KEY TAKEAWAYS
- The phase 1 trial aimed to investigate the efficacy and safety of combining mFFX with Nivolumab in pts with BRPC.
- The primary endpoint was to determine safety.
- Researchers noticed improved rates of R0 resection, PFS, and OS with neoadjuvant mFOLFIRINOX and Nivolumab in pts with BRPC; further investigation is ongoing.
Combinations of chemotherapy and checkpoint inhibitors have failed to show improvements in pancreatic cancer, with all studies to date in the metastatic setting. Perioperative strategies of PD1 inhibitor combinations have shown promise in many malignancies. The A021501 trial established modified FOLFIRINOX (mFFX) as a reference neoadjuvant regimen for patients (pts) with borderline resectable pancreas cancer (BRPC).
Z. A. Wainberg, and the team aimed to assess the present clinical and pathologic results from a phase 1/2 investigator-initiated study investigating the safety and efficacy of mFFX and Nivolumab in pts with BRPC.
Researchers performed an inclusive analysis, treating pts with ECOG PS 0-1 and BRPC confirmed by qualified surgeons with a maximum of 6 cycles of mFFX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2, and infusional 5-fluorouracil 2400 mg/m2 over 46 hours) on days 1 and 15 of a 28-day cycle, alongside Nivolumab (480 mg IV q 4 weeks).
The primary endpoint included safety (including post-operative fistula formation) and pathologic response to neoadjuvant therapy. Secondary endpoints comprised progression-free survival (PFS), overall response rate (ORR), and overall survival (OS). RNA sequencing was performed on 16 post-treatment resected tumors, 5 patient-matched diagnostic pre-treatment biopsies, and 9 resected tumors from non-trial pts treated with mFFX alone.
About 28 pts (median age 68, M: 16, F: 12) were enrolled. Twenty-six (93%) pts completed at least 3 cycles of mFFX and Nivo, with 24 (86%) undergoing surgery (23 R0/1R1). No grade 2 post-operative fistulas were observed, and the rates of grade 3 or higher adverse events were 55%, all related to mFFX and none to nivolumab.
At a median follow-up of 24 months, the median PFS was 34.8 months, and the median OS was 35.1 months. Among pts who underwent pancreatectomy, the 18-month OS rate was 90%. There were 2 pathologic complete responses and 2 near-complete responses. Compared to pre-treatment biopsies, RNA sequencing from resected specimens revealed higher CD8 (P=0.018) and Granzyme A (P=0.024) expression.
In pts with pathologically node-negative disease (n=11), elevated Granzyme A expression was associated with significantly improved PFS (P=0.046). Adenosine-related gene expression increased in 50% (n=8) of post-treatment samples (P<0.022) and correlated with the expression of adenosine-generating CD73 (P=0.008).
The study concluded that neoadjuvant FOLFIRINOX and Nivolumab demonstrated favorable rates of R0 resection, PFS, and OS compared to historical data in pts with BRPC in this pilot trial. The addition of Nivolumab did not increase rates of G3 adverse events, and no unexpected safety signals were observed.
Moreover, adding Nivolumab to neoadjuvant FOLFIRINOX may benefit some patients by enhancing cytolytic T-cell function and decreasing immunosuppressive adenosine. This represents the first trial reported with a PD1 inhibitor in neoadjuvant pancreas cancer, and a Phase II trial is currently ongoing.
The study was sponsored by the Jonsson Comprehensive Cancer Center.
Source: https://www.abstractsonline.com/pp8/#!/20272/presentation/11407
Clinical Trial: https://clinicaltrials.gov/study/NCT03970252
Wainberg Z. A., Link J., Dawson D., et al. (2024). “A pilot clinical trial of neoadjuvant modified FOLFIRINOX plus nivolumab in borderline resectable pancreas cancer.” Presented at AACR 2024 (Abstract CT031).
