SABCS 2019: Tucatinib: A New Standard of Care for HER2-Positive Metastatic Breast Cancer?

This podcast is made possible by the generous support of Lilly Oncology.

Jamie DePolo: Hello. I’m Jamie DePolo, senior editor at Breastcancer.org. We’re podcasting on location from the 2019 San Antonio Breast Cancer Symposium. My guest is Dr. Rashmi Murthy, assistant professor of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston. This morning, she presented research on the HER2CLIMB study, which is looking at using the experimental medicine tucatinib in combination with Herceptin [chemical name: trastuzumab] and Xeloda [chemical name: capecitabine] chemotherapy to treat people diagnosed with advanced-stage HER2-positive breast cancer that was previously treated with Herceptin, Perjeta [chemical name: pertuzumab], and Kadcyla [chemical name: T-DM1 or ado-trastuzumab emtansine]. The study is somewhat unique, in that people who have brain metastases are allowed to be in the trial. Dr. Murthy, welcome to the podcast.

Dr. Rashmi Murthy: Thank you for having me.

Jamie DePolo: So, to start, could you summarize the results of the study for us?

Dr. Rashmi Murthy: Sure. So HER2CLIMB showed that the addition of tucatinib to trastuzumab and capecitabine allowed for patients...for us to control a patient’s disease for longer and to improve how long that they lived. Further, we noted that there was a doubling in the response rates of the actual tumors throughout the systemic disease.

Jamie DePolo: Excellent, and if I remember right, you talked about the response rate, but there was better progression-free survival, which is how long people lived without the cancer growing, and also better overall survival. Is that right?

Dr. Rashmi Murthy: That’s correct. Yes. So, you know, HER2-positive metastatic breast cancer remains incurable, so we’re not able to make the disease go away. So the best that we can hope for is really to try to shrink or at least control the disease for as long as possible with as little toxicity as possible to enable people to continue to have a good quality of life.

Jamie DePolo: Okay, and as I said in the intro, this was kind of unique in that people with brain metastases could be in the study, and a lot of studies don’t allow that. So could you talk a little bit about why that is and also why your study allowed people with brain mets to be in it?

Dr. Rashmi Murthy: So you’re very right in that many studies exclude patients with brain metastasis. You know, this patient population has a very poor prognosis, and currently the most effective treatments that we have are local therapies. So, often, patients are recommended to undergo, for example, radiation or surgery, depending upon what their doctors feel would be the best choice, and then pursue a systemic treatment option, either a standard one or on a clinical trial to help control their systemic disease.

HER2CLIMB was unique in that with tucatinib, we have both pre-clinical as well as early clinical data to suggest that tucatinib has a potential to cross the blood-brain barrier, and so HER2CLIMB wanted… when it was designed, the idea was to confirm that concept and see if we can enlist benefits from this drug in patients both with and without brain metastases.

Jamie DePolo: Okay, and if I’m remembering right, too, it was about 48-50% of the people in the study that had brain metastases?

Dr. Rashmi Murthy: Right. So all patients were required to undergo a brain MRI at study entry, and patients with untreated disease were allowed to enroll, in addition to patients with treated disease that was progressing. And so overall, the brain metastasis patient population was nearly 50% of the whole trial population, and among those, about 40% in both arms had either untreated or progressing lesions. The rest of the patients had a history of brain metastases that was found to be stable at the time of screening.

Jamie DePolo: Okay. Okay. Now, what about side effects? That’s something that we always focus on at Breastcancer.org, because even if a treatment is amazing, if the side effects are toxic, it’s maybe not that great. So I know you said that the side effects seem to be manageable. Could you talk a little bit about what the most common ones were and maybe what the most severe were?

Dr. Rashmi Murthy: Right. So I’ve been involved in treating patients with tucatinib since the early phase 1B study, and, you know, definitely in the randomized trial it was very difficult to decide which patient was on placebo versus tucatinib because the side effects were very comparable, and it was difficult to determine who was really getting the study drug. The most common side effects were diarrhea, hand-foot syndrome, which is a very common side effect, while recognized to be associated with capecitabine.

Jamie DePolo: And that’s where they have pain or peripheral neuropathy?

Dr. Rashmi Murthy: Hand-foot syndrome is where you can get peeling of your hands and feet and almost an inflammation on the palms and the soles of your hands and feet, and so that was the second-most side effect. Others included nausea, vomiting, and fatigue. Diarrhea is certainly a side effect of interest.

Jamie DePolo: Now, I think in your study, you said that sort of an anti-diarrhea medicine up front wasn’t part of the HER2CLIMB study, but maybe that’s a possibility if people are being treated with it? Did I understand that right or no?

Dr. Rashmi Murthy: Anti-diarrheal prophylaxis was not required in the study, meaning that we didn't give medications to try to lessen or prevent diarrhea at the beginning of the study, but anti-diarrheal use was allowed on study in order to help manage and control the diarrhea. And what we found is that it’s very, very manageable. So we’re able to control the diarrhea with short courses, really, of anti-diarrheals that were noted in both arms, and those were comparable. So it’s about a median of 3 days of anti-diarrheal use that helped to control the side effect. So it was very manageable.

Jamie DePolo: Okay. Do you think treating the diarrhea up front would be a good idea, or is it really better to wait until it happens?

Dr. Rashmi Murthy: Well, because it was very manageable to take care of as it happened, you know, I would continue to probably approach it that way rather than asking all patients who are going on these treatments to be taking an additional medication on top of what they’re already having to take.

Jamie DePolo: Okay. That makes sense. And in your presentation this morning, you talked about that it looked like prolonged treatment with tucatinib was possible. Could you talk a little bit about what that might mean for patients?

Dr. Rashmi Murthy: Well, one of the concerns in the setting of having advanced breast cancer is when will the toxicity of all these drugs catch up to you? And so this is certainly a heavily pre-treated patient population who has had prior treatment with trastuzumab, pertuzumab, chemotherapy, and T-DM1. And so the fact that this regimen with tucatinib was very tolerable is very important because it means that as long as the treatment is working, we’re able to continue the treatment, which is very important when there are limited treatment options. We want to try to continue treatments that are working for as long as possible.

Jamie DePolo: Okay. Now, I realize you are not with a pharma company, but are there plans to file for FDA approval for tucatinib that you know of?

Dr. Rashmi Murthy: Yeah, with these very promising and impressive trial results, certainly the next step would be to move forward with the processes to try to get the drug approved.

Jamie DePolo: Okay. And finally, to wrap up, do you think tucatinib is going to change a standard of care for advanced-stage HER2-positive disease? Like, are these results that big?

Dr. Rashmi Murthy: I think these results are practice changing. We have yet to see a randomized trial show a survival benefit in a patient population who’s had all of the contemporary anti-HER2-targeted therapies, trastuzumab, pertuzumab, and T-DM1. So, yes, I think this is certainly practice changing and will change the standard of care.

Jamie DePolo: Excellent. Thank you so much. I appreciate your time.

Dr. Rashmi Murthy: Thank you.

Editor’s Note: On April 17, 2020, the FDA approved Tukysa (chemical name: tucatinib) in combination with Herceptin (chemical name: trastuzumab) and Xeloda (chemical name: capecitabine) to treat metastatic HER2-positive breast cancer or locally-advanced HER2-positive disease that can’t be completely removed with surgery, after the cancer has been treated with at least one anti-HER2 medicine.