Two-center phase 2 trial of one or two preoperative cycles of nivolumab plus ipilimumab for dMMR rectal cancer

Mismatch repair-deficient (dMMR) tumors are highly sensitive immune checkpoint blockade in the metastatic setting. The phase 2 RESET-R trial, at two centers in Denmark, evaluated activity and safety of a short duration of preoperative dual immunotherapy in patients with early or locally advanced dMMR rectal cancer. Adult patients with stage I-III disease, ECOG performance status 0 or 1, and no previous therapy received one cycle of nivolumab plus ipilimumab. Patients with tumor regression but no clinical complete response at day 43 received a second cycle. The primary endpoint was proportion of patients with clinical complete response at day 93. Among 16 patients (63% with stage III tumors), all patients (100%; 95% CI 79.4-100.0) had clinical complete response by day 93; 11 patients after one cycle and 5 patients after the second cycle. During watch and wait without surgery, no patients had progression or recurrence (median follow-up 16 months; IQR 9-18). Grade 3 immune-related adverse events occurred om three patients (19%); there were no grade 4 or 5 toxicities, serious treatment-related adverse events, or treatment discontinuations. The authors conclude that one or two preoperative cycles of dual immunotherapy was effective and safe among patients with stage I-III dMMR rectal cancer. Longer follow-up is needed to confirm the durability and safety of these effects.