Future of mCRC Lies in Biomarker-Directed Therapies

Christopher Lieu, MD

Some of the most exciting research being conducted in metastatic colorectal cancer (mCRC) has been in the form of biomarker-directed therapy and immunotherapy, said Christopher Lieu, MD. Although these advances have been made in only a small percentage of the overall population, these personalized approaches have led to significant improvements in survival.

“If 5% of our patients have a BRAF mutation, and we have an effective [approach] for those patients and another 5% have HER2 amplification, and we find an effective targeted therapy combination for that, just 5% here or 5% there by itself may be a small percentage,” said Lieu. “But, as you start to chip away at the ‘pie’, you start to see better personalization of therapy for our patients. The next frontier is identifying these subsets where we can find effective therapeutic strategies for patients with particular biomarkers.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, Lieu, director, GI Medical Oncology Program, deputy associate director for clinical research, and associate professor, at the University of Colorado Cancer Center, highlighted updates on biomarker-directed therapy with CRC and ongoing research being done with immunotherapy.

OncLive^®: What are some of the important biomarkers to be aware of in CRC? What are some key updates in biomarker-directed therapy?

Lieu: There are 2 biomarkers that are really becoming of significant interest. [The first are] BRAF V600E mutations; this is a subgroup that [accounts for] about 5% to 10% of our patient population with mCRC. We know that this particular mutation confers really poor prognosis. Sometimes patients who have this mutation literally have an overall survival (OS) that's about one-third of what we would normally expect. A lot of this is simply due to the fact that it's an aggressive cancer and our standard therapies do not work for it.

A recently published study in the Journal of Clinical Oncology showed results from a safety lead-in from the BEACON study. This study looked at the combination of a MEK inhibitor, a BRAF inhibitor, and an EGFR inhibitor: binimetinib (Mektovi), encorafenib (Braftovi), and cetuximab (Erbitux). What they saw with the combination of all 3 drugs was that the response rate was about 48%, which is remarkably high for a patient population where most of our therapies don't ever work.

Because of the results for the safety lead-in, we're still awaiting the results of the phase III study, where patients were randomized to this triple combination versus standard chemotherapy and an EGFR inhibitor. We'll get the results in a couple of weeks, but currently, this combination does exist on the National Comprehensive Cancer Network (NCCN) guidelines. Again, we're waiting on the full phase III data, but it's important that providers test for this mutation and that they know that not only is it prognostic, but it could also be predictive of benefit from this treatment.

We also talked about HER2-directed therapy in HER2-amplified CRC. HER2 is a gene that is very “famous” in breast cancer. We also know that there are data [with this gene] in gastric cancer, but we are now starting to have data [on it] in CRC. We know that patients who have HER2-amplified CRC may not receive any benefit from anti-EGFR therapy. We also know that there are anti-HER2 therapies available for other tumor types, and there are ongoing studies looking at the addition of anti-HER2 therapy in patients with refractory mCRC.

There is an ongoing trial being conducted across the country called SWOG 1613, looking at the combination of trastuzumab (Herceptin) and pertuzumab (Perjeta) in patients who had previously received treatment for HER2-amplified mCRC. This is an ongoing trial and we just want providers to be aware of this; there may be evidence to suggest that our anti-EGFR therapy isn't going to work in patients who have HER2 amplification. The second reason why we want providers to know about this is because there is a clinical trial available. Because that trial allows for crossover, patients are going to have a clinical option that they wouldn't otherwise have. It’s very important for providers to know about the data and to know what clinical trial options are available.

What important updates with immunotherapy have read out in this space?

In terms of relapsed/refractory mCRC, there is a trial with 2 immunotherapy drugs, durvalumab (Imfinzi) and tremelimumab. Durvalumab is an PD-L1 inhibitor; tremelimumab is a CTLA-4 inhibitor. In this Canadian trial, they were testing patients who had refractory mCRC, and they randomized them to receive either immunotherapy or best supportive care alone. What they saw was a modest improvement in median OS. There was no difference in progression-free survival, but because they saw a slight improvement in median OS, they're going to proceed with a larger phase III study. These are somewhat intriguing results, but we have to get [data from] a larger study to know fully whether or not this is going to be an effective combination for patients or not.

[There was also] the IMblaze370 trial, which tested a combination of cobimetinib (Cotellic), which is a MEK inhibitor, atezolizumab (Tecentriq), which is a PD-L1 inhibitor, versus atezolizumab alone or regorafenib (Stivarga). Unfortunately, this was a negative phase III trial; there was no arm that did statistically significantly better than the others. The combination of cobimetinib and atezolizumab was not shown to be superior to regorafenib, which is the standard-of-care therapy.

There is an ongoing clinical trial at the University of Colorado, which is testing a similar strategy, but it’s somewhat different in that it adds in another drug. The trial is binimetinib, which is a MEK inhibitor, in combination with bevacizumab (Avastin), which is a VEGF inhibitor and is already FDA approved for CRC, and pembrolizumab (Keytruda), which is a PD-1 inhibitor. This is a combination of 3 targeted drugs [being evaluated] in patients with microsatellite stable (MSS) CRC; this is a small phase II trial that's currently accruing. We will see what the results are in the future.

What was the rationale for those 3 particular drugs?

With MSS CRC, the problem is that the immune cells are just not close to the tumor or inside a tumor. I kind of liken it to this: you have a dance floor, and you have the music playing, but there is just no one on the dance floor. The key [question] is, “How do you get people onto the dance floor?”

The strategy here is to use 2 targeted therapies—binimetinib and bevacizumab—and the hope is that with the combination of those 2 targeted therapies, you might be able to get more people onto the “dance floor.” When you give all 3 drugs, you [might] see more antitumor activity. We have completed the safety lead-in with some promising results, and therefore, we're moving on with a full phase II study.

Are there any toxicity concerns with this triplet approach?

If you combine all 3 drugs, is there increased fatigue, increased hypertension, increased immune reaction? Thus far, we haven't seen any difference in safety signals regarding fatigue, blood counts going low, hypertension, or rash.

Where should future research focus in this field?

For patients with refractory mCRC, we have seen incredible improvements in median OS. However, our patients desperately need better treatment options. One of the big areas in oncology right now is immunotherapy. Immunotherapy thus far has not worked for 95% of our patients with mCR; those patients who are called MSS or mismatch repair proficient. You're going to see more and more immunotherapies being tested in clinical trials for this group of patients, but really, where I see a lot of the results that are truly positive are in small biomarker-directed subgroups.