Collisson, Eric A.

TPS4205 Background: Multiple lines of evidence support the use of platinum-based chemotherapy for patients with homologous recombination deficiency-associated pancreatic adenocarcinoma (HRD PDAC; 15-20%). However, the impact of the specific platinum agent used remains uncertain. Mechanistically, oxaliplatin and cisplatin act distinctly on cancer cells, reflected in disparate toxicity profiles and target disease indications; furthermore, preclinical studies have shown that BRCA2-deficient cell lines and mice demonstrate significantly greater sensitivity to cisplatin compared to oxaliplatin. While oxaliplatin, part of the FOLFIRINOX regimen, represents the most commonly used platinum analogue for PDAC, clinical data shows that cisplatin (in combination with gemcitabine) can produce robust response rates (~70%) specifically in patients with germline BRCA/PALB2-mutated metastatic PDAC. We therefore designed a randomized clinical trial (PLATINUM) through the Alliance for Clinical Trials in Oncology cooperative group to assess the optimal chemotherapy regimen in patients with HRD-associated metastatic PDAC following front-line FOLFIRINOX and to test the hypothesis that a platinum switch strategy will be beneficial. Methods: The study consists of a seamless phase II/III design, with the primary endpoint of the phase III component being overall survival. Eligible patients will have metastatic PDAC, a confirmed pathogenic BRCA1/2 or PALB2 mutation (somatic or germline), and demonstrated disease progression on front-line FOLFIRINOX, with or without subsequent PARP inhibitor maintenance. Patients will be randomized 1:1 to receive (1) the de facto standard of gemcitabine plus nab-paclitaxel; or (2) the experimental 3-drug combination of gemcitabine, nab-paclitaxel, and cisplatin (NABPLAGEM), which has been previously studied in non-biomarker-selected patients with advanced biliary tract cancer (SWOG1815) and metastatic PDAC. Both treatment arms will use a once every other week dosing schedule. A total of 100 patients will be enrolled, which provides 90% power to detect an effect size of hazard ratio 0.5 (median OS of 18 vs 9 months) at a one-sided alpha of 0.05. Reports containing efficacy, adverse events, and administrative information will be provided to the Alliance DSMB every 6 months. Planned correlatives include ctDNA analysis for BRCA reversion mutations in all patients, as well as whole genome and transcriptome sequencing in an optional biopsy cohort. This study was activated in December 2023. Clinical trial information: NCT06115499 .

Importance National guidelines endorse treatment with neoadjuvant therapy for borderline resectable pancreatic ductal adenocarcinoma (PDAC), but the optimal strategy remains unclear. Objective To compare treatment with neoadjuvant modified FOLFIRINOX (mFOLFIRINOX) with or without hypofractionated radiation therapy with historical data and establish standards for therapy in borderline resectable PDAC. Design, Setting, and Participants This prospective, multicenter, randomized phase 2 clinical trial conducted from February 2017 to January 2019 among member institutions of National Clinical Trials Network cooperative groups used standardized quality control measures and included 126 patients, of whom 70 (55.6%) were registered to arm 1 (systemic therapy; 54 randomized, 16 following closure of arm 2 at interim analysis) and 56 (44.4%) to arm 2 (systemic therapy and sequential hypofractionated radiotherapy; all randomized before closure). Data were analyzed by the Alliance Statistics and Data Management Center during September 2021. Interventions Arm 1: 8 treatment cycles of mFOLFIRINOX (oxaliplatin, 85 mg/m 2 ; irinotecan, 180 mg/m 2 ; leucovorin, 400 mg/m 2 ; and infusional fluorouracil, 2400 mg/m 2 ) over 46 hours, administered every 2 weeks. Arm 2: 7 treatment cycles of mFOLFIRINOX followed by stereotactic body radiotherapy (33-40 Gy in 5 fractions) or hypofractionated image-guided radiotherapy (25 Gy in 5 fractions). Patients without disease progression underwent pancreatectomy, which was followed by 4 cycles of treatment with postoperative FOLFOX6 (oxaliplatin, 85 mg/m 2 ; leucovorin, 400 mg/m 2 ; bolus fluorouracil, 400 mg/m 2 ; and infusional fluorouracil, 2400 mg/m 2 over 46 hours). Main Outcomes and Measures Each treatment arm’s 18-month overall survival (OS) rate was compared with a historical control rate of 50%. A planned interim analysis mandated closure of either arm for which 11 or fewer of the first 30 accrued patients underwent margin-negative (R0) resection. Results Of 126 patients, 62 (49%) were women, and the median (range) age was 64 (37-83) years. Among the first 30 evaluable patients enrolled to each arm, 17 patients in arm 1 (57%) and 10 patients in arm 2 (33%) had undergone R0 resection, leading to closure of arm 2 but continuation to full enrollment in arm 1. The 18-month OS rate of evaluable patients was 66.7% (95% CI, 56.1%-79.4%) in arm 1 and 47.3% (95% CI 35.8%-62.5%) in arm 2. The median OS of evaluable patients in arm 1 and arm 2 was 29.8 (95% CI, 21.1-36.6) months and 17.1 (95% CI, 12.8-24.4) months, respectively. Conclusions and Relevance This randomized clinical trial found that treatment with neoadjuvant mFOLFIRINOX alone was associated with favorable OS in patients with borderline resectable PDAC compared with mFOLFIRINOX treatment plus hypofractionated radiotherapy; thus, mFOLFIRINOX represents a reference regimen in this setting. Trial Registration ClinicalTrials.gov Identifier: NCT02839343

377 Background: Neoadjuvant therapy has been associated with a median overall survival (OS) of 18 – 23 months (mo) in patients (pts) with BR pancreatic ductal adenocarcinoma (PDAC). To establish reference regimens to which novel treatments can be compared in future studies, we evaluated neoadjuvant mFOLFIRINOX with or without RT in BR PDAC in a phase II National Clinical Trials Network (NCTN) trial. Methods: Pts with ECOG PS 0-1 and BR PDAC confirmed by central real-time radiographic review after pre-registration were randomized to either arm A: 8 cycles of neoadjuvant mFOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 over 46 hours), or arm B: 7 cycles of mFOLFIRINOX followed by stereotactic body RT (SBRT, 33-40 Gy in 5 fractions [fx]) or hypofractionated image guided RT (HIGRT, 25 Gy in 5 fx). Pts in either arm without disease progression underwent pancreatectomy, then 4 cycles of adjuvant mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 over 46 hours). The primary endpoint, 18-mo OS rate, of each arm was compared to a historical control of 50%. Planned interim analysis mandated closure of either arm in which <11 of first 30 accrued pts underwent R0 resection. Results: 155 pts pre-registered and 126 pts were enrolled to arm A (N=70; 54 randomized, 16 following closure of arm B) or arm B (N=56; closed at interim analysis, all pts randomized prior to closure). Median age (A: 63y, B: 67y), median CA 19-9 level (A: 171 U/ml, B: 248 U/ml) and ECOG PS (A: 51% PS 0, B: 57% PS 0) of registered pts were similar between arms (p > 0.05). Treatment detailed in Table. The 18-mo OS rate based on Kaplan Meier estimates was 67.9% (95%CI: 54.6 – 78.0) in arm A and 47.3% (95%CI: 33.7 – 59.7) in arm B. Among pts who underwent pancreatectomy, 18-mo OS rate was 93.1% (95%CI: 84.3 – 100) and 78.9% (95%CI: 62.6 – 99.6) in arm A and B, respectively. With median follow-up of 27 and 31 mo, median OS was 31.0 (95%CI: 22.2 – NE) mo and 17.1 (95%CI: 12.8 – 24.4) mo in arm A and B, respectively. Conclusions: Neoadjuvant mFOLFIRINOX was associated with favorable OS relative to historical data in pts with BL PDAC in this phase II NCTN trial. mFOLFIRINOX with hypofractionated RT did not improve OS compared to historical data. mFOLFIRINOX represents a reference regimen in this setting and a backbone on which to add novel agents. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org Clinical trial information: NCT02839343. [Table: see text]