Table 1 Recent combination immunotherapies with chemotherapeutics, targeted therapies, multikinase inhibitors, and radiotherapy exhibiting early signs of clinical efficacy and safety in MSS-mCRC

With CPI

Bevacizumab, capecitabine, and atezolizumab (anti-PD-L1) (NCT0287319)

Bevacizumab and capecitabine, pembrolizumab (anti-PD-1) (NCT03396926)

Lenvatinib and pembrolizumab (anti-PD1) (NCT03797326)

Cetuximab, FOLFOX, and avelumab (anti-PD-L1) (NCT03174405)

Regorafenib with CPI

Regorafenib and nivolumab (anti-PD1) (NCT03406871, NCT03712943, NCT04126733).

Regorafenib and avelumab (anti-PD-L1) (NCT03475953)

The combination of regorafenib with a checkpoint inhibitor (anti-PD1 or anti-PD-L1) in phase 1/2 trials in Japan (NCT03406871), France (NCT03475953), and the USA (NCT03712943, NCT04126733) resulted in slightly higher percentage of patients who survive beyond 1 year and partial response or stable disease in approximately 40% to 90% of the patients depending on the trial.

Radiation with regorafenib, CPI, or as monotherapy

Stereotactic body radiation therapy (SBRT) with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD1). This is a trial in refractory MSS-mCRC adding two checkpoint inhibitors to localized radiation therapy (NCT03104439) called stereotactic body radiation therapy or SBRT (often conceptualized as an “in-situ” vaccine that stimulates a T cell response to the irradiated tumor) resulted in modest disease control rates. It included one complete response which was unexpected with radiation treatment alone.

SBRT with regorafenib. An mCRC patient with liver metastases taking regorafenib who also received SBRT experienced a durable progression-free survival over 3 years [6].

SBRT monotherapy. In another study, three mCRC patients also experienced complete responses to SBRT after several prior treatments [7].