune checkpoint-inhibitors (ICI). The latter can lead to very long survival, but only in a limited number of patients. Post-hoc analyses and preclinical data suggest KRAS mutated NSCLC may respond better to ICI. We retrospectively analysed all stage IV NSCLC patients treated in our center with immunotherapy from January 2016 to December 2017 and compared KRAS mutated to wildtype patients. The clinical outcomes analysed were disease control rate (DCR), partial response (PR), progression free survival (PFS) and overall survival (OS). We performed an exploratory analysis on the impact of KRAS mutation type and concurrent mutations. 45 patients treated with ICI. 7 were excluded due to insufficient data. 38 were included. 27 patients (71%) with nivolumab, 9 patients (24%) with pembrolizumab and 2 patients (5%) with atezolizumab. 22 patients (58%) were male and 16 (42%) female. The median age was 63. 21 patients (55%) presented KRAS mutations, of which 4 (19%) had concurrent p53 mutations and 1 (5%) an EGFR mutation. 17 patients (45%) were KRAS wild-type, of which 4 (24%) had EGFR mutations and 1 (6%) had a BRAF V600E mutation. In the KRAS mutated subgroup 59% were male and 41% were female, the median age was 61 years and all patients had PS 0-1. All patients received second line immunotherapy except for 2, one in third line, one fifth line. In the intention to treat population (ITT) the DCR was 71% with 55% PR, PFS was 11.3 months, and OS 17.7 month. In the KRAS wild-type subgroup DCR was 59% with 49% PR, the PFS was 8.4 months and OS 16.8 months. In the KRAS mutated subgroup, DCR was 81%, with 62% PR, PFS was 13.6 months and OS 18.5 months. An exploratory analysis based on KRAS mutation types or co-mutations was performed. The average PFS for G12C, G13C, G12V, G61H and other mutations was 19.1, 7.8, 9.4, 2.2, 13.9 months respectively. PFS for p53 co-mutated KRAS NSCLC was 23.5 months. Further analyses for STK11 co-mutations are ongoing, as these confer resistance to ICI. At the time of analysis 7 patients were still receiving immunotherapy. In our retrospective study, KRAS mutations in NSCLC were predictive of numerically superior response to ICI compared to wildtype patients. Currently, the data is conflicting and larger clinical trials are needed to clarify this hypothesis and ascertain whether and how KRAS should be part of the treatment algorithm for the selection of ICI patients. Furthermore, more research is needed to confirm the potential role of mutation types and clinical impact of co-mutations in KRAS.