Abstract 1319P
Background
Genetic aberrations in KRAS and TP53 were common in NSCLC, and were indicated to be associated with efficacious immunotherapy. However, the inter-relation between these two gene mutations were largely unknown. We hereby interrogate the inter-relation by meta-cohort analysis involving 8 cohorts of 1129 NSCLC patients receiving ICIs.
Methods
We retrospectively collected the clinical and mutational data of the patients with EGFR/ALK WT non-squamous NSCLC receiving ICI treatment (the 3DMed cohort, n=37). In addition, another 7 public cohorts (SNCC, Van Allen, Rizvi-34, Rizvi-240, MSKCC-75, MSKCC-350, and POPLAR/OAK) involving data from 1092 patients were included to comprehensively explore the impact of KRAS/TP53 mutations on ICI benefit.
Results
In the overall population, 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). It is of great interest that the beneficial effect of each mutation was based on the mutation of the other one. 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). Conversely, 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. Table: 1319P
Pooled estimate
| Variable | ORR | PFS | ||
| RR (95%CI) | P | HR (95%CI) | P | |
| TP53-mut vs. TP53-WT | 1.94 (1.31-2.87) | 0.001 | 0.72 (0.55-0.95) | 0.019 |
| KRAS-mut vs. KRAS-WT | 1.54 (1.02-2.32) | 0.040 | 0.82 (0.56-1.19) | 0.295 |
| KRAS-mut+ TP53-mut vs. KRAS-mut+ TP53-WT | 2.86 (1.46-5.57) | 0.002 | 0.47 (0.32-0.68) | <0.001 |
| KRAS-WT+ TP53-mut vs. KRAS-WT+ TP53-WT | 1.53 (0.92-2.56) | 0.104 | 0.91 (0.65-1.27) | 0.566 |
| TP53-mut+ KRAS-mut vs. TP53-mut+ KRAS-WT | 1.98 (1.17-3.35) | 0.011 | 0.66 (0.47-0.93) | 0.017 |
| TP53-mut+ KRAS-mut vs. TP53-mut+ KRAS-WT | 1.28 (0.61-2.71) | 0.518 | 1.04 (0.60-1.79) | 0.885 |
| TP53/KRAS-co-mut vs. the rest | 2.59 (1.63-4.12) | <0.001 | 0.58 (0.43-0.79) | 0.001 |
Conclusions
Meta-cohort analysis involving 8 cohorts of 1129 patients demonstrate the interdependence of KRAS and TP53 mutations in predicting ICI benefit. 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.
Clinical trial identification
Legal entity responsible for the study
Lin Li.
Funding
National Natural Science Foundation of China (81974361 to Xiaoyan Li) and CAMS Innovation Fund for Medical Sciences (2018-I2M-1-002 to Lin Li).
Disclosure
All authors have declared no conflicts of interest.