FDA Grants Orphan Drug Designation to Quemliclustat in Pancreatic Cancer

The investigational small molecule CD73 inhibitor quemliclustat was granted orphan drug designation for the treatment of patients with pancreatic cancer by the FDA, according to a press release from the developer, Arcus Biosciences.¹

“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,” stated Richard Markus, MD, PhD, chief medical officer at Arcus Biosciences, in the press release.¹ “We expect the phase 3 PRISM-1 study [NCT06608927] 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.”

The ARC-8 Trial

Results from the phase 1 ARC-8 trial (NCT04104672), which evaluated quemliclustat plus chemotherapy in those with advanced pancreatic cancer, were shared in January 2024.²

In all patients (n = 122), the median overall survival (OS) was 15.7 months (95% CI, 12.4-20.9), the 12-month OS rate was 62.7%, and the 18-month OS rate was 42.8%. In those who received quemliclustat plus gemcitabine and nab-paclitaxel (n = 29), the median OS was 19.4 months (95% CI, 12.1-23.0), the 12-month OS rate was 72.3%, and the 18-month OS rate was 54.2%. In those who received quemliclustat and zimberelimab plus gemcitabine and nab-paclitaxel (n = 61), the median OS was 14.6 months (95% CI, 10.6-21.5), the 12-month OS rate was 60.9%, and the 18-month OS rate was 43.5%. In the pooled analysis of all who received 100 mg of quemliclustat and zimberelimab plus gemcitabine and nab-paclitaxel (n = 93), the median OS was 13.9 months (95% CI, 11.1-18.7), the 12-month OS rate was 59.6%, and the 18-month OS rate was 39.3%.

The investigators noted improvements over gemcitabine and nab-paclitaxel in benchmark trials such as the phase 3 MPACT trial (NCT00844649), which had a median OS of 8.5 months (95% CI, 7.9-9.5), the phase 3 NAPOLI-3 trial (NCT04083235), which had a median OS of 9.2 months (95% CI, 8.3-10.6), and the phase 3 CanStem111P trial (NCT02993731), which had a median OS of 11.7 months (95% CI, 10.7-12.7).

In ARC-8, the overall median progression-free survival (PFS) was 6.3 months (95% CI, 5.4-7.7).

In all patients, the overall response rate (ORR) was 38.5% (95% CI, 29.9%-47.8%) compared with 36.2% (95% CI, 31.4%-41.2%) in NAPOLI-3; the disease control rate (DCR) was 77.8% vs 62.3%, respectively; and stable disease was noted in 39.3% and 26.1%.

The trial enrolled patients with first-line metastatic pancreatic ductal adenocarcinoma (PDAC). A dose-escalation phase consisted of 25 to 125 mg of quemliclustat with zimberelimab, gemcitabine, and nab-paclitaxel. The recommended dose for expansion was 100 mg of quemliclustat. In the dose-expansion phase, patients were split into 2 cohorts: cohort A (n = 26), where patients with first-line PDAC received 100 mg of quemliclustat and zimberelimab plus gemcitabine and nab-paclitaxel, and cohort B (n = 21), where patients with second-line PDAC received the same regimen. Patients in cohort A were randomly assigned, in a 2:1 ratio, to receive either 100 mg of quemliclustat plus zimberelimab, gemcitabine, and nab-paclitaxel (n = 61), or 100 mg of quemliclustat plus gemcitabine and nab-paclitaxel (n = 29).

The median age of patients was 65.5 years; the majority were female (58%), White (93%), and had an ECOG performance status of 1 (80%). Additionally, 79% of patients had liver metastasis at baseline, 21% had prior pancreatic cancer surgery, and 15% received any prior systemic anti-cancer therapy.

Regarding safety, any-grade treatment-related adverse events (TRAEs) occurred in 99.2% of patients; grade 3 or higher TRAEs occurred in 73.0%. Serious TRAEs and grade 5 TRAEs occurred in 27.9% and 4.1%. AEs led to dose reduction, dose delay, and study discontinuation in 53.3%, 75.4%, and 23.0%.

The PRISM-1 Trial

The global, randomized, double-blind phase 3 PRISM-1 trial will evaluate quemliclustat plus gemcitabine and nab-paclitaxel chemotherapy compared with placebo plus gemcitabine and nab-paclitaxel.³ The trial is intended to be fully enrolled by the end of 2025, with an expected enrollment of 610 patients who will be randomly assigned to one of the trial arms in a 2:1 ratio.

Eligible patients will have histologically or cytologically confirmed metastatic PDAC, no previous treatment for metastatic PDAC, an ECOG performance status of 0 or 1, and at least 1 target lesion measurable by CT or MRI.³ Patients will be permitted to receive prior neoadjuvant or adjuvant therapy if completed at least 12 months before radiation, prior palliative radiotherapy if completed at least 2 weeks prior to randomization with AEs resolving to grade 1 or less, and prior placement of a biliary stent if TRAEs have improved to grade 1 or less.

Those with a history of brain metastases or leptomeningeal metastases, prior treatment with a CD73 antagonist or inhibitor, previous treatment for locally advanced and unresectable PDAC, and underlying medical conditions will be excluded from trial participation.

The trial’s primary end point will be OS. The secondary end points will be PFS, ORR, duration of response, DCR, and safety.

References

1. Arcus Biosciences’ quemliclustat receives orphan drug designation for pancreatic cancer. News release. Arcus Biosciences. July 10, 2025. Accessed July 11, 2025. https://tinyurl.com/2wa7kyu8
2. Wainberg ZA, Mani GA, Bahary N, et al. ARC-8: Phase 1/1b randomized study of quemliclustat + gemcitabine/nab-paclitaxel ± zimberelimab in patients with treatment-naive metastatic pancreatic adenocarcinoma. J Clin Oncol. 2024;42(suppl 3):665. doi:10.1200/JCO.2024.42.3_suppl.665
3. Study of quemliclustat and chemotherapy versus placebo and chemotherapy in patients with metastatic pancreatic ductal adenocarcinoma (PRISM-1). ClinicalTrials.gov. Updated June 26, 2025. Accessed July 11, 2025. https://tinyurl.com/3tykrvpv