Feasibility of stereotactic radiotherapy with pembrolizumab in patients with deficient mismatch repair/microsatellite unstable metastatic colorectal cancer

Background: Patients with metastatic colorectal cancer (mCRC) carrying a deficit in the mismatch repair system/microsatellite instability (dMMR/MSI) show great responses to immune checkpoint inhibitors. However, 30% of patients with dMMR/MSI are primarily immunoresistant, and another 30% develop secondary resistance. Thus several combinations such as anti-programmed cell death protein 1 (anti-PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) are being pursued. The combination of radiotherapy and immunotherapy is another avenue of research that can increase the release of neoantigens resulting in the abscopal effect. This phenomenon has demonstrated promising potential activity in colon cancer preclinical studies; nevertheless, clinical results are limited to just a few case series. Patients and methods: We conducted a prospective interventional single-institution study to assess the feasibility, safety, and disease control rate of the combination of pembrolizumab and stereotactic ablative radiotherapy (SABR) in a cohort of 14 consecutive patients with dMMR/MSI mCRC. Results: Among the 14 patients enrolled, 11 received SABR in combination with pembrolizumab as the first to the fourth line. The disease control rate was 50% in the intention-to-treat population, with six patients still maintaining the response after >15 months. Any-grade treatment-related adverse events occurred in 50% of patients, with grade 3 (G3) events in three patients; no treatment-related death occurred. Conclusions: Our findings convey no signal of enhanced systemic efficacy compared with historical data on pembrolizumab alone even if the local control rate is high. To our knowledge, this represents the largest study conducted in this population; further studies could extend the knowledge on the toxicity profile of this combination.