KRAS subtype may modify the poor immunotherapy response in pancreatic cancer: Evidence from early phase trials

Background: PDAC is characterized by a near universal presence of KRAS mutations and limited responsiveness to immunotherapy. Biologic heterogeneity among KRAS subtypes may shape tumor immunobiology and treatment resistance. Methods: We evaluated 109 patients with advanced PDAC treated on early phase trials (08/2014 to 08/2023). PFS and OS were estimated, cox regression models assessed clinical and molecular predictors of survival. Results: Of 109 patients, 64% had KRAS mutations, 18% were KRAS wild, and 17% had unknown KRAS status. Median age was 65 and 83% had liver metastases. KRAS subtype distribution was G12D (46%), G12V (31%), G12R (13%), and other variants (10%). Immunomodulatory agents were administered in 39% of patients, most commonly in the 1L (49%). mOS and PFS for the entire cohort were 5.65 and 2.73 months, respectively. The restricted mean OS (7.54 vs. 8.65, p=0.53) and PFS (3.82 vs. 4.24, p=0.7) did not differ between KRAS-mutant and KRAS wild. Among KRAS-mutant patients, those receiving immunomodulator therapy had shorter OS compared with those who did not, with the strongest association observed in KRAS G12D (Table 1). This pattern was not seen in the KRAS wild-type. On univariate analysis, immunotherapy exposure, number of prior treatment lines, and liver metastasis were each associated with inferior OS. On multivariate analysis, immunotherapy exposure demonstrated a non-significant trend toward inferior OS (HR 1.61, 95% Cl 0.98-2.66; p=0.06), while others remained independently associated with worse OS, suggesting confounding in the unadjusted association between immunotherapy and survival. Conclusion: Our findings suggest that among KRAS mutant PDAC - particularly G12D - receipt of immunotherapy in early phase trials was associated with shorter OS. This may reflect underlying biology or confounding by treatment line and disease burden and warrant validation by KRAS subtype-informed studies. Table 1: mOS by KRAS and immunotherapy exposure KRAS Immunotherapy (n) mOS (months) p wild yes (n=7) 4.47 0.08 no (n=13) 7.43 mutant yes (n=27) 2.63 0.03 no (n=43) 7.52 G12D yes (n=13) 2.07 0.04 no (n=19) 7.79 G12V yes (n=7) 4.04 0.48 no (n=15) 10.22 others yes (n=7) 2.33 0.20 no (n=9) 5.75