Immunotherapy Success for Microsatellite Stable Colorectal Cancers—Searching for the Horizon

Mené sur 39 patients atteints d'un cancer colorectal avec microsatellites stables et de stade métastatique (âge médian : 54 ans), cet essai non randomisé de phase I détermine la dose maximale tolérée du régorafénib en combinaison avec l'ipilimumab et le nivolumab et évalue l'efficacité, du point de vue du taux de réponse globale, de cette combinaison après l'échec d'une chimiothérapie

Résumé en anglais

In this issue of JAMA Oncology, Fakih et al present a phase 1 trial of regorafenib, ipilimumab, and nivolumab for patients with microsatellite stable (MSS) colorectal cancer (CRC) who had disease progression while receiving prior chemotherapy. The investigators hypothesized that the addition of ipilimumab to the previously studied combination of regorafenib and nivolumab (REGONIVO) would improve the response rate and clinical outcomes in this population. They performed a 3 + 3 dose de-escalation, single-center study with the primary objective of determining a safe dose for use in phase 2 evaluation. Post hoc unplanned analyses were also performed that focused on the patients with metastatic disease other than liver metastases and were based on detected differences in at least 1 prior study from some of the same investigators. That study used regorafenib with nivolumab. Regorafenib was used at a starting dose of 80 mg daily, and no dose-limiting toxic effects were observed in the first 9 patients; thus, this was determined to be the safe dose for phase 2 dosing. Effectiveness was also examined, with an overall response rate of 27.6%, a median progression-free survival of 4 months (IQR, 2-9 months), and a median overall survival reaching 20 months (IQR, 7 months to not estimable). Each of these 3 outcomes was higher for patients with nonhepatic forms of metastatic disease (36.4%, 5 months, and unreached, respectively). The investigators concluded from post hoc analysis that the clinical responses with this 3-drug combination were substantial and merited further investigation. The addition of the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitor ipilimumab appeared to be associated with an improvement of lower effectiveness, including response rates less than 10% from REGONIVO alone from a single-group phase 2 study, and was associated with an improvement of the previous signal of potential higher effectiveness in patients without liver metastases that was previously observed with the dual drug combination (overall response rate, 21.7%). As would be expected with regorafenib, a significant number of patients experienced tyrosine kinase inhibitor–related skin toxic effects, and established potential immune-related adverse events were observed that were attributable to nivolumab, the ipilimumab infusions, or both. One patient experienced sudden cardiopulmonary death, the exact cause of which was not discernible, but immunotherapy as an inciting cause could not be excluded. For cases in which patients continued experimental therapy beyond radiographic disease progression, further radiologic assessment was performed with the modified Response Evaluation Criteria in Solid Tumours guideline for immunotherapy criteria, presumably as a way to account for potential pseudoprogression.