Recently, the NICHE‑1 [9] and NICHE‑2 [10] studies demonstrated high pathological response rates of 100 and 98% with complete pathological response in about two thirds of patients with combined immunotherapy with one dose of ipilimumab (1 mg/kg) on day 1 and two doses of nivolumab (3 mg/kg) on days 1 and 15 followed by surgery 6 weeks after study inclusion in patients with localized dMMR colon cancer. The combined immunotherapy was well tolerated and none of the patients had a recurrence during follow-up. In the NICHE-1 study also patients with proficient MMR (pMMR) were included with pathological response in one third of patients (9/30) and complete pathological response in 3 patients. In the NICHE-3 study [11], two doses of nivolumab plus relatlimab (anti-LAG3) resulted in 100% overall pathologic response rate among 19 patients with 79% complete pathological response and 89% major pathological response. The therapy was well tolerated with grade 3 immunotherapy-related adverse events in only 1 patient. At ASCO 2024, three further studies investigating neoadjuvant immunotherapy in dMMR colon cancer were presented.

The NEOPRISM-CRC study [12] investigated an interesting approach, namely whether all dMMR colon cancers should be treated with immunotherapy or only those that are particularly immunogenic with a high TMB (Fig. 2). In all, 32 patients with high-risk stage II or stage III dMMR colon cancer were included. All patients received one dose of immunotherapy with pembrolizumab. Then patients were randomized according to the amount of TMB. Patients with TMB high (< 20 Mut/MB) or TMB medium (5–19 Mut/MB) received two further cycles of pembrolizumab followed by surgery and patients with TMB low (< 5 Mut/MB) underwent immediate surgery. The administration of adjuvant chemotherapy with FOLFOX or CAPOX was physician choice. Primary endpoint was complete pathological response rate. Of the patients, 82% had stage III and 62% had a T4 tumor. All patients (n = 33) except 1 patient had a high TMB; therefore, the hypotheses of the study could not be answered. However, 59% of patients had a complete pathological response. A grade 3–4 immunotherapy-associated adverse event was documented in 6.2% of patients. One patient died due to immunotherapy-associated pneumonitis. The study will be now expanded to 70 patients. Secondary endpoints have not yet been reported.

Neoadjuvant immunotherapy with pembrolizumab according to tumor mutation burden (TMB) in mismatch repair deficient (dMMR) colon cancer. FOLFOX Oxaliplatin, Leucovorin, 5-Fluorouracil; CAPOX Capecitabin, Oxaliplatin

A further phase II study investigated in 33 patients with stage II–III dMMR colon cancer 3 cycles of neoadjuvant tislelizumab, an PD‑1 antibody, followed by surgery (Fig. 3; [13]). Primary endpoint was major pathological response. The median age of the participating patients was 52 years, 30% had rectal cancer and 70% had colon cancer; furthermore, 75% of the tumors were classified as T4 tumor and 82% were node positive. About 90% of patients had a major pathological response (≤ 10% residual viable vital tumor) and 62% of patients had a complete pathological remission. Surgery was not performed in 4 patients, 3 of whom were managed nonoperatively and 1 patient had disease progression. The immunotherapy was well tolerated. Grade 1–2 immunotherapy-associated adverse events occurred in 30% of patients.

Neoadjuvant immunotherapy with tislelizumab in mismatch repair deficient (dMMR) colorectal cancer

In the third presented phase Ib study [14], the question of whether immunomonotherapy is sufficient or a whether combined immunotherapy in the neoadjuvant setting is more effective in dMMR colon cancer was investigated (Fig. 4). In all, 101 patients with stage IIb or stage III dMMR colon cancer were included. In the experimental arm patients received combined immunotherapy with one cycle of IBI310, a CTLA‑4 antibody, and 2 cycles of sintilimab, an PD‑1 antibody. In the control group patients were treated with 2 cycles of sintilimab monotherapy. Primary endpoint of the study was pathologic complete remission rate. The results showed that complete pathological remission was achieved in 80% of patients with combined immunotherapy and in 47.7% of patients complete pathological remission was achieved with immunomonotherapy. One patient died due to immunotherapy-related myocarditis. In China, a phase 3 study is currently investigating this combined immunotherapy versus adjuvant chemotherapy in dMMR colon cancer.

Neoadjuvant combined immunotherapy vs immunomonotherapy in mismatch repair deficient (dMMR) colon cancer