Research Efforts Poised to Redefine Role of Immunotherapy in mCRC

Neil H. Segal, MD

Combination strategies could provide an opportunity to extend the utility of immunotherapy to more patients with colorectal cancer (CRC), according to Neil H. Segal, MD, PhD.

Currently, immunotherapy is approved for use in the second-line setting for patients with microsatellite instability—high (MSI-H)/mismatch repair deficient (dMMR) CRC. In May 2017, the FDA granted an accelerated approval to pembrolizumab (Keytruda) for the treatment of adult and pediatric patients with unresectable or metastatic MSI-H/dMMR solid tumors that have progressed after prior therapy and who have no alternative treatment options, as well as for those with MSI-H/dMMR CRC following progression on a fluoropyrimidine, oxaliplatin, and irinotecan.

In July 2018, the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) joined pembrolizumab in the MSI-H/dMMR CRC indication.

“We are very cognizant of the benefit we've seen with immunotherapy in CRC, [other] gastrointestinal cancers, and across oncology. We can see truly remarkable and durable responses in some patients; however, many patients still do not derive as much benefit from immunotherapy as we would like,” said Segal. “The challenge going forward will be identifying appropriate combinations and predictive markers that will shed light on where immunotherapy is most applicable.”

One challenge, according to Segal, is how to provide benefit with this approach in the majority of patients with microsatellite stable (MSS) CRC whose tumors have historically not been responsive to single-agent checkpoint inhibition. To this end, several research efforts are focused on exploring novel combinations.

In an interview during the 2020 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, Segal, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed the current role of immunotherapy in CRC and the work being done to define its role in earlier-line settings and among patients with MSS disease.

OncLive: Could you discuss the research showcasing the benefit of immunotherapy in patients with MSI-H/dMMR CRC?

Segal: All patients should be tested for MSI-H, whether by immunohistochemistry for MMR deficiency, polymerase chain reaction, or next-generation sequencing. We have the opportunity to use immunotherapy, as it is indicated for patients whose tumors are [MSI-H] and who have had prior chemotherapy. Data from the KEYNOTE-164 study looked at patients who had 1 prior line of therapy or more than 1 prior line of chemotherapy. The data confirmed the efficacy of PD-1 inhibition with pembrolizumab in this patient population.

There are also some emerging clinical trials for patients with MSI-H tumors, specifically those looking at frontline chemotherapy versus immunotherapy; these trials will define the role of first-line immunotherapy in patients with MSI-H tumors. A trial from Memorial Sloan Kettering Cancer Center is evaluating the role of induction immunotherapy in patients with MSI-H rectal cancer. There is another trial that is evaluating circulating tumor DNA (ctDNA) in patients with all types of MSI-H tumors who have completed standard therapy. [If patients have ctDNA], they will be randomized to a trial that includes PD-1 blockade.

We know there is a role for immunotherapy in patients with MSI-H tumors who have had prior chemotherapy. We’re starting to see [immunotherapy take on] an emerging role, and we're trying to determine how that approach fits [into the paradigm].

What does the future treatment landscape look like for patients with MSI-H tumors?

The future holds clarity regarding when to treat with immunotherapy and whether there is potential synergy with chemotherapy. Will there be a role for combination therapy with PD-L1 and CTLA-4 inhibitors? Some of the trials looking at nivolumab with ipilimumab showed a high response rate in patients who received combination chemotherapy. Ongoing trials are comparing PD-1 blockade alone with combined PD-1/CTLA-4 blockade; this research will shed light on the role of combination therapy.

How would you treat a patient who has both an MSI-H tumor and a driver mutation?

A patient with an MSI-H tumor and a driver mutation would be treated the same as a patient who did not have a driver mutation. We would expect immunotherapy to be effective regardless of the presence of a driver mutation.

How does the role of immunotherapy differ for patients with MSS tumors?

It has been a challenge to determine the role of immunotherapy in the majority of patients with metastatic CRC, specifically those with MSS tumors. Multiple clinical trials have examined PD-1 blockade alone, which we know is ineffective in these patients. The real challenge now is identifying effective combinations. Ongoing clinical trials are looking at the combination of, for example, bispecific antibodies with PD-L1 inhibitors. Other trials are evaluating combinations composed of PD-1 inhibitors and VEGF TKIs. We saw compelling data [at the 2019 ASCO Annual Meeting with this approach]. [We also want to know] whether there is a role for radiation with immunotherapy. We still have a lot to learn about how to target conventional CRC.

What are some of the remaining challenges that need to be addressed in the field?

It's important to have these ongoing trials [so that we can further understand the utility of immunotherapy in this disease]. It’s important to understand the biology behind the responses we’re seeing so that we can [better] design the next clinical trial.