Experts on HER2+ metastatic colorectal cancer review the MOUNTAINEER study on tucatinib plus trastuzumab.
Cathy Eng, MD, FACP, FASCO: Dr Foote, can you review recent efficacy and safety data from the MOUNTAINEER study, the trial that we’ve been mentioning, regarding tucatinib [Tukysa] and HER2 [human epidermal growth factor receptor 2]–positive metastatic colorectal carcinoma?
Michael Foote, MD: To recap the trial, this was a phase 2 single-arm trial for all practical purposes. There was a separate cohort that wasn’t analyzed in the primary analysis that received tucatinib monotherapy. The main cohort got trastuzumab [Herceptin]–tucatinib, and these were patients in the second line or later who had been exposed to irinotecan, oxaliplatin, and 5-florouracil. These are our best drugs in colorectal cancer, although about half the patients didn’t get EGFR therapy, and many were indicated for it. That’s an important point.
Despite that, the patients did really well. The overall response rate, which was the primary outcome for the evaluated population, was 38% in the later lines. That’s very high. The duration of response was over a year, which is incredible. The patients who responded to the therapy were able to stay on it. The progression-free survival was around 8 months, which is very impressive in later lines. Overall survival rate was amazing at over 2 years. In the later lines, we don’t see anything like that. One of the most interesting aspects is that the drugs were very well tolerated. It’s hard to imagine, but it was effective, and the patients could stay on it so long because the adverse effects weren’t as bad. About 38%, the same amount that had an overall response rate, had a grade 3 event. But for the majority of patients, it was diarrhea. Anybody who has prescribed the drugs has seen this; it’s manageable. The treatment discontinuation rates were only 6%. Almost everyone was able to stay on the drug, and it’s manageable with antidiarrheals, etc. It was an extremely exciting trial. It led to FDA approval.
Another abstract that’s been presented talked about the quality of life on the drugs, and it’s a testament to how well-tolerated they are. Quality-of-life outcomes of the patients didn’t change when they were on the drugs. They were perfect. It’s a very exciting study. We’re all excited about it and looking forward to using HER2 going forward.
Cathy Eng, MD, FACP, FASCO: It’s very exciting because it’s a phase 2 study. And because it’s such a rare patient population, we’re wondering, was it enough to determine whether the FDA would approve it? They did, and it’s extremely important for our patients because it’s such a rare patient population. That’s what’s pivotal about this study.
Dr Kamath, besides diarrhea and how to manage that, because that’s an issue for our patients, what other adverse events are you be concerned about potential toxicities with? How would you recommend managing it for a new patient? This is a new drug to them. What would you recommend?
Suneel Kamath, MD: Dr Foote stole my thunder a little bit. Diarrhea is by far the biggest and most common toxicity. We do see some fatigue, which is very mild, and skin toxicity as well—dryness, hand-foot syndrome. But that’s usually rare and easy to manage. Diarrhea is front and center, and it’s not the level of what you’d see with neratinib [Nerlynx], where you probably want to prophylactically start people on antidiarrheals. It’s not to that degree, but I definitely have a very low threshold. It’s a situation where I try to touch base with patients very soon after initiating because often I find they’re going to have significant grade 3 or higher diarrhea. It happens quickly, so touching base with them quickly and intervening soon is key. But it’s very easy to manage with loperamide [Imodium], Lomotil [diphenoxylate/atropine], or things of that nature. I often find very brief dose holds, even for a week or so. can be great to reset the clock. Then you can resume even at the same dose many times.
Cathy Eng, MD, FACP, FASCO: That’s great to know. That’s important for our audience because this is a new drug. It’s also important to emphasize the importance of communication among the patient, yourself, and the clinical team.
Suneel Kamath, MD: Definitely. There’s so much research now on postnursing follow-up. That’s critical with this drug.
Cathy Eng, MD, FACP, FASCO: Dr Foote, is there anything else you’d like to mention with the study design regarding MOUNTAINEER? It sounds as if it’s the most appropriate. Obviously, we’re trying to move forward with the role of HER2 positivity for our patients and the potential impact in the frontline setting. Do you have any other comments you’d like to add?
Michael Foote, MD: It’s a great study. It’s combining therapies earlier that work in later lines. This is a molecular-driven therapy that has shown a lot of success on the second line. It’s a well-done study. The primary end point is progression-free survival, which has its pros and cons. But overall, it’s appropriate.
One point you made earlier is that patients with RAF mutations and PIK3CA mutations are allowed on the trial. They’re not excluded. The only patients who are excluded are RAS mutant. It’s something to think about when you’re thinking about this study. We’ll see how that plays out with the data.
In terms of patients it benefits, if you have a patient who’s unfortunate enough to have brain metastases, which are extremely rare in colorectal cancer but very serious, then this is something you want to get that patient started on. It’s a great study.
Cathy Eng, MD, FACP, FASCO: It’s important to mention that it’s commendable to the company to allow that patient population to participate. Because a lot of the trials automatically exclude patients with brain metastases. We see these patients live for many years despite the development of brain metastases, as long as they’ve been following up with their surgeon, radiation oncologist, etc.
Aparna Parikh, MD: There’s also an earlier brief plug for trials. There’s some movement in the area of ctDNA [circulating tumor DNA] to think about some of these targeted approaches earlier in the ctDNA-positive place. Dr Foote and I are involved with a study that has adjuvant HER2-directed therapy for stage III colon cancer if you’re ctDNA positive. BRAF is being tested by 1 of Dr Foote’s colleagues as well. It will be interesting to see not only earlier lines of metastatic disease but also if any targeted therapies move into earlier stages of the disease as well with the right biomarker.
Cathy Eng, MD, FACP, FASCO: That’s a great point. That’s going to change the future landscape, obviously for the metastatic setting. Really important points.
Transcript edited for clarity.