Grothey Grapples With Treatment Options in mCRC

Axel Grothey, MD

It is still debatable which EGFR or VEGF inhibitors provide the greatest benefit when added to chemotherapy in the first-line setting of metastatic colorectal cancer (mCRC), but the identification of RAS, BRAF, and microsatellite instability (MSI) has helped physicians to refine treatment decisions.

Additionally, every patient with mCRC should undergo a mutational analysis for RAS and BRAF mutations, MSI-high (MSI-H) status, and HER2 amplification, explained Axel Grothey, MD.

Immunotherapy is another interest in the field of mCRC. In March 2018, the FDA granted a priority review designation to nivolumab (Opdivo) and ipilimumab (Yervoy) for patients with metastatic MSI-H/mismatch repair deficient (dMMR) CRC following progression on a fluoropyrimidine, oxaliplatin, and irinotecan. Single-agent nivolumab was also approved for this indication in August 2017.

OncLive: Please provide an overview of your presentation on mCRC.

In an interview during the 2018 OncLive^® State of the Science Summit™, Grothey, an oncologist at Sanford Burnham Cancer Center, discussed sidedness and first- and second-line treatments for patients with mCRC.Grothey: I spoke about how to integrate molecular markers into the choice for first-line treatment of patients with CRC. We all intuitively look at patient and tumor characteristics, as well as patient wishes when we choose first-line treatment and the intensity of treatment, but more molecular markers have become available. [We’re using markers] like RAS and BRAF mutation status and, more recently, mismatch repair deficiency or MSI-H status to select which treatments we should offer patients.

Over the last 2 or 3 years, we’ve also realized that independent of all these factors, cancer sidedness is important to make a treatment decision, particularly regarding the EGFR antibodies cetuximab (Erbitux) and panitumumab (Vectibix). [One of] the questions we have right now is, “Which targeted agents should be added to first-line chemotherapy? Is it the EGFR antibodies or is it the VEGF inhibitor bevacizumab (Avastin)?”

How often should a patient with CRC undergo a mutational analysis?

We have learned that the ideal candidate for EGFR-antibody therapy is limited to patients without RAS mutations, BRAF V600 mutations, and right-sided cancers. We’ve refined the patient population that can benefit from cetuximab and panitumumab. In my eyes, about 20% to 25% of patients with mCRC should receive EGFR antibodies added to a chemotherapy backbone in first-line treatment.Every patient with mCRC should undergo mutational analysis for RAS and BRAF mutations with MSI testing and, in the future, likely HER2 amplification. When we look at where we are right now, it’s very easy to see that the next-generation sequencing (NGS) approach will likely be applied to the initial workup of the majority of patients in the United States.

Are there any indications as to why the left side of the colon reacts differently than the right side?

Now, this might lead to some delays in therapy. When we subject every single patient with metastatic disease to NGS to find these molecular alterations, it is probably a 2- to 3-week delay before we know what mutations the tumor has. [At that point], we’ll feel more comfortable regarding choice of therapy. The turn-around time will be shortened over time. Five years from now, comprehensible testing will be part of the initial workup of patients with mCRC.There are differences in the molecular pathways that are activated. We know that right-sided cancers are more likely to be BRAF mutated and BRAF V600 mutations. There is a higher prevalence of DNA methylation in right-sided cancers. Even when we consider all of these factors, sidedness still remains an independent predictive and prognostic marker.

How do you approach second-line treatment?

We have not completely wrapped our heads around the differences in the left and right microbiome. We know that there are differences in the bacterial colonization in the right and left side of the colon. It’s still a mystery, and it’s embarrassing in some ways because with all of our molecular techniques, we should be able to figure out why these tumors are different.Second-line treatment is interesting. If you go by evidence, we have not yet seen a second-line trial with EGFR antibodies that show a survival benefit. On the other hand, we have 3 phase III trials with VEGF inhibitors, including bevacizumab, ramucirumab (Cyramza), and aflibercept (Zaltrap) that show survival benefit. We have treatment options at hand. The choice of second-line [therapy] depends on what we did in the first-line [setting]. If we stuck with a bevacizumab-based combination in first-line treatment, we have the choice of either bevacizumab beyond progression or VEGF inhibition beyond progression.

In RAS wild-type, BRAF wild-type, and left-sided tumors, [using] EGFR antibodies might depend on the clinical situation. Do we need a more reliable response? These agents can lead to a more reliable and profound anatomical response. Patients who are symptomatic from their disease benefit more from switching to an EGFR antibody.

What is an area of research you would like to see addressed?

In patients where it’s not necessarily important to have anatomical shrinkage, VEGF inhibition beyond progression is favored in my eyes, [as] opposed to reserving receptor antibodies for later lines of therapy. Now, in left-sided, RAS, and RAS wild-type tumors, we have not yet seen solid data on EGFR inhibitors beyond progression. My preference would then be to switch to a VEGF inhibitor like bevacizumab.The key issue right now is immunotherapy. Everybody is set on immunotherapy for good reason because patients may be long-term responders. There are even some patients with hyper-mutated MSI-H cancers like Lynch syndrome, or Lynch syndrome-like patients who I believe we can cure with immunotherapy. These patients only make up about 4% to 5% of all mCRCs. The holy grail will be to make these 95% of patients who are currently not responding to immunotherapy in CRC recognizable to the immune system.

Is there anything else you would like to emphasize?

There have been several attempts to make these tumors immunogenic, to activate the immune system and get T cells into the cancer. There was the highly anticipated cobimetinib (Cotellic)/atezolizumab (Tecentriq) phase III study. There were interesting preliminary data, though the press release showed that the combination did not improve survival compared with regorafenib (Stivarga). We are still dealing with some disappointment on the road toward making immunotherapy [available] to more than the 4% to 5% of patients with MSI-H cancers.In my presentation, I highlighted the differences in the European and United States guidelines. I’m a member of both the NCCN and the ESMO guideline committees, in which we look at the same data and come to somewhat different conclusions as to how to sequence and start treatments. It’s really an interesting phenomenon. The interpretation of the data is in the eye of the beholder.

For instance, in the United States, first-line treatment with bevacizumab is so common, whereas in Europe, EGFR antibodies are used whenever possible in first-line therapy. It’s a very different approach in the way we’re thinking, and it impacts guidelines and treatment patterns.