Paradoxically, KRYSTAL-1 biomarker data showed a numerically higher ORR in CDKN2A-mutated patients (58.3% vs. 44.9%),34 possibly confounded by small sample sizes, coexisting mutations (e.g., KEAP1 or SMARCA4), or epigenetic mechanisms, considering that p16 promoter methylation (observed in 33% of NSCLCs) was synergistically enhanced by KRAS mutations in colon cancer and positively correlated with NSCLC.105. This evidence concerns the gene CDKN2A and non-small cell lung carcinoma.