Case 3

Van Morris:

We’ll move on to the third case now. This is looking at upfront therapies for BRAF V600E metastatic colorectal cancer in the non MSI-high setting. This is a 51-year-old woman who presents in your clinic with a new diagnosis of stage IV colon cancer. Hers is in the descending colon, and it was detected initially by her primary care physician when she was found to have an asymptomatic iron deficiency anemia. Further workup reveals the presence of peritoneal disease on imaging studies. She otherwise has no significant medical history and as you can see here, her ECOG performance status is 0. She clearly does not live in the Houston, Texas, summer because she hikes multiple days every week.

My question to Dr. Parikh is, in this patient who has a very good performance status with no significant medical history. She’s now been diagnosed with a microsatellite-stable BRAF V600E adenocarcinoma of the left colon. What therapy do you recommend in a patient like this?

Aparna Parikh:

Yeah. This is a great, great question and I think independent of sort of BRAF V600E status comes up a lot in terms of triplet therapy versus doublet therapy. And there seems to be some institutional biases and just practice pattern differences, too. I think the most compelling data, again, independent of BRAF V600E to start with was from TRIBE, which was in The New England Journal in around 2014 and did show us a small benefit to survival with triplet therapy versus doublet therapy. And we know that when you give triplet therapy with FOLFOXIRI, you’ll also get higher response rates and especially for patients, you’re thinking about conversion potentially down the line to resection. If they have liver-limited disease, for example, you could make the argument that triplet therapy may be better, but again comes at a cost of a little bit higher toxicity.

My practice has been actually, I feel like with a little bit of dose reductions and things too, you can actually get in triplet quite well. Especially for younger patients who are good performance status patients, and then peel back to maintenance. TRIBE2 sort of looked at a maintenance approach as well and showed the survival benefit. I think people reference sometimes based on TRIBE, there seemed to be maybe a trend toward benefit, especially for the BRAF V600E subgroup, but I think ultimately was not statistically significant, but again was just a post hoc analysis of that subgroup. But I think the feeling of patients and even providers is that these patients tend to do poorly, have more aggressive disease. It feels like you’re helping them to give triplet therapy versus doublet therapy. But I would love to hear your practice patterns on this. It’s something I struggle with, but entirely understanding that I tend to be a little bit more triplet heavy in general.

Van Morris:

Yeah, I very much agree with this, exactly echo your sentiments on the TRIBE analyses. Even though there was a trend, those were small numbers of patients in that subset analysis. This is also something when we’re teaching our fellows here at MD Anderson is just to keep in mind that it was a limited number of patients. I think as well, our experience in the second-line setting and beyond with cytotoxic chemotherapy in the BRAF V600E-mutated setting is that once a patient progresses on front-line cytotoxic chemotherapy, the subsequent PFS is for second-, third-line and beyond what standard cytotoxic is very, very short. All the more reason I think to optimize exposure to as much cytotoxic treatment upfront as the patient can tolerate. I think in an otherwise healthy 51-year-old like this, who remains very active, I absolutely agree with you.

Katrina Pedersen:

I also agree 100%. If they performed better later on, maybe I’d withhold it, but they don’t. They’re going to be best upfront, in my opinion.

Aparna Parikh:

Well 3/3 very concurring opinions, which is good.

Van Morris:

Well, to shake things up a little bit then. Dr. Pedersen, there’s been a lot of movement in recent years as we treat patients with metastatic colorectal cancer in general, especially in patients who have KRAS/NRAS wild-type tumors to consider the sidedness of the tumor and choosing a biologic agent to combine with cytotoxic chemotherapy. I guess in this particular context of a patient with a left-sided BRAF V600E colorectal cancer, should oncologists be considering sidedness in the deciding if they’re going to use an anti-EGFR versus an anti-VEGF antibody as their biologic of choice?

Katrina Pedersen:

I mean, I think in a broader context in just BRAF V600E disease paradigms presentation as a plenary at ASCO last year really reignited I think a lot of the discussion around upfront EGFR and should it really be given preferably for left-sided tumors. At that exact same meeting though there was also the triplet data or TRIPLETE, I’m not exactly sure how to pronounce that, but that also came out of the GONO group out of Italy where they randomized patients to get... And again, this is not necessarily BRAF V600E specifically not, but to get FOLFOX-panitumumab versus FOLFOXIRI-panitumumab. And that showed that actually the triplet had essentially the same outcomes but more toxicity as the doublet with panitumumab. That I think quenched a lot of fire for adding panitumumab to the triplet regimen, at least for me it did.

And using the word fire as the perfect segue to FIRE-4.5, which was specifically looking at BRAF V600E patients, I do believe, who were randomized to receive either FOLFOXIRI with cetuximab versus FOLFOXIRI with bevacizumab. It did suggest that, really, the cetuximab did not seem to add any additional benefit over the bevacizumab group. I believe that the response rate for BEV was 90%, 81% for the cetuximab triplet regimen, and then the PFS in the BEV group actually outperformed that of the cetuximab group as well. The data is still somewhat limited, it wasn’t a particularly large study. Though in these rare cohorts, I think there’s a lot to be said for the data that it did provide. And I’m not currently giving the EGFR inhibitor, I’m saving that for my BRAF V600E inhibitors.

Van Morris:

Yeah, absolutely. There are multiple trials that have looked at novel combination approaches. Dr. Parikh, recently we had data come out from the ANCHOR study that looked at BRAF/EGFR and MEK. What are your thoughts on that in the front-line setting for patients with untreated MSS BRAF V600E colorectal cancer?

Aparna Parikh:

Yeah. The ANCHOR study, just to remind people, it was a phase II study. It was looking at the efficacy, safety, and quality of life with encorafenib, binimetinib, and cetuximab. Again, single-arm, phase II and primary endpoint was ORR and secondary endpoints, PFS/OS. And the ORR from the published data was 47%. And I believe the median PFS was around 6 months, 5.8 months if I'm correct. And I think the median OS was around 18 months. Again, looking forward to the other first-line study that we’ll talk about. But at least shows that the combination in the first-line setting seems to have some efficacy. We have lots of other first-line data that we will look to. But showed again, not only some encouraging efficacy data, but manageable safety as well.

Van Morris:

Exactly. The ANCHOR study that the encorafenib-cituximab-binimetinib as you referenced, was the overall response rate was 47%. If we think about the BEACON study, looked at the same exact combination. But in the second-line setting, the overall response rate was 27%. Again, we can’t compare head-to-head these results. But certainly some intriguing data that earlier in the treatment course for these patients that we can get exposure to BRAF/EGFR/MAP kinase–targeted therapies. There’re some exciting and promising signal that may translate to better outcomes.

I think the other trial is the BREAKWATER trial, which is currently enrolling patients across the globe. And this is looking at adding encorafenib and cetuximab to standard cytotoxic chemotherapy with FOLFOX in the previously untreated setting. And early data that from the safety lead-in that came out of ESMO last year reported that encorafenib, cetuximab with FOLFOX response rate in the front-line setting approached 70%. We’re seeing, again, just very exciting early data for moving BRAF/EGFR-targeted therapies, in combination with other agents, to the front-line setting. And ultimately, again, as Dr. Pedersen referenced, we just want to push the fast-forward button on time here. But very excited to see what the BREAKWATER study will report out here.

Aparna Parikh:

I could just mention I think good to also, when you’re talking about earlier lines of therapy, there’s actually now some movement in the adjuvant space, right? Dr. Yaeger has a cooperative group study looking at adjuvant BRAF V600E-directed therapy. I think based on ctDNA status. We have another study looking at post–stage III, adjuvant BRAF V600E-directed therapy if you’re ctDNA-positive after receiving standard adjuvant chemotherapy. I think what’s really interesting, and we’re seeing this even with MOUNTAINEER with HER2; is earlier better? And then MOUNTAINEER is also doing BREAKWATER with a chemo combination, but can these patients like ANCHOR do without chemotherapy too? Really interesting to see the targeted therapy space in general. And does earlier exposure potentially even in an adjuvant setting ultimately end up helping these patients or not?

Van Morris:

It’s a talk for another day, but I see these trials you’re referencing and, are we doing good by waiting until the very, very treatment-refractory line to test combinations in oncology? But certainly a talk for a different day.

Katrina Pedersen:

Well, there is a little bit of a corollary here too where we might still have some question after BREAKWATER comes out because it doesn’t have that triplet nonchemo-containing arm. Will there still be an open question about how would that fit into the context of purely targeted therapy versus one with a chemo combination? So, it is hard though because ANCHOR and BREAKWATER are a bit different just because of when BEACON reported out its updated results, one was already underway and then the other one wasn’t, so different approaches.

Van Morris:

For sure. Yeah, I think there had been encorafenib-cetuximab arm initially in that design, but I think that’s been removed in the more recent past here.