Immunotherapy, Sidedness Strategies Enhancing mCRC Treatment

Chloe E. Atreya, MD, PhD

Combination immunotherapy has shown great promise in patients with metastatic colorectal cancer (mCRC), specifically in the CheckMate-142 study in which nivolumab (Opdivo) plus ipilimumab (Yervoy) yielded a 55% overall response rate and 80% disease control rate in patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC).

Although pembrolizumab (Keytruda) is FDA approved for all MSI-H/dMMR solid tumors, and nivolumab for MSI-H/dMMR mCRC, there is still a question as to how ipilimumab is going to fit into clinical practice, according to Chloe E. Atreya, MD, PhD.

“Whether the combination of ipilimumab and nivolumab will take the place of single-agent therapy is still to be determined,” she said in an interview with OncLive.

Aside from immunotherapy, what is clear, says Atreya, is that tumor sidedness is not just a surrogate for other prognostic factors, and therapies should be selected with this in mind. The NCCN guidelines state that EGFR-targeted antibodies are an option for patients who have left-sided RAS wild-type tumors but exclude their use in those with RAS-mutated or right-sided tumors in the first-line setting.

OncLive: What are some recent developments in the mCRC landscape?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, Atreya, an assistant clinical professor, Department of Medicine, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, discussed the latest treatment advances in mCRC, including tumor sidedness and emerging immunotherapy strategies.Atreya: I focused on sidedness and maintenance strategies for specific subgroups, including patients with MSI-H and BRAF-mutated CRC. With sidedness, I gave an overview of recent research, including Study 80405. I highlighted the NCCN guidelines, which state that EGFR-targeted antibodies are an option for patients with left-sided RAS wild-type tumors. These antibodies should not be considered for patients who have RAS-mutated tumors or right-sided tumors in the first-line setting.

In terms of maintenance strategies, the NCCN guidelines highlight certain studies that show some benefit in progression-free survival (PFS). These include either 5-fluorouracil (5-FU) or capecitabine with or without bevacizumab (Avastin). There is also a new study showing that bevacizumab alone is no better than observation on all endpoints. Other strategies that include 5-FU with or without bevacizumab showed no significant difference in overall survival (OS). The jury is still out about maintenance therapies, so it should be a personalized decision.

Where is the field in terms of research on tumor sidedness?

With regard to the different subgroups, specifically MSI-high and BRAF-mutated tumors, I highlighted the CheckMate-142 study that combined nivolumab with or without ipilimumab. For BRAF-mutated tumors, the recent NCCN guidelines now include the strategy of irinotecan and cetuximab (Erbitux) with or without vemurafenib (Zelboraf) as a potential option for patients in the second-line setting. Although it is not FDA approved, its inclusion in the NCCN guidelines will make it more available for these patients to receive vemurafenib.Initially, there were a lot of questions about whether or not sidedness was just something related to tumor burden or prognostic and potentially predictive mutations. Now we know that sidedness is an independent prognostic factor.

Can you reflect on immunotherapy data from the 2018 Gastrointestinal Cancers Symposium?

Do you foresee more immunotherapy agents coming to the forefront?

Are there other data from the 2018 Gastrointestinal Cancers Symposium you would like to highlight?

Regarding maintenance strategies, what regimens are currently being explored?

What does a metastatic diagnosis in CRC mean now opposed to 5 to 10 years ago?

We know that there are differences in the microbiome of the right and left side of the colon. We don't necessarily know why, but we believe the microbiome is playing an increasingly important role in CRC research. It is something that's going to impact how we treat patients. There is also research investigating the potential with cancer stem cells on the right and left side of the colon. Each side has different embryologic origins, and that may impact potential treatment.We are still figuring out where ipilimumab will fit into the landscape. The [CheckMate-142] study wasn’t necessarily designed to be a direct comparison between arms, but every endpoint that they looked at reflected a higher response rate and longer survival with the addition of ipilimumab. Ipilimumab is not yet FDA approved. It is certainly the easier route to give patients nivolumab or pembrolizumab. These agents also have amazing response rates and durations of response and survival. It’s no question that these patients have excellent options.Absolutely. Having more combinations is very important for the 96% of patients who have metastatic microsatellite stable colon cancer. We're trying to figure out what combination is going to induce responses like those in MSI-H tumors. That's where we need to look at innovative combinations. There are a huge number of trials that are currently enrolling or rolling out shortly. There was a study that showed that lower dose regorafenib (Stivarga) reflected better outcomes than full dose regorafenib. In our group, we typically start regorafenib at less than full dose for tolerability reasons. It's important to note that similar data have been shown in hepatocellular carcinoma with sorafenib. Higher doses of multikinase inhibitors are really hard to tolerate, but a lower dose may be a good alternative.The first question was, “Is maintenance better than no maintenance therapy?” It looks like maintenance therapy can improve PFS but, to my knowledge, no study has shown that it improves OS. In my practice, it's a case-by-case basis as to whether or not I give a patient maintenance therapy. It also depends on patient preference, their response to prior treatment, and toxicities. Finally, I’ll look at the disease biology in terms of tumor burden, location, and any other cancer-related factors. There are other strategies that are being investigated, but it's a pretty tough space to be able to show a difference. We also can't necessarily control what therapies a patient will get after maintenance therapy which also impact OS. It’s an exciting time with a lot of new therapies on the horizon. I've been telling my patients that the median OS has improved. Studies like CALGB/SWOG 80405 showed historic OS that hadn't been seen before with approved agents. We’re on the cusp right now. I'm telling patients, “That even though we are talking about a median OS of 2 years, there’s still a huge amount of improvement we want to make.”

I think about our approved therapies as a way to keep patients going while we wait for these new immunotherapy combination strategies and other strategies to mature. We know that when patients respond to immunotherapy, the duration of response can be impressive. I'm really hoping that we are going to see some substantial gains in the lifetimes of my current patients.

Andre T, Lonardi S, Wong M, et. al. Nivolumab + ipilimumab combination in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): first report of the full cohort from CheckMate-142. J Clin Oncol. 2018;36(4):553. doi: 10.1200/JCO.2018.36.4_suppl.553.