Azacitidine and Pembrolizumab in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDA) has the worst prognosis of any major malignancy in the United States and, unlike other common cancers, annual deaths from PDA are rising. Despite recent advances, cytotoxic chemotherapy for PDA has been disappointing. Even among the small subset of patients who are suitable for surgical resection at the time of diagnosis, complete resection is followed by recurrence in majority of patients without further systemic therapy. Thus all PDA patients require systemic chemotherapy and more effective regimens are urgently needed.

Combination chemotherapy is effective in controlling disease and prolonging survival in patients with advanced pancreatic cancer. Despite recent successful phase 3 studies in the first-line setting, there is no defined second-line treatment for patients who experience disease progression following first-line therapy. Consensus guidelines (such as the National Comprehensive Cancer Network (NCCN) guidelines) recommend clinical trial participation in this setting.

The investigators' pre-clinical data suggests that decitabine treatment in the KPC model of pancreatic cancer leads to a significant up-regulation of interferon-related genes and a polarization of the infiltrating immune cells. Based on these results, the investigators have evaluated the effect of single agent decitabine or anti-PD1H (a homologue of PD1 with very similar function and expression pattern) compared to combination therapy (treatment with decitabine followed by PD1H blockade). The investigators' preliminary results showed minimal effect of either agent alone on tumor growth but marked decrease in tumor progression in the combination arm. These results form the foundation of this phase II study.

This study will treat patients with the combination of azacitidine and pembrolizumab. A direct comparison between azacitidine and decitabine in terms of efficacy within a controlled clinical trial has not been performed thus far. In randomized myelodysplastic syndrome (MDS) trials, the remission rates were similar for azacitidine and decitabine but the overall survival in the experimental arm was significantly shorter in the decitabine trial compared to the azacitidine trial. A primary reason to utilize azacitidine in this setting is our desire to amply reduced dose therapy with the goal of maintaining subjects on therapy Low-dose azacitidine is being tested in phase I/II clinical trials for advanced solid tumors-mainly colorectal cancer, small-cell lung carcinomas, ovarian cancer, and breast cancer.

• Pembrolizumab (Drug), also known as Keytruda: Pembrolizumab 200 mg IV every 3 weeks until progression
• Azacitidine (Drug), also known as Vidaza: 50 mg/m2 subcutaneous daily for 5 days every 28 days

Primary outcomes

• Progression-Free Survival (PFS) [24 months]: PFS is defined as the time from the first day of trial treatment to the first documented disease progression per RECIST 1.1 (At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression)) or death due to any cause, whichever occurs first.

Secondary outcomes

• Objective Response Rate (ORR) [Throughout study duration, up to approx 80 months]: ORR is defined as the percentage of the participants in the analysis population who have a complete response (CR) or partial response (PR). Responses are based on assessments per RECIST 1.1.
• Duration of Response (DOR) [Throughout study duration, up to approx 80 months]: For subjects who demonstrate CR or PR, based on assessments per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first.
• Disease Control Rate (DCR) [Throughout study duration, up to approx 80 months]: DCR is defined as the percentage of participants who have achieved CR, PR, or stable disease (SD) based on assessments per RECIST 1.1.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Be willing and able to provide written informed consent for the trial.
* Age ≥18 years of age on day of signing informed consent.
* Have confirmed diagnosis of pancreatic ductal adenocarcinoma
* Have a predicted life expectancy of greater than 3 months.
* Have measurable disease based on RECIST 1.1.
* Have a performance status of 0 or 1 using the Eastern Cooperative Oncology Group (ECOG) Performance Scale within 3 days of first dose of study drug.
* Have documented radiographic progression to or documented intolerance of first line systemic chemotherapy which included either gemcitabine or Fluorouracil (5-FU) based regimen (including capecitabine).
* Subjects who have documented disease recurrence within 6 months of completing neoadjuvant or adjuvant chemotherapy for limited disease will be eligible for study. Subjects who recur greater than 6 months after completing adjuvant or neoadjuvant chemotherapy will not be eligible unless they receive additional chemotherapy for advanced disease.

Exclusion Criteria:

* Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy, or herbal/complementary oral or IV medicine within 2 weeks of the first dose of treatment.
* Has received chemotherapy or radiotherapy within 14 days of first dose of study medication.

Participant flow

Outcome results

• Progression-Free Survival (PFS) (Primary), Median, months: Pembrolizumab 1.49 (1.38 to 1.74)
• Objective Response Rate (ORR) (Secondary), Number, percentage of participants: Pembrolizumab 9.7
• Duration of Response (DOR) (Secondary), Number, days: Pembrolizumab 2274
• Disease Control Rate (DCR) (Secondary), Number, percentage of participants: Pembrolizumab 35.5

Adverse events

Time frame: Throughout study duration, up to approx 80 months

Serious adverse events by term

Other adverse events by term

24 more terms not shown.

• Results publication: Safyan RA, White RA, Gonda TA, Lee SM, Han J, Kuriakose N, Yamamoto NK, Kugel S, Jamison JK, Manji GA, Schwartz GJ, Oberstein PE, Bates SE. Phase 2 study of azacitidine plus pembrolizumab as second-line treatment in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma. Oncologist. 2026 Mar 9;31(4):oyag091. doi: 10.1093/oncolo/oyag091. PMID 41844546
• Results publication: Tost J, Ak-Aksoy S, Campa D, Corradi C, Farinella R, Ibanez-Costa A, Dubrot J, Earl J, Melian EB, Kataki A, Kolnikova G, Madjarov G, Chaushevska M, Strnadel J, Tanic M, Tomas M, Dubovan P, Urbanova M, Buocikova V, Smolkova B. Leveraging epigenetic alterations in pancreatic ductal adenocarcinoma for clinical applications. Semin Cancer Biol. 2025 Feb;109:101-124. doi: 10.1016/j.semcancer.2025.01.003. Epub 2025 Jan 23. PMID 39863139

• Study Protocol and Statistical Analysis Plan (PDF, 2022-03-17)

• Susan E Bates, MD, Principal investigator, Columbia University