Phase II, single-arm, open-label study of dostarlimab monotherapy in previously untreated patients with stage II/III dMMR/MSI-H locally advanced rectal cancer.
Authors: Cercek Andrea , Bachet Jean-Baptiste , Capdevila Jaume , Starling Naureen , Chen Eric Xueyu , Di Bartolomeo Maria , Yoshino Takayuki , Vlahovic Gordana , Zografos Eleftherios , O'Donnell Sean , Szijgyarto Zsolt , Heinemann Volker 
Published: June 2023

TPS3639 Background: For patients (pts) with locally advanced rectal cancer (RC), organ-sparing non-operative management (NOM) following a clinical complete response (cCR) to treatment avoids the potential complications and quality of life impact associated with surgery/chemoradiotherapy. Although neoadjuvant chemotherapy is standard treatment, pts with mismatch repair deficient (dMMR) tumors respond poorly. Efficacy of the programmed death (PD)-1 inhibitor dostarlimab in previously untreated pts with locally advanced dMMR RC was evaluated in a Phase II study. All 12 pts who completed 6 months of treatment had clinical complete response (cCR) and received NOM, with no Grade ≥3 adverse events reported. Further research with a larger multicenter population/longer follow-up is needed to confirm these findings. AZUR-1 will evaluate the efficacy and safety of dostarlimab in pts with previously untreated locally advanced dMMR/microsatellite instability-high (MSI-H) RC. Methods: AZUR-1 (NCT05723562) is a global, multicenter, single-arm, open-label, Phase II study. ~100 pts will be enrolled across 10 countries. Key eligibility criteria include age ≥18 years, no prior radiation/systemic therapy or surgery for RC, Eastern Cooperative Oncology Group performance status 0–1 and no tumor-caused symptomatic bowel obstruction. Pts must have a tumor with dMMR status or MSI-H phenotype, determined locally or by the central reference laboratory. Prescreening is available at sites without local dMMR/MSI-H testing; prescreening is not required if dMMR/MSI-H status has been previously determined. Dostarlimab (500 mg) will be administered intravenously every 3 weeks for ≤9 cycles. The primary endpoint is cCR by independent central review (ICR) at 12 months, defined as achieving and maintaining cCR for 12 months (the 12-month period starts from the first disease assessment after last dose of study intervention that demonstrates cCR by ICR). Secondary endpoints include cCR by ICR at 36 months, 3-year event-free survival (EFS3) by investigator assessment, 5-year disease-specific survival, and 5-year overall survival. Pts with cCR by end of treatment will be assessed (CT/MRI, rectal MRI, endoscopy, rectal primary biopsy) every 4–6 months for recurrent disease for 5 years (NOM). Efficacy and safety will be assessed in all pts who received ≥1 dose of dostarlimab. For a range of plausible observed cCR12 rates (60–95%) in the primary analyses, the planned sample size of 100 pts will provide a Clopper–Pearson exact binomial two-sided 95% confidence interval with lower confidence limit within ~10% of the observed cCR12 rate. No interim analyses are planned. References: [1] Cercek, A et al. NEJM 2022;386:2363–76. Funding: GSK (219369). Editorial support provided by Fishawack Health, funded by GSK. Clinical trial information: NCT05723562 .