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Key takeaways
- Orphan drug designation for quemliclustat highlights regulatory momentum and unmet need in pancreatic cancer treatment development.
- PRISM-1 Phase III trial design reflects gold-standard methodologies (randomized, double-blind, placebo-controlled) with a large global patient population.
- ARC-8 survival data and use of a Synthetic Control Arm (SCA) underscore the growing role of adaptive and historical control strategies in oncology trial design.
The FDA has granted orphan drug designation to Arcus Biosciences’ quemliclustat, an investigational small molecule CD73 inhibitor, for the treatment of pancreatic cancer. Additionally, Arcus provided an update on its Phase III clinical trial evaluating quemliclustat plus chemotherapy, PRISM-1 (NCT06608927), and expects enrollment to be completed by the end of this year.1
In a press release, Richard Markus, MD, PhD, chief medical officer at Arcus Biosciences, said: “The orphan drug designation indicates the importance of developing new treatment options for rare diseases like pancreatic cancer, which has the highest mortality rate of all major cancers, and which has seen few treatment advancements over the past 30 years. We expect the Phase III PRISM-1 study to be fully enrolled this year and, if positive, intend to quickly bring this new first-line treatment option to patients, with the goal of prolonging survival for those with metastatic pancreatic cancer.”
PRISM-1 trial targets first-line mPDAC
- PRISM-1 is a Phase III, global, multi-center study involving approximately 610 patients with previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC).
- The trial uses a randomized, double-blind, placebo-controlled design.
- Participants are assigned in a 2:1 ratio to receive either quemliclustat plus gemcitabine/nab-paclitaxel or gemcitabine/nab-paclitaxel with a placebo.
- The main outcome measure is overall survival (OS).
- Additional endpoints include progression-free survival (PFS), objective response rate (ORR), duration of response, disease control rate, and safety.
Phase Ib ARC-8 trial showed encouraging survival results
Arcus initiated the PRISM-1 trial based on positive data from another study of quemliclustat, ARC-8 (NCT04104672). The study, co-developed with Gilead, evaluated quemliclustat plus chemotherapy with or without zimberelimab, an investigational anti-PD-1 antibody, in patients with previously untreated mPDAC.2
In January 2024, Arcus shared encouraging outcomes from ARC-8. According to trial data, the median OS was 15.7 months for all patients treated with 100 mg quemliclustat-based regimens, exceeding historical benchmark data for chemotherapy alone.
In a press release from the time, Zev A. Wainberg, MD, MSc, co-director of the GI oncology program at University of California Los Angeles and a principal investigator of the ARC-8 trial, said: “A quemliclustat-based regimen appears to meaningfully prolong survival compared to what we typically observe in patients with mPDAC who receive chemotherapy alone, the standard of care for more than 30 years. CD73 is highly expressed on pancreatic cancer cells, and I am encouraged to see early evidence that inhibiting CD73 with a small molecule has the potential to improve outcomes for people with mPDAC, without an observed clinically meaningful increase in toxicity, when combined with standard of care chemotherapy relative to historical data for chemotherapy alone.”
Synthetic control arm strengthens ARC-8 results
In addition to the treatment’s mark in median OS, quemliclustat-based regimens showed a 37% reduction in risk of death and a 5.9-month improvement in median OS when compared to a Synthetic Control Arm (SCA) of patients treated with chemotherapy alone in a post-hoc analysis. No new safety signals were observed in ARC-8, with the most common adverse events being neutropenia and anemia.
ARC-8 design and dosing overview
- ARC-8 is a Phase Ib, open-label platform trial.
- The study included a dose-escalation phase, followed by a dose-expansion phase using quemliclustat 100 mg every two weeks as the selected dose.
- In Cohort A (treatment-naïve mPDAC), patients in the expansion phase were randomized 2:1 to:
- Cohort A1: quemliclustat + zimberelimab + chemotherapy
- Cohort A2: quemliclustat + chemotherapy (without zimberelimab)
- Key endpoints included safety, ORR, median OS, and PFS.
- To adjust for baseline imbalances—particularly, fewer liver metastases in Cohort A2—an SCA using historical trial data on gemcitabine/nab-paclitaxel was used for comparison.
References
1. Arcus Biosciences’ Quemliclustat Receives Orphan Drug Designation for Pancreatic Cancer. News release. Arcus Biosciences. July 10, 2025. Accessed July 11, 2025. https://investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2025/Arcus-Biosciences-Quemliclustat-Receives-Orphan-Drug-Designation-for-Pancreatic-Cancer/default.aspx
2. Data from a Phase 1b Study of Quemliclustat-Based Regimens Showed Promising Overall Survival in Treatment-Naïve Metastatic Pancreatic Cancer. News release. Arcus Biosciences. January 16, 2024. Accessed July 11, 2025. https://investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2024/Data-from-a-Phase-1b-Study-of-Quemliclustat-Based-Regimens-Showed-Promising-Overall-Survival-in-Treatment-Nave-Metastatic-Pancreatic-Cancer/default.aspx