Addition of Quemliclustat to This Triplet Combination Raises OS for mPDAC

Metastatic pancreatic ductal adenocarcinoma (mPDAC) is difficult to treat, with a median survival rate of less than 1 year. A combination therapy that includes quemliclustat, an investigational small molecule CD73 inhibitor, showed promising efficacy for the treatment of mPDAC in the recent ARC-8 study.

Extracellular adenosine (eADO) produced via ATP is released by tumor cells from the disease and suppresses antitumor immune responses. CD73 is a key enzyme involved in the production of eADO in the tumor microenvironment, and elevated expressions of the enzyme are linked to poor clinical outcomes. Quemliclustat is a selective small-molecule inhibitor of soluble and cell-bound CD73 that may aid the treatment of this patient population.

Lead author Zev Wainberg, MD, and colleagues combined quemliclustat with gemcitabine and nab-paclitaxel (G/nP), with and without zimberelimab, to determine safety and median overall survival (OS), their primary end points. The phase 1b dose escalation and expansion study examined the combination in patients with treatment-naïve mPDAC.

Previous research has shown that quemliclustat 100 mg is the recommended dose for expansion. During ARC-8, a dose-escalation cohort (cohort A) received quemliclustat 100 mg with standard doses of G/nP with zimberelimab 240 mg administered intravenously every 2 weeks. Patients were also randomized 2:1 into cohorts that examined quemliclustat and G/nP with zimberelimab (cohort A1) and without zimberelimab (cohort A2).

A total of 122 patients with untreated mPDAC were included in the study, with 93 patients receiving quemliclustat plus G/nP with zimberelimab, and 29 receiving quemliclustat plus G/nP. The median age of the full patient cohort was 66 years, and 66% of patients had an Eastern Cooperative Oncology Group score of 1. Liver metastasis at baseline was found in 65% of patients.

In patients treated with quemliclustat plus G/nP, the median OS was 19.4 months, with a median OS follow-up of 21.1 months. Median progression-free survival (PFS) was 8.8 months, and the overall response rate (ORR) was 38%.

In patients treated with quemliclustat plus G/nP with zimberelimab, the median OS and OS follow-up were 14.6 and 17.6 months, respectively. Median PFS was 4.9 months, and the ORR was 34%.

Treatment-related adverse events (TRAEs) were reported in 100% of patients, with grade 3 or higher events occurring in 85% of patients and treatment discontinuation occurring in 23%. The most common grade 3 or higher TRAEs were decrease in neutrophil count (31%) and anemia (25%).

Results from the ARC-8 study showed that the addition of quemliclustat to G/nP with zimberelimab was safe and tolerable, with no significant added toxicity to G/nP. The OS results warrant further investigation of quemliclustat for the treatment of mPDAC.