Expert panelists review data from the MOUNTAINEER study, which tested tucatinib alone or in combination with trastuzumab in patients with metastatic colorectal cancer.
Tanios S. Bekaii-Saab, MD:Let's talk about the big trial that was presented at World GI ESMO and your efforts with Dr Strickler for the MOUNTAINEER trial. Can you give us a synopsis of, basically, the study design, and tell me what does this mean for our patient population? At the contact of the study and remains quite involved, and I speak on behalf of all of us. The MOUNTAINEER study started, interestingly, as an investigative-initiated trial with limited sites. I went through on a crew research consortium as a single-arm cohort, which ended up being cohort A in the MOUNTAINEER study with tucatinib, which is a tyrosine kinase inhibitor that is highly specific and potent for the HER2 receptor. And the other, I think, saving grace compared to, say, to lapatinib, which we've traditionally used by default as an oral TKI, it seems to have almost no effect to very low effect on the EGFR pathway unlike lapatinib, which was equally potent. And then that helps when we get to the discussion relating to the toxicities. This ends up being less toxic. And then after cohort A, the study was transferred essentially to CL genetic CGEn, who took the idea into the study and to a randomized setting of cohort B and C, and cohort B was essentially tucatinib/trastuzumab with the combination of the TKI plus trastuzumab. And cohort C had an interesting question. Traditionally, we've known that trastuzumab is a single agent across all malignancies, doesn't surpass the ten percent response rate on its own, even in the highly HER2-driven tumors such as breast. And the question was mostly related to can we understand whether a single agent tucatinib will drive enough of a response to explain the initial interesting results we've seen with the combo. And the tucatinib, the cohort C had a crossover design where patients were allowed, essentially, to receive trastuzumab in addition to tucatinib at the time of progression. The primary endpoint of this study was response rate, since it was a single arm study in that sense, at least assessing tucatinib and trastuzumab. And the outcome were updated and reported at ESMO, essentially, showing that when you combine tucatinib and trastuzumab, looking at the 2 cohorts, A plus B, which is about 84 patients. As such, the largest reports on, if not the largest report on essentially the combination of a TKI and a HER2 antibody so trastuzumab. The response rate was 38%, and that was centrally reviewed. There were about a quarter of the patients who had progressive disease, and the median duration of response was above a year, which is impressive. The tucatinib monotherapy arm had essentially one responder only, and the progressives that were about 13%, but about three-quarters of the patients had stable disease, and ultimately most of them crossed over to tucatinib and trastuzumab. What was interesting it as we go to the crossover tucatinib/trastuzumab, the response rate was essentially 18%. And essentially the rest were mostly stable disease. It's interesting to see that for those patients who haven't had an optimal response for tucatinib monotherapy progressed when adding trastuzumab, although the response rate is interesting, but it never ended up being as interesting as starting with the combo. The message, and not to go overboard since this is a smaller cohort, but the message is it's important to hit early and hit strong. Meaning you start with tucatinib/trastuzumab. It's interesting to see that tucatinib on its own had some level of activity, but it wasn't active enough to think about any other than the combo to start with. Regarding the safety, it's, again, very interesting safety results here. When we look at the grade 3 or more toxicities, it was less than 40% of the patients experienced any significant toxicity. There were no death from the adverse events, and only 6% of the patients ended up discontinuing tucatinib from adverse events, very low rate of significant toxicities. And the most common adverse events were diarrhea, which you would expect with these agents, some level of fatigue, and abdominal pain, most likely from tucatinib as a major contributor to those. But overall, incredibly well-tolerated and very active regimen. The progression-free survival at the median was a little bit more than 8 months, and the survival close to 2-plus years. Again, single-arm studies, the survival is a bit difficult to make sense of, but it's pretty impressive. It's the highest survival rate reported in this patient population, at least with historical comparison. Overall, I think very active, quite safe. It's at the FDA now for review. If approved by the FDA, this will be essentially the first HER2-targeted therapy or combination therapy with tucatinib/trastuzumab approved in colorectal cancer in the US.
Transcript edited for clarity.