...higher ORR was linked with KRAS/TP53 mutation, while longer PFS was merely associated with the mutation in TP53 (HR 0.72, 95%CI 0.55-0.95, P=0.019), but not KRAS (P=0.295). TP53 mutation brought improvement of ORR and PFS in patients with KRAS mutation (ORR, p=0.002; PFS, p<0.001), but not KRAS-WT population (ORR, p=0.104; PFS, p=0.566). KRAS mutation was associated with better ORR and PFS in TP53-mut (ORR, p=0.011; PFS, p=0.017), but not TP53-WT population (ORR, p=0.518; PFS, p=0.885). We further investigated the predictive efficacy of the co-mutation of TP53 and KRAS, and observed remarkably improved ORR (2.59-fold, P<0.001) and PFS (HR 0.47, 95%CI 0.32-0.68, P=0.001) in co-mutated patients. Co-mutation of KRAS and TP53 is identified as a potential immunotherapeutic predictor of better ORR and PFS in patients with EGFR/ALK WT non-squamous NSCLC.

Moreover, in the entire population, patients with TP53 mutation (11.0 months vs. 8.5 months, P=0.038), positive PD-L1 expression (9.0 months vs. 8.5 months, P=0.041), or common mutations such as KRAS G12C/G12D/G12V showed better PFS (PFS: 14.5 months vs. 8.0 months, P=0.045)....The patients were divided into two groups according to their timing of receiving immunotherapy, as 105 patients (63.3%) received first-line treatment (1L) and 61 (36.7%) received second-line and above treatment (2L+). The 1L group had better prognosis than the 2L+ group, reflected in ORR (50.5% vs. 29.5%, P=0.001), mPFS (13.5 months vs. 5.0 months, P < 0.001), and mOS (20.0 months vs. 11.0 months, P=0.004)....Bringing immunotherapy to first-line use in NSCLC patients with KRAS mutation might prolong their survival, and combination therapy is a preferable option compared to monotherapy.

In subgroup analysis by treatment received (chemotherapy, immune checkpoint inhibitors (ICI) or combination), only patients in the mutTP53 group treated with ICI had a significant improvement in OS compared to patients in the wtTP53 group. The mOS was 24.7 (95% CI, 20.8-NR) vs 10.6 months (95% CI, 4.5-NR) (HR 0.30, 95% CI 0.14-0.64, p= 0.002) for ICI group, and mOS was 20.5 (95% CI, 8.8-NR) vs 16.8 months (95% CI, 8.1-NR) for combination group (HR 1.73; 95% CI, 0.61-4.91, p= 0.3).

NSCLC patients with KRAS and/or TP53 mutations treated with ICIs showed significantly higher objective response rate, disease control rate, PFS, and OS compared to NSCLC patients with wild-type KRAS/TP53 (P < 0.05).

CONTRADICTING EVIDENCE: Among 480 advanced NSCLC patients (pts) treated with IO at Istituto Nazionale Tumori of Milan, 113 pts who performed cell-free DNA sequencing....PD-L1 positively correlated with DCR, ORR and OS. Among the G features, SHAP detected TP53 as the most relevant gene negatively correlated with outcome. KIT gene was identified as the second most important gene negatively correlated with the outcomes. BRAF was found to correlate with worse response....The explainable AI algorithms suggested a negative predictive role of TP53 and KIT mutational status.

CONTRADICTING EVIDENCE: A total of 235 NSCLC pts were enrolled and received ICIs...Pts with TP53 or STK11/KRAS co-mut (n = 3) had worse OS (12.3 m, 95% CI: 9.2-15.4; HR = 3, 95% CI: 1.6-5.8, p = 0.001 and 5.9 m, 95% CI: 1.4-7.6; HR = 2.9, 95% CI: 1.4-6.3, p = 0.007) and worse irPFS (2.8 m, 95% CI: 1.7-3.9, HR = 1.8 95% CI: 1.1-3.1, p = 0.03 and 1.2 m, 95% CI: 0.9-1.5, HR = 2.2 95% CI: 1.2-4.1, p = 0.01).