KRAS Subtype Modifies Outcomes with Immunomodulatory Therapy in Advanced Pancreatic Ductal Adenocarcinoma: Evidence from Early-Phase Trials

Background: Pancreatic ductal adenocarcinoma (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 in early-phase trials between August 2014 and August 2023. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method, and Cox proportional hazard models were used to assess the clinical and molecular predictors of survival. Results: Among the 109 patients, 64% harbored KRAS mutations, 18% were KRAS wild type, and 17% had an unknown KRAS status. The median age was 65 years, and 83% had liver metastases. Among the KRAS-mutant tumors, subtype distribution was G12D (46%), G12V (31%), G12R (13%), and other variants (10%). Immunomodulatory agents were administered to 39% of the patients, most commonly in the first-line setting (49%). The median OS 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 = 0.70) did not differ between patients with KRAS mutants and wild-type KRAS. Among patients with KRAS mutations, receipt of immunomodulatory therapy was associated with shorter OS compared with those who did not receive immunomodulatory therapy, with the strongest association observed in the KRAS G12D subgroup. This pattern was not observed in KRAS wild-type tumors. On univariate analysis, immunomodulatory therapy exposure, number of prior treatment lines, and presence of liver metastases were each associated with inferior OS. On multivariable analysis, immunotherapy exposure demonstrated a non-significant trend toward inferior OS (hazard ratio [HR] 1.61, 95% Cl 0.98–2.66; p = 0.06), while the other variables remained independently associated with worse OS, suggesting confounding in the unadjusted association between immunomodulatory therapy and survival. Conclusions: Among patients with KRAS-mutant PDAC—particularly those with G12D—receipt of immunomodulatory therapy in early-phase trials was associated with shorter OS in this exploratory analysis. These findings should be considered hypothesis-generating and require validation in prospective, KRAS-subtype-informed studies.