Quad Combo Shows Safety, Tolerability in Pancreatic Cancer

Paul E. Oberstein, MD

A quadruplet regimen consisting of of canakinumab (Ilaris), spartalizumab, gemcitabine, and nab-paclitaxel in patients with metastatic pancreatic cancer was shown to be safe and tolerable in the phase 1b PanCAN-SR1 trial (NCT04581343), in findings presented at the American Association for Cancer Research (AACR) Special Conference: Pancreatic Cancer by Paul E. Oberstein, MD.¹ The primary end point was to determine the incidence of dose-limiting toxicity (DLT) in the fi rst 56 days of dosing and to confirm the recommended phase 2/3 starting dose (FIGURE1).

Ten patients were enrolled in the initial dose-confimation cohort. They received 250 mg of canakinumab, 400 mg of spartalizumab, 1000 mg/m² of gemcitabine, and 125 mg/m² of nab-paclitaxel.

To be eligible for the study, patients had to have metastatic pancreatic cancer, and all were required to have a tumor biopsy at initiation and remain on treatment after 8 weeks of therapy. Patients were treated until disease progression or intolerance.

“Although the primary goal was to identify a phase 2 dose, there was a huge emphasis placed on collecting as much [tissue and serum] as we could to start asking questions about the role of IL-1β in pancreatic cancer,” Oberstein said.

IL-1β is a p otent i nducer o f myeloid-derived suppressor cells, which have been shown to modulate immunosuppression in the tumor microenvironment and may promote tumor invasiveness. Further, elevated levels of IL-1β in serum and tumors have been correlated with tumor fi brosis and resistance to chemotherapy.²

The median age of patients in the study was 65 years (range, 49-81) and patients had an ECOG performance status of either 0 or 1. “Most patients had liver metastasis, 1 had peritoneum involvement, and 1 patient received prior neoadjuvant therapy,” Oberstein noted.

Oberstein said that adverse events (AEs) were consistent with known AEs associated with chemotherapy and the experimental agents in the past. The most common grade 3/4 AEs were anemia (50%) and decreased neutrophil count/neutropenia (60%). One patient had a grade 3 influenza-like AE, which could have been caused by all 4 drugs; additionally, a grade 3 pneumonitis resulted in the discontinuation of spartalizumab in 1 patient.

Based on these fi ndings, the investigators recommended a phase 2 dose of 250 mg of canakinumab administered every 28 days, 400 mg of spartalizumab administered every 28 days, plus the standard of care of 1000 mg/m² of gemcitabine and 125 mg/m² of nab-paclitaxel on days 1, 8, and 15. Oberstein said the phase 2 trial had been initiated and is currently enrolling patients.

Oberstein also touched on preliminary efficacy but cautioned, “to be very clear, there was no chemotherapy arm in this phase 1 study.” He continued, “The database is not locked or finalized and these data come from the site investigators, not the database.” Based on site-level reporting, the preliminary response rate is 40% (4 of 10 patients). Twelve-month overall survival (OS) was achieved in 50% of patients and the median OS was 13.5 months.

These preliminary findings will help defi ne the major research questions moving forward: What is the definitive role of IL-1β i n p ancreatic c ancer? And w ill PD-1 blockade lead to reactivation of T cells in pancreatic cancer?

In addition, Oberstein expects hypothesisgenerating studies are on the horizon. Notably, the work coming out of the laboratory of Stephanie Dougan, PhD, principal investigator in cancer immunology and virology at Dana-Farber Cancer Institute and an assistant professor of immunology at Harvard Medical School in Boston that focuses on serum cytokine/chemokine changes that lead to changes with CD8 T-cell activation holds interest among investigators.

Oberstein said that the investigators were able to obtain serial biopsies and multiple serum samples for most patients. “At least in early data, it does suggest that there is an impact on both the activation of T cells as well as reduction of myeloid-derived suppressor cells from this quadruplet therapy,” Oberstein said. “This will be further studied in ongoing follow-up studies,” he concluded.

_REFERENCES:

_{1. Oberstein PE. Primary results of Pancan-SR1: A phase 1b study evaluating gemcitabine, nab-paclitaxel, canakinumab, and spartalizumab to target IL-1 and PD-1 metastatic pancreatic cancer with correlative tissue and blood biomarker analysis. Presented at: AACR Special Conference: Pancreatic Cancer; September 13-16, 2022; Boston, MA.}

_{2. Das S, Shapiro B, Vucic EA, Vogt S, Bar-Sagi D. Tumor cell–derived IL1 promotes desmoplasia and immune suppression in pancreatic cancer. Cancer Res. 2020;80(5):1088-1101. doi:10.1158/0008-5472.CAN-19-2080}