The CCTG PA.7 phase II trial of gemcitabine and nab-paclitaxel with or without durvalumab and tremelimumab as initial therapy in metastatic pancreatic ductal adenocarcinoma

Abstract

Immunotherapy-based monotherapy treatment in metastatic pancreatic ductal adenocarcinoma (mPDAC) has shown limited benefit outside of the mismatch repair deficiency setting, while safety and efficacy of combining dual-checkpoint inhibitor immunotherapy with chemotherapy remains uncertain. Here, we present results from the CCTG PA.7 study (NCT02879318), a randomized phase II trial comparing gemcitabine and nab-paclitaxel with and without immune checkpoint inhibitors durvalumab and tremelimumab in 180 patients with mPDAC. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and objective response rate. Results of the trial were negative as combination immunotherapy did not improve survival among the unselected patient population (p = 0.72) and toxicity was limited to elevation of lymphocytes in the combination immunotherapy group (p = 0.02). Exploratory baseline circulating tumor DNA (ctDNA) sequencing revealed increased survival for patients with KRAS wildtype tumors in both the combination immunotherapy (p = 0.001) and chemotherapy (p = 0.004) groups. These data support the utility of ctDNA analysis in PDAC and the prognostic value of ctDNA-based KRAS mutation status.

Fig. 1. Combination dual checkpoint inhibition and chemotherapy was not associated with OS, PFS nor ORR in an unselected population of patients with metastatic PDAC.

A Kaplan-Meier curve comparing overall survival (OS) between treatment arms. B Kaplan-Meier curve comparing progression-free survival (PFS) between treatment arms. C Forest plot showing results of subgroup analysis based on OS. Measure of center for error bars represents mean values. D Bar plot comparing differences in objective response rate (ORR) between treatment arms. Hazard ratio and confidence intervals (CIs) based on stratified Cox models are shown along with log-rank p values, and statistical tests were two-sided. Source data are provided as a source data file.

Fig. 2. Somatic mutation landscape of mPDAC detected using liquid biopsy (ctDNA) sequencing at baseline.

A Oncoprint depicting most frequently mutated genes detected by baseline ctDNA sequencing in the cohort of 173 patients with mPDAC. Upper bars indicate blood tumor mutation burden (TMB; mut/Mb) levels and are colored based on microsatellite instability (red) or stable (grey) status. B Histogram with overlaid density curve showing distribution of blood tumor mutational burden levels across the cohort. C Histogram with overlaid density curve showing distribution of the number of SNV/indels detected by ctDNA sequencing. Source data are provided as a source data file.

Fig. 3. ctDNA-based KRAS mutation status is highly prognostic in patients with mPDAC.

A Kaplan-Meier curve comparing overall survival (OS) between patients with KRAS wildtype (red) versus mutant (grey) tumors in the gemcitabine, nab-paclitaxel, durvalumab and tremelimumab (Gem+Nab-P+Durva+Treme) treatment group. B Kaplan-Meier curve comparing OS between patients with KRAS wildtype versus mutant tumors in the gemcitabine, nab-paclitaxel (Gem+Nab-P) treatment group. Hazard ratio and confidence intervals (CIs) based on stratified Cox models are shown along with log-rank p values, and statistical tests were two-sided. Source data are provided as a source data file.