Tanios Bekaii-Saab, MD
Microsatellite instability-high (MSI-H) tumors comprise approximately 4% of patients with colorectal cancer (CRC), and those patients are likely to respond to checkpoint inhibitors, such as nivolumab (Opdivo) and pembrolizumab (Keytruda), according to Tanios Bekaii-Saab, MD.
An emerging area of research is attempting to have the remaining 96% of patients with CRC respond to immunotherapy. An ongoing phase III study is investigating that question by combining the MEK inhibitor cobimetinib (Cotellic) with the PD-L1 inhibitor atezolizumab (Tecentriq; NCT02788279). Results of this trial are expected to read out in the coming months.
“Strategies such as introducing a MEK inhibitor seem to invite tumor-infiltrating lymphocytes, which could perhaps increase the yield of response,” explained Bekaii-Saab, a professor of medicine at Mayo Clinic.
In an interview during the 2017 OncLive®
State of the Science SummitTM
on Gastrointestinal Malignancies, Bekaii-Saab discussed the emerging role of immunotherapy in patients with MSI-H tumors and beyond.
OncLive: Please provide an overview of your presentation.
My discussion focused on the role of immunotherapy, specifically PD-1 and PD-L1 inhibitors, in patients who have MSI-H tumors. Those are cancers that lack the expression of some proteins. This is a surrogate marker for tumors that are loaded with mutations, such as hypermutated tumors.
The presence of this MSI-H phenotype is dependent on 2 elements. Firstly, it could be acquired through the genetics of the patients, such as in the setting of Lynch syndrome. The other group would acquire this sporadically. This is 4% of patients in the metastatic setting.
In the earlier stages, the percentage is higher. Stages II to III are anywhere between 15% to 18% of patients. In the earlier stages, it is a good prognosis; whereas, in the later stages, it is an incredibly poor prognosis. In those patients with hypermutated or hyperinflamed tumors, there is a higher likelihood to see responses from immunotherapies. When looking across the board at single-agent PD-1 inhibitors with pembrolizumab or nivolumab, there are no responses in CRC.
On the other hand, when looking at the patient population that has this MSI-H phenotype, you do see a response rate up to 50% to 60%. More interestingly, as we look over time in recent publications from the authors of a study that looked at pembrolizumab in patients with MSI-H, many of the patients who had either stable disease or a partial response (PR) ended up with complete response (CR). However, it was an average of about 24 to 26 weeks before they had better responses. Some of these benefits can be seen earlier, but they also accumulate with time. Many of these patients may end up with a CR or a very solid PR after 6 months on the therapy.
In that study, pembrolizumab had 3 cohorts. The first cohort was the MSI-H CRC cohort. The second cohort was non-CRC with MSI-H. The third cohort was microsatellite stability (MSS). The MSS cohort had 0% response or 0% benefit. There was no control arm.
The 2 arms that seemed to benefit were the non-CRC and the CRC arms with MSI-H. Many of these responses that were seen in the CRC arm were very impressive, even more so than the non-CRC arm. The patients with pancreas cancer, endometrial cancer, and other forms of cancer, which is at a lower baseline of MSI-H than CRC, had even more pronounced responses that happened earlier.
Across the board, at least with pembrolizumab, our accumulative knowledge is that patients with MSI-H tumors will have a high likelihood of response or benefit from the application of pembrolizumab.
With nivolumab, our only experience so far is with CRC. There was a study that looked at the effects of nivolumab plus the CTLA-4 inhibitor ipilimumab (Yervoy). That led to an additional approval for nivolumab, similar to pembrolizumab, in MSI-H CRC tumors. In this study, we saw similar benefits with nivolumab in MSI-H CRC. When adding ipilimumab to nivolumab, there seems to be a trend towards improving the likelihood of response, but the toxicities were much worse.
The question as this study continues is whether there is a true benefit to adding the CTLA-4 inhibitor. It’s toxic, expensive, and the likelihood of response doesn’t appear to be significantly better. Although the trends are there—taking into perspective the toxicity and the cost—one would question whether this is going to be a viable option.
At this point, we need to wait for the study to complete before we arrive to any conclusions. What’s clear for patients with MSI-H tumors is that there are 2 options—pembrolizumab and nivolumab. For all other non-CRC tumors that are MSI-H, pembrolizumab is the only FDA-approved drug.