Emerging Combinations for Triple-Positive Breast Cancer

Lisa A. Carey, MD, FASCO: I have to say, I think the CLEOPATRA survival data and its design—where you could drop out the chemotherapy after, I think, 6 cycles, and on average, the people in that trial only got 8 cycles—drove a lot of what we did. In PERTAIN, as V.K. commented, it didn’t look like those with this induction phase did better, and they actually did a little bit worse. That could be selection, but it wasn’t a compelling argument. I think, with this new study where there wasn’t induction, just endocrine therapy [ET] and anti-HER2, or chemo [chemotherapy] and anti-HER2, the quibbling is that the chemotherapy choices weren’t all a taxane. The options were taxane, CAPE [capecitabine], and I think, vinorelbine. For ET, I think you could use a variety of agents for the endocrine therapy.

It was a very practical study, and it was a noninferiority study, but the hazard ratio favored the endocrine therapy-based thing, not that it was meaningful, but it was certainly in the wrong direction for chemotherapy. The only group that seemed to do better with chemotherapy, and it looked like there was an interaction there, were those patients who had a short disease-free interval. I think, at 2 years, those who had short disease-free intervals, which may get back to the HER2-enriched, more aggressive types of biology, seemed to do better with a chemotherapy-based approach. To be honest, I agree, I think that was a practice-changing presentation in my mind.

Lee S. Schwartzberg, MD, FACP: One other comment, Lisa, I think we need to stress for community doctors that even if you do start with chemotherapy, a la CLEOPATRA, you should definitely add endocrine therapy either with it, or afterward.

Lisa A. Carey, MD, FASCO: After you finish the chemotherapy part.

Lee S. Schwartzberg, MD, FACP: Right, because I think there’s still this dichotomy that it’s chemotherapy and continue the anti-HER2, and people haven’t completely bought that it’s chemotherapy in ER+ [estrogen receptor-positive] and then endocrine plus HER2. At the very least, you suggest that.

Reshma Mahtani, DO: Building on that, I want to highlight the ongoing PATINA trial, which is looking at adding a CDK4/6 inhibitor to endocrine therapy and that HER2 backbone, looking at the potential value of CDK inhibition in triple-positive patients. I think that’ll be an important study as well.

Vijayakrishna Gadi, MD, PhD: Reshma, that’s a transition to the other studies. Sticking to the concept that no 2 drugs are too dumb to try, there’s a lot of interest looking beyond that initial ER sensitivity. Some of these cancers can also, even with HER2, pick up PIK3 mutations, can get cyclin alterations, and so forth. Then the question naturally is, what are the downstream targets we need to hit with the monoclonal antibodies and some of these newer agents?

We have the monarcHER trial, which was presented 2 years ago and published by Sara M. Tolaney, MD, MPH, last year. That’s a combination in the “Nth line,” the third line or beyond, looking at abemaciclib plus fulvestrant plus trastuzumab as a combination, and that was, I’ll say, mildly positive. It looked good, but it wasn’t powered enough to say a whole lot.

Lisa A. Carey, MD, FASCO: Versus chemotherapy and trastuzumab, yes.

Vijayakrishna Gadi, MD, PhD: Correct. I had patients on that trial. I was very pleased, and the patients I had did quite well. I’m a believer in this concept that there are downstream targets we can hit. You just highlighted the PERTAIN trial, sorry, what’s it called?

Reshma Mahtani, DO: PATINA.

Vijayakrishna Gadi, MD, PhD: PATINA, thank you. That study is now closed, but it had an induction phase with a taxane, then they dropped the taxane and transitioned to the CDK4. So, it’s a slightly different study design, but in many respects a first-line study, and we’ll see what that teaches us.

Then there are the new molecules, combinations with tucatinib, and palbociclib, and letrozole. These are all phase 1 and 2 trials, so very early. But I think the message is clear, that in these triple-positives, there are still these downstream regulators of ER that we may need to hit in order to see efficacy. There’s a study looking at the PIK3 inhibitor alpelisib in this population, when they have PIK3 mutations, as well.

Lee S. Schwartzberg, MD, FACP: I think that’s a great point. We already know that PI3 kinase mutations portend to poor prognosis for HER2, so that might be an important area to follow. As we do more molecular characterization, as you were saying, we might understand better. We see HER2 mutations occur as another alternative resistance mechanism, and they can be targeted by TKIs [tyrosine-kinase inhibitors]. It’s a rich area of biologic discovery that will allow us to develop clinical trials that are focused on those.

Transcript Edited for Clarity