Quadruplet Regimen for Pancreatic Cancer Yields High Response, Safety Concerns

Findings from an early phase 2 clinical trial (NCT04156087)show that a novel combination therapy for patients with unresectable nonmetastatic locally advanced pancreatic cancer yielded promising median progression-free survival (PFS).¹

The study combined dual immune checkpoint inhibitors durvalumab (Imfinzi) and tremelimumab (Imjudo), local tumor ablation via minimally invasive surgical microwave ablation (MIS-MWA), and gemcitabine chemotherapy. The trial was terminated prematurely with only 12 patients enrolled. Of the 12 patients, 8 received the full per-protocol treatment regimen and demonstrated a median PFS of 11.2 months compared with a historical benchmark of approximately 6 months.

Of the 12 patients, 4 were found to have occult metastatic disease during the staging laparoscopy prior to the planned ablation.These patients did not receive MIS-MWA.

The median PFS of the total enrolled patients (n = 12) was 8.9 months (range, 3.2–18.4), and the median PFS of the 8 patients who received the full treatment regimen was 11.2 months (range, 4–18.5). The median overall survival (OS) of the total enrolled patients was 15.4 months (range, 3.9–23.6), and the median OS of the treated patient group was 17.3 months (range, 9.2–23.6).

The primary end point of PFS at 12 months was not met for the full cohort but was nearly achieved in the patient group that received full treatment.

Safety Findings

The combination therapy was associated with a notable rate of adverse events (AEs). Of the 12 patients, 7 (58%) experienced at least 1 treatment-related AE. The most common AEs of any grade were fatigue (33%), nausea (25%), and diarrhea (25%). Grade ≥3 treatment-related AEs occurred in 3 of 12 patients (25%) and included colitis, hyperglycemia, and muscle weakness. One patient developed severe, refractory immune-related colitis requiring hospitalization and discontinuation of treatment.One patient suffered a grade 5 serious AE (death) due to hemorrhagic shock following a postoperative pancreatic fistula that developed after the laparoscopic biopsy and MWA procedure.

Trial Design and Treatment Regimen

The study was a mono-center, open-label trial. Of 16 patients screened, 12 were enrolled in the intention-to-treat analysis.

In the priming phase of the trial, patients received 1500 mg of durvalumab plus 75 mg of tremelimumab. Two weeks after the first dose, patients underwent MIS-MWA and were then administered the second dose of durvalumab plus tremelimumab2 weeks later. Six and 10 weeks after MIS-MWA, patients received the third and fourth doses of the drug combination. After week 10, patients received durvalumab monotherapy every 4 weeks. Six weeks after MIS-MWA, patients received 1000 mg weekly for 3 weeks of gemcitabine followed by 1 week of rest concurrent with durvalumab and tremelimumab.^1,2

Biomarker Analysis

The most significant insight from the trial is the identification of CD8-TEMRAcells (CD45RA+ effector memory CD8 T cells) as a potential biomarker for immunotherapy efficacy.¹ High pretreatment abundance of NK/T cells, particularly CD8-TEMRA cells, was strongly associated with longer survival. This finding was further supported by analysis of an independent dataset, where a high CD8-TEMRA gene signature correlated with significantly improved OS.

The study utilized advanced single-cell transcriptomics and T-cell receptor (TCR) profiling on tumor and blood samples to characterize the immune response.Analysis of the tumor microenvironment (TME) revealed several strong associations between immune cell populations and patient survival outcomes.

A higher relative abundance of NK/T cells in pretreatment tumor biopsies was strongly and significantly correlated with longer PFS (P =.0048).

While not reaching statistical significance due to the small sample size (n=3 paired samples), trends suggested that long-term survivors exhibited more pronounced T-cell expansion and a higher proportion of shared TCR clonotypes between the tumor and peripheral blood compared to short-term survivors.

Shared TCRs found in both the TME and peripheral blood were primarily localized in CD8-TEMRA and CD8-TEM cell populations.

“Given the small, nonrandomized nature of this trial, the findings should be interpreted as hypothesis-generating and warrant further evaluation in larger, controlled studies,” concluded Topal et al, authors of the study. “Therefore, future prospective trials with larger patient cohorts are needed to confirm whether the abundance and activation state of [CD8-TEMRA] cells can serve as early biomarkers of immunotherapy response.”

REFERENCES

1.Topal H, Venken T, Bassez A, et al. Progression-free survival for unresectable non-metastatic locally advanced pancreatic cancer after surgical microwave ablation plus durvalumab and tremelimumab: phase-2 non-randomized prospective clinical trial. Commun Med. 5, 475 (2025). doi:10.1038/s43856-025-01186-x

2.Progression-free survival after MWA plus durvalumab and tremelimumab for unresectable locally advanced pancreatic cancer (MIMIPAC). ClinicalTrials.gov. Updated September 19, 2024. Accessed November 20, 2025. https://clinicaltrials.gov/study/NCT04156087