Role of Immunotherapy Being Defined in Colorectal Cancer

A. David McCollum, MD

The first-line setting for patients with colorectal cancer (CRC) has a handful of options; however, there are additional regimens that could show promise if moved upfront, explains A. David McCollum, MD.

For example, following the August 2017 FDA approval of nivolumab (Opdivo) for the treatment of adult and pediatric patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic CRC that progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan, researchers are now questioning whether these agents should be moved upfront and in combination with other systemic therapies.

“The very exciting field of checkpoint inhibitors is still evolving, and we are trying to understand where they fit in the world of CRC therapy,” said McCollum, a hematologist and medical oncologist at Texas Oncology.

OncLive: Can you discuss current developments in the field of CRC?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Gastrointestinal Cancers, McCollum discussed the optimal management of CRC in the first-line setting and the ongoing research with checkpoint inhibitors designed to benefit larger groups of patients.McCollum: We had a big burst of activity in the early part of this millennia when many new agents were approved. There was a decade of research to sort through to decide what the optimal therapy is—either with chemotherapy or a biologic agent—for patients with CRC. During that time, we understood that there were some molecular features that we could use as a biomarker to help predict optimal regimens for a particular form of CRC.

The most widely used is RAS testing, which physicians are familiar with. We now understand that BRAF and HER2 alterations might also specify certain therapies for patients.

How do you determine the sequencing of these agents once a patient progresses after first-line treatment?

In my lecture, I mainly discussed optimizing first-line therapy. Some of the important points are that chemotherapy doublets and a biologic agent are standard as a first-line therapy. There are many options and there is not necessarily one best option. It is becoming clearer that the sidedness of the primary tumor may help to predict which biologic agent we should use. The EGFR-targeted agents do not seem to provide as much benefit for patients who have a right-sided primary tumor. We see that those are used more commonly in patients with left-sided tumors. We would discuss a biologic drug with a combination chemotherapy platform. FOLFOX or FOLFIRI are standard-of-care regimens at this point. We treat to a maximum response. The maintenance studies have varied with how long patients are on treatment; it has been from 3 months all the way up to 6 months. There are some modifications needed in the intensity of the chemotherapy to maintain that benefit for as long as we can.

The best maintenance therapy for a patient depends on what their frontline regimen is. Some would argue that it is fluoropyrimidine alone where as others would argue it is fluoropyrimidine and a biologic agent. Some patients who are treated with an EGFR-targeted agent in the frontline setting believe that it could be a continuation of the EGFR-targeted agents alone or until patients have progression.

What current regimens in the pipeline are exciting?

There is also some debate about what constitutes enough progression that you then need to transition onto second-line therapy. A lot of things go into play there, not necessarily how patients are doing radiographically, but also how they do clinically, where the progression is, or if the patient is symptomatic or not. There are many different features that go into that decision.The most exciting thing for the whole field of CRC is how to integrate the checkpoint inhibitors. We know the patients who have MSI-H phenotype or a mismatch-repair deficient immunohistochemistry profile seem to be the patients who derive the most benefit from PD-1/PD-L1 inhibitors. There are subsets of patients who are outside of that subgroup who also have some benefit, but patients with MSI-H tumors clearly have the most benefit.

The question now is, “Do we try to use these agents upfront?” There is an ongoing trial at my institution looking at chemotherapy versus a PD-1 inhibitor. It is accruing slowly, as it is only a small subset of patients and there is already a lot of belief in the community that this group needs to receive a checkpoint inhibitor.

Is there thought of bringing immunotherapy into patients with microsatellite-stable CRC?

What do the next 5 years of this treatment landscape look like?

We are unclear whether it should be given in the frontline setting. The patients may benefit more if they receive cytoreduction with chemotherapy first and then go on to one of those agents. Do you use them with chemotherapy? Do you use them as a second-line agent? Where do they fit in the world of adjuvant therapy? All those are interesting questions and we hope we are going to move the field forward for our patients. There are trials that are looking at how we can combine checkpoint inhibitors, specifically PD-1/PD-L1 agents to perhaps sensitize them to an immuno-oncology drug. Or, can you give MEK inhibitors with chemotherapy? Can you sequence them after chemotherapy as a form of maintenance therapy? Many of these concepts hold a lot of water, but we do not have much clinical data to show where they are best used.We are still badly in need of refractory agents. Hopefully, we will start to see something that adds to patients’ options once they progress through standard first- and second-line therapies. We know there are some patients who do badly. It appears that BRAF V600E mutations have a very aggressive phenotype and do not do very well. We need to add to what we can provide for that subgroup of patients and further refine what the role of PD-1/PD-L1 immuno-oncology agents are.