Efforts Continue to Expand Immunotherapy in CRC

Johanna C. Bendell, MD

Anti—PD-1 inhibitors are effective in treating patients with microsatellite-instability high (MSI-H) colorectal cancer (CRC), with the FDA approving pembrolizumab (Keytruda) and nivolumab (Opdivo) for use in this setting.

However, the overwhelming majority of CRC patients are microsatellite-stable (MSS) and do not tend to respond well to single-agent immunotherapy, noted Johanna Bendell, MD. Researchers are are looking to improve immunotherapy options for these patients, exploring regimens such as the combination of the PD-L1 inhibitor atezolizumab (Tecentriq) with the MEK inhibitor cobimetinib (Cotellic).

The combination is currently undergoing investigation in the 3-arm phase III COTEZO IMblaze370 trial (NCT02788279) and will be compared with single-agent atezolizumab as well as regorafenib (Stivarga). The study has completed accrual but results will not readout until 2019.

“When you give [cobimetinib] in combination with atezolizumab, it might help stimulate the immune response for MSS disease,” Bendell explains on the combination’s potential.

OncLive: What are some of the immunotherapy advances in CRC?

In an interview with OncLive, Bendell, a medical oncologist at Sarah Cannon Research Institute, discussed the current and emerging treatment landscape of immunotherapy for patients with CRC.Bendell: We have seen very exciting data for patients with MSI-H CRC. These are patients who have a higher rate of mutations than others. They are very responsive to immunotherapies. In fact, we have seen FDA approvals of pembrolizumab for patients with MSI-H cancers, as well as nivolumab for MSI-H CRC, which shows what the benefit of these agents can be for these patients with CRC.

However, 95% of patients with metastatic CRC are not MSI-H. What do we do for these patients who are MSS? We know that they do not tend to be responsive to single-agent immunotherapy, but what could we do to potentially make them responsive? We have seen some preliminary work showing that combinations of immunotherapy and other agents may get the immune system excited within these patients and cause them to respond.

We have seen some initial data with the combination of the PD-L1 inhibitor atezolizumab (Tecentriq) with the MEK inhibitor cobimetinib (Cotellic). The preliminary data led to a randomized phase III global study which has completed accrual. Hopefully we will see some data from this study [in the future].

We have also seen drugs such as bispecific antibodies [enter the space]. There were data presented at the 2017 ASCO Annual Meeting of a drug called CEA-TCB, which binds both to the CEA in the tumor and the CD3 receptors on the T cells to bring the T cells into proximity with the tumor. We saw responses both with the single-agent bispecific antibody as well as this antibody in combination with atezolizumab. This agent is going on to further studies for patients with CRC.

Can you highlight the data that we have seen with pembrolizumab in these patients with MSI-H CRC?

If the atezolizumab and cobimetinib combination is approved, can you discuss how that will factor in with other available treatments?

There are other combinations that are currently being looked at, but these two are the furthest ahead. There is promise for patients with metastatic MSS CRC to respond to immunotherapies.We initially saw data for MSI-H CRC with pembrolizumab with response rates above 50%—not only in MSI-H CRC but in other MSI-H tumors, as well. This has subsequently matured and we have seen a response rate between 30% and 40%, which led to the FDA approval of this agent for patients with MSI-H cancers. This was the first time the FDA has ever approved an agent based on a biomarker rather than a tumor type. Hopefully, we will start to see more approvals based on biomarker status.The combination of atezolizumab and cobimetinib is for patients with MSS rather than MSI-H disease. The thought is that cobimetinib brings CD8-positive T cells into the tumor to have an immune response, as well as increases the tumor’s expression of MHC class 1, which is a receptor that lets the immune cells recognize the tumor cells better.

If patients with MSI-H progress on pembrolizumab and nivolumab, what is the next step of treatment?

When you give that in combination with atezolizumab, it might help stimulate the immune response for MSS disease. The trial itself is being done in a refractory setting, so these are patients who would otherwise be candidates for regorafenib. The randomized phase III comparison was the combination versus atezolizumab alone versus regorafenib.For patients with MSI-H disease, they can still have the general standard chemotherapies that are available to them, as well as targeted agents if they progress on checkpoint inhibitor therapy. The checkpoint inhibitors were approved in the refractory setting, so patients had to have at least 2 lines of chemotherapy. If a patient progresses on the checkpoint inhibitor, they could potentially go on to regorafenib, TAS-102, or they could go on to clinical trials. There are many clinical trials that are looking at patients who have had progressive disease on single-agent immunotherapies and [testing whether] combinations make them respond again.

The other big question is, “Where do we use these agents now that they are approved for the treatment of patients with MSI-H CRC? Could they be used in earlier lines of therapy?” Randomized studies are attempting to determine which line of therapy would they see the most benefit.