- •Mismatch repair proficient (pMMR) colon cancer (CRC) is unresponsive to immunotherapy.
- •Regorafenib (REGO) may enhance the antitumor activity of nivolumab (NIVO).
- •The dose-limiting toxicity of REGO/NIVO was rash.
- •REGO/NIVO showed limited anticancer activity in pMMR CRC.
- •REGO/NIVO showed anticancer activity in non-liver or lung metastatic pMMR CRC.
In contrast to mismatch repair deficient (dMMR) colorectal cancer (CRC), mismatch repair proficient (pMMR) CRC is usually unresponsive to anti-PD-1 immunotherapy. Recent preclinical data suggest that regorafenib may enhance the antitumor activity of anti-PD-1 immunotherapy. However, the safety and efficacy of regorafenib plus nivolumab have not been established in patients with refractory metastatic pMMR CRC. This study aimed to evaluate the safety and efficacy of regorafenib plus nivolumab in metastatic pMMR metastatic CRC.
This was a phase I/Ib study with standard 3 + 3 design plus dose expansion of the maximum tolerated dose (MTD) in patients with refractory metastatic pMMR CRC. Patients were treated with regorafenib combined with nivolumab. The primary end-points were dose-limiting toxicity (DLT) and MTD. The secondary end-points were objective response rate, safety and overall survival (OS).
A total of 52 patients were enrolled, and 51 patients received at least one dose of treatment. Three patients experienced DLT (all grade 3 rash). MTD was regorafenib 80 mg and nivolumab 240 mg every 2 weeks. Most common grade 3/4 treatment-related adverse events were hypertension (16%), rash (10%) and anaemia (6%). Among 40 evaluable patients, four (10%) achieved partial response, including one unconfirmed response, 21 (53%) achieved stable disease, and disease control rate was 63%. The median progression-free survival and OS were 4.3 and 11.1 months, respectively.
Regorafenib plus nivolumab appears to be well tolerated with limited anticancer activity in metastatic pMMR CRC.
ClinicalTrials.gov identifier: NCT03712943.
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Published online: May 06, 2022
Accepted: March 19, 2022
Received in revised form: March 7, 2022
Received: January 14, 2022
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