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Dr. John Strickler:
Welcome to The ASCO Post Roundtable Series on targeted therapy for colorectal cancer. I'm Dr. John Strickler, Associate Professor of Medicine at Duke University Medical Center. Joining me today are two of my colleagues, Dr. Stacey Cohen and Dr. Harsh Singh. If you could both introduce yourselves.
Dr. Harsh Singh:
I'm Dr. Harsh Singh. I'm a GI medical oncologist and an instructor in medicine at Dana-Farber Cancer Institute in Boston.
Dr. Stacy Cohen:
Hi, I'm Stacy Cohen. I am also a GI medical oncologist. I am an associate professor at the Fred Hutchinson Cancer Center and University of Washington in Seattle.
Today we will be discussing the evolving treatment landscape for colorectal cancer and integrating these new developments into three patient case studies. Our second installment will focus on BRAF V600E–mutated colorectal cancer. I'll start first with a case from my clinic. This is a 40-year-old woman with no significant past medical history who presents to the emergency room with severe abdominal pain. CT scan of the chest, abdomen, and pelvis revealed a cecal mass with adjacent nodularity, abdominal lymphadenopathy, and multiple liver lesions consistent with metastatic disease. Colonoscopy demonstrates a non-obstructing mass in the ascending colon, and pathology confirms adenocarcinoma. Biopsy of a liver lesion also confirms adenocarcinoma consistent with the colon primary. Performance status is limited by severe abdominal pain related to metastatic disease. Dr. Cohen, I'll start first with you. In this otherwise healthy fit woman who now has widely metastatic colon cancer, what would you think first for this patient with symptomatic disease?
In my clinic, I will treat to the disease and also to the patient's goals. If a patient is young and desiring a very aggressive therapy, I certainly entertain the idea of doing a triplet, so something such as FOLFOXIRI or FOLFIRINOX and bevacizumab. Of course, I would want to know the molecular status before we did this. For my patient population, if we're doing tumor-based testing, we'll often start with FOLFOX. Then, we'll escalate to FOLFIRINOX/bevacizumab, or FOLFOX with an EGFR inhibitor, depending on the molecular status. We're trying to integrate liquid biopsy a little bit sooner to get some of these results before the first dose since that has been a limitation in the past. But it really depends on the location of the primary and, again, what the patient is desiring in terms of quality of life and toxicities. In this case, with it being a cecal mass, a right-sided primary, I typically would be starting with a triplet and bevacizumab for a patient desiring aggressive care.
Great. What happened first with this patient was that given her performance status, she was started on FOLFOX and bevacizumab. On that, the pain rapidly improved. Now, while that was going on, the commercial tissue NGS profile came back. It showed a classic APC mutation with a SMAD4 and TP53 mutation. But in addition, we saw BRAF V600E. Now, the patient's performance status has improved. She's tolerating treatment well. Dr. Singh, what would you think next, based on the tissue NGS results?
I think BRAF V600E is a canonical driver mutation, which is enriched in tumors on the right side of the colon. This would be a classic presentation for such a tumor. These tumors tend to be more aggressive. Patients do worse than patients without this mutation. I think that is a cause of concern. What is helpful is that there has been a lot of research and clinical trials showing activity of anti-BRAF therapy in this disease, especially with doublet and triplet therapy, targeting the BRAF mutations with encorafenib, and then inhibiting EGFR with cetuximab showing an improvement in overall survival and responses in the BEACON CRC study. That's something I would consider strongly in this patient for next line of therapy.
Okay. Dr. Cohen, would you ever think about an anti-EGFR therapy alone for somebody with this type of molecular profile?
No. We know that patients with a BRAF mutation tend to not respond to anti-EGFR therapy. Now, if you combine it, as Dr. Singh mentioned... If you combine the anti-BRAF with the anti-EGFR, that seems to be beneficial. But in the current state, I wouldn't give anti-EGFR by itself since it seems to be that these BRAF-mutant cases are resistant to EGFR inhibition.
Dr. Singh, why is colon cancer different? It's taken a lot longer to figure out a way to attack BRAF-mutant metastatic colon cancer than, say, BRAF-mutant melanoma. What could explain that driver of resistance to say a single agent BRAF inhibitor?
This is a great question, and I think one which perplexed us for a long period of time, and I think really required a lot of translational science to be done to figure out bypass mechanisms for reasons which, as you stated, that single agent BRAF agents really did not show much response in colorectal cancer. I think what we found is that inhibition of BRAF leads to a de-repression of the MAP kinase signaling pathway in colon cells. Through normal RAF and RAS signaling and EGFR hyperactivation, which is so common in colon tumors, I think the pathway gets reactivated very, very quickly. Hence, even though you see transient inhibition of this pathway in cell lines when you treat with single agents really in patients, that really doesn't translate into inhibiting the pathway.
Now, if you can come up and vertically inhibit the pathway at multiple nodes by adding either an EGFR inhibitor or an EGFR inhibitor and a MEK inhibitor, that leads to have more sustained inhibition of the pathway. That has translated into an improvement in response rates, with responses to doublet agents being in the low 20s and then responses to triplet vertical inhibition with EGFR, BRAF, and MEK inhibition being even higher. I think that this bypass pathway activation seems to be quite unique to colon cells, and hence, colon cancer's derived from them.
So Dr. Cohen, after this patient progresses on first-line FOLFOX/bevacizumab, what would you be thinking about next? What's the best approach for somebody in the second-line setting? Should we just do standard chemotherapy, maybe FOLFIRI/bevacizumab or a doublet of encorafenib/anti-EGFR or a triplet of encorafenib/anti-EGFR/MEK inhibitor, like binimetinib? What does the data tell us?
I would be taking a brief step back and just looking at the MSI status since we glossed over this a little bit. But if a patient is both MSI and BRAF, I would be starting with immunotherapy for that patient. But assuming that we're talking about a BRAF-mutant patient with a V600 mutation and they are microsatellite stable, I'd be thinking about BRAF-targeted therapy at that point. Based on the BEACON phase III study, we actually can answer the question that you asked, which is, what is better: chemotherapy or targeted therapy?
In that three-arm study, they looked at the triplet, looking at BRAF, EGFR, and MEK. They also looked at the doublet of BRAF and EGFR and compared those each to chemotherapy. What we saw is that the combination of encorafenib and cetuximab had much better survival compared to the control chemotherapy arm.
Similarly, the triplet did better than the control. But we did not see significant benefit from the triplet compared to the doublet, though was not a true statistical comparison. But in terms of what we did have as available response rates, it was slightly better in the triplet. But it was not felt that the toxicity was necessarily merited. From that, our takeaway is that we tend to use encorafenib and cetuximab in the second line. We anticipate an objective response rate of about 20%, which vastly exceeds what we see for chemotherapy at about 2%. But still, even with this very effective regimen, we're not seeing responses in all of our patients. We're not seeing complete responses or even partial responses in many of the patients. It remains elusive how we can better target BRAF mutations, and possibly thinking that we need to highlight other vertical pathways such as immunotherapy in combination with BRAF.
Interesting. Dr. Singh, in your experience, what's the longest response you've seen to this BEACON regimen of encorafenib/anti-EGFR? What's the longest period of benefit, and what do you think drives resistance for these patients?
I think, in my experience, I've had one patient who was on this therapy for around 11 months. That's the longest I've seen this therapy work. Resistance is really the norm. We're learning a lot more about how resistance is happening. I think we're learning that there's resistance mutations more downstream of BRAF inhibition in MAPK genes, which can lead to reactivation of the pathway. There are other mechanisms of resistance which remain poorly characterized and are not necessarily easy to attribute to genetic mutations. It's an active area of research. I think we're learning a lot about this.
Dr.. Cohen, what would you give third-line therapy to somebody, now, who's received FOLFOX/bevacizumab front-line then goes on to second-line encorafenib/anti-EGFR? What's next for that patient, assuming they still have performance status?
That is, I think, one of the million-dollar questions right now. Again, as we think about having more targeted therapies, the question of how to sequence them comes up. It really highlights the fact that if we don't understand where the resistance came from. We don't know if we should be targeting them with another BRAF combination or if we should switch completely maybe to an irinotecan-based regimen to try to desensitize and decrease some of those resistant clones. I'll say it depends on the patient, their tolerance of the prior BRAF therapy, and maybe what trial options are available. I've had patients go on to an immunotherapy and BRAF combination. I've had patients go to something like FOLFIRI and see if that was effective. But this is where, I think, the data really falls off, and we don't really know the answer to that.
Yeah. BRAF V600E–mutant metastatic colon cancer is such a difficult disease entity. These mutations are associated with poor prognosis overall. They do drive resistance to our anti-EGFR therapies and just have an aggressive natural history. It's something that I think we're all appreciative that we now have some strategies for these patients. But we know we're still a long way away from solving this problem.
In the first-line setting, in our clinics, a chemotherapy backbone is frequently chosen based on the patient's age, performance status, the goals of the treatment, and comorbidities. We've got FOLFIRI/bevacizumab, FOLFOX/bevacizumab, and FOLFOXIRI/bevacizumab. All of those regimens can be considered in a healthy fit patient. I think a triplet of FOLFOXIRI/bevacizumab is very reasonable. After that patient progresses on that front-line chemotherapy, then it sounds like all of us agree that a second-line encorafenib plus an anti-EGFR would be the preferred approach. Then, once they've progressed on those first two lines of therapy, essentially, that's where we get into a tougher situation where we can either go to a FOLFIRI-based regimen if they receive FOLFOX front-line. Or, ideally, it would be a clinical trial to help push the needle on this disease.
This brings us to the end of this case. Please see the other segments for further discussion about latest data in colorectal cancer, or visit ascopost.com. Thank you.