Adding Nivolumab to Neoadjuvant Chemotherapy Spurs More Evaluation in Pancreatic Cancer

Pancreas or pancreatic cancer with organs and tumors or cancerous cells 3D rendering illustration with male body. Anatomy, oncology, disease, medical: © matthieu - stock.adobe.com

The combination of modified FOLFIRINOX (mFOLFIRINOX; leucovorin calcium, fluorouracil, irinotecan hydrochloride, oxaliplatin) and nivolumab (Opdivo) in the neoadjuvant setting was associated with favorable rates of R0 resection in patients with borderline resectable pancreatic cancer (BRPC), according to results of a phase 1/2 single-center study (NCT03970252) presented at the American Association for Cancer Research 2024 Annual Meeting.¹

“Borderline resectable pancreatic cancer is an increasingly recognized group of patients, about 20%, whose tumors are resectable with or without vascular resection and reconstruction but at high risk for positive margins,” said lead author Zev A. Wainberg, MD, professor of medicine at UCLA and codirector of the UCLA Gastrointestinal (GI) Oncology Program in Santa Monica, California, during a presentation of the data.

Historically, chemotherapy and checkpoint inhibitors have failed to improve outcomes in pancreatic cancer, but studies to date have evaluated only patients with advanced disease, Wainberg noted.^2,3 To be enrolled in the trial, patients needed to have adequate hepatic, biliary, and renal function. All patients were treated from 3 to 6 months with nivolumab and mFOLFIRINOX.¹

The primary end point was determination of the risk of patients developing clinically relevant fistulas; neoadjuvant treatment in pancreatic cancer had not previously been evaluated, Wainberg said. Secondary end points were resection rate, response, progression-free survival (PFS), and overall survival (OS). Exploratory end points were biologic changes on T-cell function and infiltration after nivolumab and chemotherapy were administered.¹

A total of 28 patients were enrolled with a median age of 67.5 years (range, 44-79). The majority were men (57%), and the most common race and ethnicity was White (57%), followed by Asian (21%), and Hispanic or Latino (14%).¹

The median number of cycles patients completed was 5.5, and patients had a partial response of 21%, with 71% reporting stable disease.

Wainberg cautioned that the response rate of primary tumors of the pancreas is “notoriously unreliable and has no predictive potential for long-term outcome.”

Turning to safety, the most common grade 3 hematologic adverse events (AEs) were hypokalemia (11%), anemia (7%), and decreased neutrophil counts (7%). The most common grade 2 hematologic toxicities included hypokalemia (18%), anemia (11%), and decreased platelet count (11%).¹

The most common grade 3 nonhematologic toxicity was musculoskeletal disorders and aches (4%). The most common grade 2 nonhematologic AEs were dehydration (36%), nausea (32%), and diarrhea (25%). No grade 2 postoperative fistulas were observed, and there were no significant postoperative complications.¹

Among 28 patients, 22 (78.5%) underwent surgery. Regarding tumor location, 50% were located in the head of the pancreas, and 14% each were located in the uncinate and body.

Wainberg said there were distributions of lymphovascular and perineural invasion consistent with the literature.¹ “Among patients who underwent resection [n =22], there were 2 complete pathologic responses or near complete pathologic responses, and 15 patients [68%] were considered to have a spatial pathological response by standard criteria,” Wainberg said.

Regarding efficacy, Wainberg said the median PFS for all comers was 21.9 months, but it was 27.3 months for the group of patients who underwent resection. The median OS of all patients was 34.6 months but among those who underwent resection, it was 44.0 months after a median follow-up of 25.6 months.

“The 12-month OS rate on this study was 82%, and the 18-month OS was 77%, which is higher than historical controls,” Wainberg said.

In the neoadjuvant setting, the impact of nivolumab remains somewhat cloudy. Investigators reported an increase in histopathologic immunostimulatory phenotypes when nivolumab was added vs FOLFIRINOX alone, Wainberg said. He reported a prognostic difference that was consistent with the literature involving transcriptional signatures of classical and basal-like tumors.

“This is consistent with metastatic disease, where the patients who have a basal- like phenotype do very poorly regardless of treatment, whereas patients with the classic phenotype had a great response, including complete and near complete pathological responses,” Wainberg said.

Overall, favorable rates of R0 resection, PFS, and OS were observed relative to historical data, with no increase in grade 3 AEs associated with the addition of nivolumab.¹

“Results from this trial support ongoing investigation of chemoimmunotherapy in pancreatic cancer but rather than exclusively evaluating this in metastatic disease, we need to be studying these drugs earlier in both borderline and locally advanced disease to understand the impact of these agents on tumor biology,” Wainberg concluded.

REFERENCES:

1. Wainberg ZA, Link JM, Dawson D, et al. A pilot clinical trial of neoadjuvant modified FOLFIRINOX plus nivolumab in borderline resectable pancreas cancer. Presented at: American Association for Cancer Research 2024 Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT031.

2. Wainberg ZA, Hochster HS, Kim EJ, et al. Open-label, phase I study of nivolumab combined with nab-paclitaxel plus gemcitabine in advanced pancreatic cancer. Clin Cancer Res. 2020;26(18):4814-4822. doi:10.1158/1078-0432. CCR-20-0099

3. O’Reilly EM, Oh DY, Dhani N, et al. Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 randomized clinical trial. JAMA Oncol. 2019;5(10):1431-1438. doi:10.1001/ jamaoncol.2019.1588