Neoadjuvant Chemo/Nivolumab Yields Deep Responses in Borderline-Resectable PDAC Subset

Neoadjuvant modified FOLFIRINOX (mFOLFIRINOX)—oxaliplatin, leucovorin, irinotecan, and 5-fluorourcail—plus nivolumab (Opdivo) was safe and efficacious in patients with borderline-resectable pancreatic ductal adenocarcinoma (PDAC), according to findings from a pilot phase 1 trial (NCT03970252) published in Nature Communications.¹ The integration of PD-1 blockade into a standard-of-care chemotherapy backbone was feasible and achieved durable clinical outcomes in this high-risk patient population.

Clinical Efficacy

The clinical efficacy analysis included 28 enrolled patients who received at least 1 dose of the investigative regimen. Of these, 22 patients (79%) underwent surgical resection, and all 22 successfully completed tumor resection. Histopathologic evaluation revealed that 86% of patients who had resection achieved an R0 resection, defined as having no tumor cells at the surgical margins. According to the College of American Pathology (CAP) scoring system, 9% of patients reached a complete pathologic response, 9% achieved a near-complete response, and 72% demonstrated a partial pathologic response.

Objective response assessments indicated that primary tumor size decreased in 81% of patients, with an overall response rate (ORR) of 27%. The remaining 73% of patients achieved stable disease as their best response, resulting in a 100% disease control rate among evaluable participants. Biochemical activity was also noted, with CA 19-9 levels decreasing in 73% of patients throughout treatment; notably, 31% of patients converted from abnormal baseline levels to normal levels by the final cycle.

Survival outcomes were encouraging at a median follow-up of 48 months, with a median progression-free survival (PFS) of 22 months (95% CI, 14.5-29.4) for the total population and 26 months (95% CI, 14.7-34.3) for those who underwent resection. The median overall survival was 35 months (95% CI, 22.0-not reached [NR]) for all patients and 38 months (95% CI, 27.9-NR) in the resected subgroup.

“By testing this novel drug combination in the preoperative setting, we were able to directly compare pre-treatment biopsies with surgical resection specimens to better understand why the therapy works in some patients, and, just as importantly, why it does not in others, and what additional strategies might improve responses,” stated senior author Timothy R. Donahue, MD, chief of surgical oncology and professor of surgery at the David Geffen School of Medicine at UCLA, in a press release on the findings.¹ “Establishing this platform within the Agi Hirshberg Center for Pancreatic Diseases positions us to evaluate multiple new therapeutics in a systematic and translationally integrated way in the future.”

Trial Breakdown

The investigator-initiated pilot trial evaluated neoadjuvant mFOLFIRINOX combined with nivolumab in patients who were treatment-naive with biopsy-proven borderline-resectable PDAC. Nivolumab was administered intravenously at 480 mg on day 1 of each cycle. Participants received a median of 5.5 cycles of therapy, with the protocol allowing for up to 6 cycles administered every 14 days. Surgery was scheduled following a multi-disciplinary review after the completion of neoadjuvant cycles.

Eligibility criteria required a histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma classified as borderline-resectable based on vessel involvement per NCCN guidelines. All patients were required to have an ECOG performance status of 0 or 1.

The primary end point of the trial was safety and tolerability, with special attention paid to rates of post-surgery complications, increased rates of other post-operative complications, and delays in surgery. Pathologic complete response using CAP treatment response scoring was also a co-primary end point. Secondary end points included R0 resection rate, percent chance of CA19-9, and disease-free survival.

Safety and Tolerability Profile

The addition of nivolumab to the mFOLFIRINOX backbone did not result in unexpected or additive toxicities. Grade 3 or higher treatment-related adverse events occurred in 11% of the study population. Grade 4 events were limited to neutropenia (n = 3) and hypokalemia (n = 1). Significantly, there were no grade 3 or higher immune-related adverse events, and no grade 3 toxicities were specifically attributed to nivolumab. Surgical safety was preserved, with no treatment-related delays, per protocol, and no Grade C pancreatic fistulas occurred post-resection. No treatment-related deaths were reported.

References

1. Wainberg ZA, Link JM, Premji A, et al. Neoadjuvant modified FOLFIRINOX plus nivolumab in borderline-resectable pancreatic ductal adenocarcinoma: a pilot phase 1 trial. Nat Commun. 2026. doi:10.1038/s41467-026-68976-2.
2. Immunotherapy plus chemotherapy before surgery shows promise for pancreatic cancer. News release. UCLA Health. February 17, 2026. Accessed February 19, 2026. https://tinyurl.com/38y2bv6x