Emerging Targets in the Treatment of Metastatic Colorectal Cancer


A panel of expert oncologists discusses advances in the treatment of BRAFV600E metastatic colorectal cancer and also reviews novel targets being investigated in the setting of metastatic colorectal cancer.


Cathy Eng, MD: I just want to touch upon one thing. Friendly reminder of that rare patient population. We all remember when we were told, oh, you should test for BRAF. There's a lot of interest. Obviously, in melanoma, we saw single-agent BRAF inhibitors in metastatic colorectal cancer didn't have much benefit, less than 5% response, but when you saw these patients, these were such poor prognostic patients with just standard chemotherapy. Their overall survival was 12 to 14 months, and what could we do potentially help these patients? As an example of success for a rare patient population. We saw the BEACON trial get completed, the phase 3 trial looking at the triplet with encorafenib, and now cetuximab is the standard of care. Doublet versus the triplet, omitting the MEK inhibitor in the refractory BRAF setting, demonstrating that obviously for our patients we can provide them a trial, specifically, for patients with the BRAF mutation, but it really emphasizes the importance of testing and education to providers as well as patients. At this year's ASCO, [American Society of Clinical Oncology] there was a lot of discussion about some of the acquired RAS mutations that could occur in this patient population, and once again, we're tying back is there a role of circulating tumor DNA looking at drug sensitivity as well? I just want to mention very briefly, at this year's ESMO, they did update the role of acquired RAS mutations in the role of circulating tumor DNA at this year’s ESMO. In most patients in 91% of patients at baseline they could detect the BRAF (V600E) mutation in the baseline circulating tumor DNA. And then very similar to other studies, they noted acquired RAS mutations do occur, specifically, standard KRAS and RAS and MET amplification was also noted. Obviously, more to follow, we are learning, I know other studies have indicated as well that when EGFR therapy is provided in subsequent lines of therapy, not necessarily in frontline, you’re more likely to have acquired RAS mutations and that’s something to keep in mind and once again, when you are thinking about EGFR therapy for our patient population, you may want to test for circulating tumor DNA. Jaclyn, just out of curiosity the unique aspects of your job and how we can learn so much more, what do you think is, before we focus more about some of the upcoming data that was presented at this year’s ESMO, what do you think is exciting that’s coming up in regards to your work and others that you’re excited to learn more about in the future and how it may apply to our metastatic patient population?

Jaclyn F. Hechtman, MD: Some of the data, particularly ctDNA and how that’s going to help us kind of predict what to do for the stage 2-3 patients. That will be interesting. There are essays out there that are becoming more and more sensitive, that’s one thing. One study that I saw I guess from MSKCC, my alma mater, was that rectal cancer with mismatch of PARADIGM responded well and I wonder what’s going to happen with this population a couple of years out. When we talk about total neoadjuvant, will we be seeing that more for any sorts of alterations as we get out there, you know. That would help us prevent indications with rectal cancer. Any other markers? And then RET was just approved for pan tumor and there are a couple of RET fusions that have been detected in colon cancer. All this data, the new biomarkers and how are we going to deal with this patient in the middle of stage II-III as CFD and takes off.

Cathy Eng, MD: And just as a tangent to that, to what Jaclyn has mention, Kristen, do you just want to briefly mention the MSI data that just came out and obviously, we have seen Andrea's data. Where do you think it’s going and how it applies to ongoing trials?

Kristen K. Ciombor, MD: Everyone is excited to see the data, the dostarlimab data out of memorial. And then at ESMO as well Mirriam saw this data in NICHE-2, so in the Memorial data that refers to study showing a very small population so far but very consistent results at least early that patient who with MSI high locally advanced rectal cancer do very well with neoadjuvant dostarlimab and potentially can avoid surgery and radiation and other treatment modalities that we typically use in this stage of patient. You know the medium follow-up is short and we have a lot to see going forward to see if this is durable and to see if this is reproducible in non-memorial populations as well. For instance, you and I have this study and ECOG study turning to a one looking at nivolumab and ipilimumab in the same population and that study is open across the country, not just for patients in New York. The next few years will be interesting in this smaller but important patient subset in the same wane than NICHE-2 data presented at ESMO was looking at just very short course nivolumab and ipilimumab in localized colon cancer. And despite very short course of therapy, there was a very high pathologic complete response rate and very good responses in general even if they weren’t complete. That’s encouraging. It makes us think, all these data are showing us that maybe earlier stage treatment is better, but there are a lot more answers to come and we need good follow-up, we need ongoing perspective enrollment in the trials that are currently open so that we can get the answers, so that we can depend on those data in the future.

Cathy Eng, MD: One thing it’s important I mentioned the starlimub data was for 6 months, the NICHE-2 is just few weeks, so we still don’t know the duration. It is going to be interesting and it’s great for patients at the end of the day.

Transcript edited for clarity.

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