Timothy R. Donahue

Chemotherapy and immune checkpoint inhibitor combinations have failed to improve survival in pancreatic ductal adenocarcinoma (PDAC), except in rare microsatellite instability-high cases; most studies focused on advanced disease. Here, we present clinical and translational results from a single-arm, prospective phase 1b/2 investigator-initiated study (NCT03970252) evaluating neoadjuvant modified FOLFIRINOX (mFFX) plus nivolumab in patients with borderline-resectable PDAC. The co-primary endpoints of safety and pathological response rate were met, with 22 (79%) of 28 patients proceeding to surgery and no grade ≥3 immune-related adverse events. All grade 3-4 treatment-related adverse events were chemotherapy-related. By CAP scoring, 9% of patients achieved a complete pathologic response, 9% a near-complete response, and 72% a partial response. Secondary endpoints included CA 19-9 response rate, R0 resection rate, objective response rate, and disease-free survival (median 19.7 months, 95% CI: 7.3-30.8). In post-hoc analyses, median progression-free survival was 26 months (95% CI: 14.7-34.3), and median overall survival was 38 months (95% CI: 27.9-not reached). Exploratory gene expression, immunohistochemistry and spatial transcriptomics showed increased intratumoral plasma cells and CD8 T cells in treated patients versus mFFX-only controls, and lymphoid aggregates with high plasma-cell-to-B cell ratios enriched for terminally exhausted CD8 T cells with fewer progenitor exhausted CD8 T cells and central memory CD4 T cells.

Background: Although the relationship between higher surgical volume and improved outcomes for pancreatic operations is well established, centralizing care to high-volume centers (HVC) may prolong the interval from diagnosis to surgery. This study sought to compare outcomes of patients who had longer wait times for upfront surgery for pancreatic cancer (PDAC) at HVCs with those of patients who underwent earlier surgery at low-volume centers (LVCs). Methods: Patients undergoing upfront pancreatic surgery for T1-3N0-2M0 PDAC were identified from the 2004–2023 National Cancer Database. High-volume centers were defined using Leapfrog criteria as centers performing ≥ 20 pancreatic resections/year, with others defined as LVCs. Patients who waited more than 28 days for resection at HVCs were classified as “long wait/high volume,” whereas those who underwent surgery in ≤ 14 days at LVCs were classified as “short wait/low volume.” Results: Among 15,310 patients meeting the inclusion criteria, 9598 (63%) were short wait/low volume and 5712 (37%) were long wait/high volume. In unadjusted analysis, long wait/high volume demonstrated superior 5-year survival (23% vs. 19%, P < 0.001, log-rank). After comprehensive risk adjustment, waiting for surgery at an HVC remained associated with reduced mortality hazard during 5 years of follow-up evaluation (hazard ratio [HR], 0.81; 95% CI, 0.77–0.85; P < 0.001). Considering acute endpoints, the long-wait/high-volume group demonstrated greater likelihood of complete (R0) resection and reduced 30-day mortality, but higher risk of nodal disease and upstaging at resection. Conclusion: Waiting for surgery at an HVC is associated with improved acute outcomes and superior overall survival compared with earlier operations at an LVC. These findings assuage concerns regarding the potential longer wait times for surgery associated with centralization of surgical care for PDAC.

MRTX1133 selectively inhibits KRASG12D and downstream MAPK signaling in vitro

MRTX1133 is selective for KRASG12D in immunocompetent implantation tumor models

MRTX1133 reduces metastatic burden in a tail vein model

Supplementary Figures and Table with legend arranged in a single presentable package

MRTX1133 exerts in vivo effects early in treatment