Emerging Therapies for HER2+ MBC

Lisa A. Carey, MD, FASCO: Since we’re on the theme of new and emerging things, let’s do a rapid fire on some of the new stuff that’s coming out. Pyrotinib, which is approved in China, who wants to talk about it? Lee, tell us a little about pyrotinib. What do you think is happening with it?

Lee S. Schwartzberg, MD, FACP: I think there are good data in the Chinese studies that led to its approval. It’s another TKI [tyrosine-kinase inhibitor] with a very low IC50 [half maximal inhibitory concentration], so it has good efficacy. We don’t know yet where it’s going to fall, is it better after other TKIs, now that we have tucatinib? It appears to be very active in combination with capecitabine. It’s that same design of capecitabine, and we don’t know if we need dual anti-HER2 therapy there, is that a regimen? But if it was approved, I think it could find a place in late-line therapy. It speaks to the point that we can develop next generations of these drugs that are more effective, and presumably, less toxic as well. Diarrhea, for all of these, is the major toxicity.

Lisa A. Carey, MD, FASCO: I think PHOEBE, the sentinel trial you pointed out, was a NALA-like comparison vs lapatinib, CAPE [capecitabine]. So yes, how it’s going to stack up will be interesting.

Lee, while you’re on it, what about poziotinib?

Lee S. Schwartzberg, MD, FACP: Poziotinib is another drug that’s a TKI. It has activity in exon 20 mutations, as one aspect for HER2, and I believe, also for EGFR. That’s one stratum where it’s being looked at. But it also has activity in patients with HER2-positive metastatic disease, where it’s been looked at in late line, early phase 1, and phase 2 data—mostly in Asia. It’s another potential drug that could be developed. We may have a whole series of these TKIs that have value, and unfortunately, we won’t know about cross-resistance.

Lisa A. Carey, MD, FASCO: Because you’re going around in circles, yes. The sequencing of these things is going to be difficult. Reshma, what about the TULIP trial?

Reshma Mahtani, DO: I think we’re starting to see several of these so-called second-generation ADCs [antibody-drug conjugates] targeting HER2, which may supersede T-DM1 [trastuzumab emtansine] by using a cleavable linker and a more potent payload. The TULIP trial is looking at one of these agents, SYD985, which is a second-generation ADC consisting of trastuzumab bound to this potent duocarmazine payload with a cleavable linker. There are some data that this agent, just like trastuzumab deruxtecan has shown us, may have this bystander effect in patients who are HER2-low, meaning IHC [immunohistochemistry testing score] 1+/2+ and FISH [fluorescence in situ hybridization] negative. Just 3 days ago, we heard top-line press results on the TULIP trial, indicating that the primary end point of progression-free survival [PFS] was met. We’ll be interested to hear more data on this agent.

I think it’s also important to recognize that there are other ongoing studies looking at, for example, trastuzumab deruxtecan compared head-to-head to T-DM1 [trastuzumab emtansine]. As I brought up this concept of the second-generation ADC, we’re going to get a head-to-head comparison in the DESTINY-Breast03 trial, which may move trastuzumab deruxtecan into earlier lines of therapy.

Lisa A. Carey, MD, FASCO: Fascinating. The ADCs are going to be a huge, new world. The way we categorize HER2-positive disease may be completely disrupted and need to be revised in this setting. It’s an interesting time. Are there any other compounds or drugs that you think warrant noting?

Vijayakrishna Gadi, MD, PhD: I’ll comment. We’ve been at the cutting edge with most of the discussion today, but there’s the bloody tip. In terms of the bloody tip, there are cell therapies, novel constructs to the ADCs, and oncolytic viruses. A lot of this development is because the HER2 metastatic space, as a clinical trial development space, is very congested. You’re seeing a lot of this being developed in gastric cancer, in colorectal cancer, lung cancer, and other spaces. If we look across the spectrum at some of the other disease spaces, there may be things that will eventually find their way back to us. One example is this company Zymeworks. They were originally a breast cancer drug company, and now they’re everything else but breast cancer, and maybe they’ll come back to breast cancer because it’s such a congested space for them to do clinical trial development.

Having said that, we talked about this, despite all this richness we have, there’s still an unmet need. I think we still have to keep the foot down on the accelerator in order to develop new, safer ways to do this. A lot of these newer therapies may be safer than what we’ve got. I’m really optimistic about us having more tools.

Lee S. Schwartzberg, MD, FACP: I think that’s a great point. We’re not curing metastatic HER2-positive breast cancer for the most part, even today, with 5 years and greater median survival. It’s harder to do clinical trials now because we have these, and that’s a challenge. We have to continue to focus on that.

Lisa A. Carey, MD, FASCO: Yes. You raise an important point. I’ll make the last comment, which is in metastatic disease, with all these wildly active drugs, should we make a curative intent run at it, and is there an opportunity to do that? Are there mechanisms to do that? I think there will be trials. There’s a concept in development in the TBCRC [Translational Breast Cancer Research Consortium] about that. I don’t know if it’s going to come to fruition, but there’s a lot of enthusiasm for it. We can all see this coming. As the drugs get better, we want to revisit the algorithm that the goals of therapy are palliative. We may be able to do something about that.

Transcript Edited for Clarity