Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma

Abstract

IMPORTANCE New therapeutic options for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) are needed. This study evaluated dual checkpoint combination therapy in patients with mPDAC. OBJECTIVE To evaluate the safety and efficacy of the anti-PD-L1 (programmed death-ligand 1) antibody using either durvalumab monotherapy or in combination with the anticytotoxic T-lymphocyte antigen 4 antibody using durvalumab plus tremelimumab therapy in patients with mPDAC. DESIGN, SETTING, AND PARTICIPANTS Part A of this multicenter, 2-part, phase 2 randomized clinical trial was a lead-in safety, open-label study with planned expansion to part B pending an efficacy signal from part A. Between November 26, 2015, and March 23, 2017, 65 patients with mPDAC who had previously received only 1 first-line fluorouracil-based or gemcitabine-based treatment were enrolled at 21 sites in 6 countries. Efficacy analysis included the intent-to-treat population; safety analysis included patients who received at least 1 dose of study treatment and for whom any postdose data were available. INTERVENTIONS Patients received durvalumab (1500 mg every 4 weeks) plus tremelimumab (75 mg every 4 weeks) combination therapy for 4 cycles followed by durvalumab therapy (1500 mg every 4 weeks) or durvalumab monotherapy (1500 mg every 4 weeks) for up to 12 months or until the onset of progressive disease or unacceptable toxic effects. MAIN OUTCOMES AND MEASURES Safety and efficacy were measured by objective response rate, which was used to determine study expansion to part B. The threshold for expansion was an objective response rate of 10% for either treatment arm. RESULTS Among 65 randomized patients, 34 (52%) were men and median age was 61 (95% CI, 37-81) years. Grade 3 or higher treatment-related adverse events occurred in 7 of 32 patients (22%) receiving combination therapy and in 2 of 32 patients (6%) receiving monotherapy; 1 patient randomized to the monotherapy arm did not receive treatment owing to worsened disease. Fatigue, diarrhea, and pruritus were the most common adverse events in both arms. Overall, 4 of 64 patients (6%) discontinued treatment owing to treatment-related adverse events. Objective response rate was 3.1% (95% CI, 0.08-16.22) for patients receiving combination therapy and 0% (95% CI, 0.00-10.58) for patients receiving monotherapy. Low patient numbers limited observation of the associations between treatment response and PD-L1 expression or microsatellite instability status. CONCLUSION AND RELEVANCE Treatment was well tolerated, and the efficacy of durvalumab plus tremelimumab therapy and durvalumab monotherapy reflected a population of patients with mPDAC who had poor prognoses and rapidly progressing disease. Patients were not enrolled in part B because the threshold for efficacy was not met in part A.

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

“…The prevalence of therapy resistance to these treatments is a persistent problem. PDAC patients have not benefited from single agent or combination ICI therapy (194)(195)(196) despite increased expression of PD-L1 in tumors (197)(198)(199). Significant efforts are underway to improve immunotherapy efficacy, including studies investigating regulatory B cell inhibition (e.g., Bruton's Tyrosine Kinase (BTK) inhibitors), IDO inhibition, and vaccine therapy (200).…”

Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer

“…Consistent with our results, in a recent phase II pancreatic cancer trial no patients responded to anti-PD-L1 monotherapy and one patient (3.1%) responded to combination therapy with anti-PD-L1 plus anti-CTLA-4. 28 Although efficacy with combination therapy was limited, these results do support further mechanistic exploration in preclinical models regarding the pancreatic tumor microenvironment. The limited efficacy of acalabrutinib monotherapy seen here is also consistent with the recently reported negative phase III clinical trial investigating the addition of the BTK inhibitor ibrutinib to gemcitabine and nab-paclitaxel in the first-line treatment of metastatic pancreatic adenocarcinoma (NCT02436668).…”

Determinants of Resistance to Checkpoint Inhibitors

“…While anti-CTLA-4 and anti-PD-1/PD-L1 immune checkpoint blockade has shown varying success in cancers, including melanoma, non-small cell lung carcinoma (NSCLC), and urothelial carcinoma, many show low or no response, including gastrointestinal, breast, pancreatic, prostate, sarcoma, and colorectal cancers [39][40][41][42][43][44][45][46][47]. Resistance to immunotherapy is classified as primary resistance in which the cancer is completely refractory or acquired resistance, in which there is initial response yet the cancer relapses and progresses [48].…”