Concurrent mutations in DNA damage repair genes <i>BRCA1</i> , <i>POLE</i> , <i>ATM</i> and <i>FANCA</i> to predict overall and progression-free survival for patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with chemotherapy in combination with dual checkpoint inhibition in the CCTG randomized PA.7 trial.

Abstract

4178 Background: CCTG PA.7 (NCT02879318) was a randomized phase II trial comparing gemcitabine (G) and nab-paclitaxel (N) with and without dual immune checkpoint inhibition with durvalumab (D) and tremelimumab (T) as 1st-line therapy in pts with mPDAC. Matched plasma and tissue-based sequencing was performed for exploratory correlative biomarker analysis. Methods: Pts received G+N+D+T (n = 11 run-in, 119 randomized, 2:1 randomization) or G+N (n = 61). Long-term trial analysis was performed with a median follow-up time of 81.6 months. Correlative analysis was performed for pts with baseline ctDNA sequencing using a 600-gene PredicineATLAS panel (n = 173), with a subset having matched archival tissue available for whole-genome sequencing (WGS; n = 46). Cox-based elastic net regression models were used to identify and rank combinations of mutations by their ability to predict survival hazard. Results: Long-term follow up analysis demonstrated no significant difference in median overall survival (mOS) between pts randomized to G+N+D+T vs G+N (9.8 vs 8.8 months; hazard ratio (HR) = 0.88; p = 0.46). Median progression-free survival (mPFS) was also not significantly different between treatment arms (5.5 vs 5.4 months, respectively; HR = 0.95, p = 0.77). Landmark analysis demonstrated 4-year survivorship of 5.4% in pts treated with G+N+D+T arm compared to 1.6% with G+N (p = 0.07). Two or more ctDNA-based mutations (somatic and germline considered separately) in DNA damage repair (DDR) genes BRCA1 , POLE , ATM or FANCA was present in 18/173 pts (10.4%) and was associated with improved OS with G+N+D+T vs G+N (mOS 26.2 months vs. 7.1 months; HR = 0.22 [0.07-0.7]; p = 0.0041, p-interaction = 0.012) as well as PFS (mPFS 14.6 vs. 4.6; HR = 0.17 [0.05-0.6]; p = 0.0020, p-interaction = 0.0070). In pts treated with G+N+D+T, partial response (PR) was seen in 63.6% of pts with ≥2 DDR gene mutations compared to 26.9% in other pts (p = 0.033), and this effect was not observed with G+N (p = 0.18). The DDR gene biomarker was validated in 5/6 (83%) biomarker-positive samples using archival tissue WGS. Conclusions: The presence of ≥2 DDR gene mutations was strongly associated with benefit from the combination of chemotherapy with dual immune checkpoint inhibitor therapy, and pts with this signature had prolonged mOS of over 2 years. This represents the first prospective study in PDAC to define a predictive biomarker beyond mismatch repair deficiency for benefit from immune checkpoint therapy. Given the long-term survival noted in this subgroup, assessment of DDR gene mutations could be considered as part of routine standard of care testing for mPDAC pts. Clinical trial information: NCT02879318 .