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.
Bibliographic record
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 .
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".