Updates in the Treatment of HER2+ mBC from ASCO 2022

Vijayakrishna Gadi, MD, PhD: I would say that, in all of this HER2 disease, sadly if you have HER2-postivie breast cancer, although we’ve done a tremendous job extending the lives of those patients, ultimately the majority of those patients still die. We can’t rest on our laurels, and we’ve got to keep innovating in this area. There are many, many new molecules and entities that are being considered, and I’m excited to test those. We’ve heard about a number of them at this 2022 ASCO [American Society of Clinical Oncology Annual] Meeting, and obviously in it’s early days, and we hope that those will come in.

The other emphasis or way to look at it is, now that we have all these tools, what can we put together in a safe manner that could still be effective for our patients? I’ll highlight a few trials in this regard. One is looking at combining T-DM1 [trastuzumab emtansine] with tucatinib; the so-called HER2CLIMB-02 study [NCT03975647]. That’s a trial that’s ongoing. We hope that it’ll accrue quickly, and then we’ll have answers, but here’s a generally well-tolerated antibody-drug conjugate being combined with tucatinib, which has the CNS [central nervous system]-penetrating ability. You can see where I’m going with this with covering our bases above the neck but also below the neck. That could be one option. If it’s successful, it’s a randomized phase 3 trial, so it could be a new standard of care depending on what we learn from that.

There’s a DESTINY-Breast trial looking in a phase 2 setting at patients with CNS metastases and the combination of tucatinib. That study is still looking at safety initially, and then hopefully we will be able to expand out to efficacy cohorts. It’ll be a smaller study, but it may give us a signal that then we can formally test in a larger randomized control trial. That’s another option. Then lastly, [we are] looking at combinations with drugs like tucatinib and conventional things like chemotherapy: trastuzumab and pertuzumab. Although it’s not from the metastatic setting, when we try to do that in the I-SPY2 trial [NCT01042379] in the preoperative setting, that was actually too toxic. It was effective, but it was too toxic and should not be pursued at this time, so we’ve got to go back to the drawing board on that one. It’s not all wins. We are going to look at these combinations, but certainly, with the tools we have, we may be able to push the needle quite a bit by just combining them. The adage is, “If you can’t beat them, join them,” so that’s what we’re seeing in this space.

At2022 ASCO, a standing ovation talk claimed there is a new standard of care, which was the DESTINY-Breast04 trial [NCT0373402].. To refresh everybody’s memory just in case, DESTINY-Breast04 was a trial that looked at patients with HER2-low disease—I’m going to talk about the definition of HER2-low in a minute—and using trastuzumab deruxtecan vs physician’s choice chemotherapy options. In that trial, [there was a] running away nice separation of the curves for this HER2-low population favoring the trastuzumab deruxtecan. Fortunately, [there were] not a lot of new emergent [adverse] effects or toxicities that make us take pause in this. [They were] very familiar in terms of toxicities and were in many cases favorable compared to chemotherapy. [It is] very easy to say, “Yeah, this could be a new standard of care.”

Now I’m Monday-morning quarterbacking on this molecule in this study. First off, what is HER2-low? We know that some cancers, when they express HER2 strongly, we call it HER2+. Those are cancers where the driver is the HER2 gene. Those are cancers that we can target with all our conventional therapies that we’ve had access to: trastuzumab, pertuzumab, tucatinib, neratinib, and all these molecules become relevant. For these, HER2, IHC [immunohistochemistry] 2-positive and below, this is not a driver. It’s a target of convenience. The expression is necessary to get the antibody-drug conjugate to the location, internalize the chemotherapy, and then kill the cancer cell. Fortunately, with trastuzumab deruxtecan, you have this wonderful thing called bystander killing. The chemotherapy leaks out and kills the neighboring cells as well. Even if you have low or heterogeneous expression of the HER2 target as a target of convenience, it’s localizing the chemotherapy to where we need it to be, and that chemotherapy is very potent. That has now formally been tested in a randomized controlled [phase] 3 trial and that hypothesis is true. This is an effective molecule for that disease space.

As we try to integrate this, a lot of these patients have hormone receptor–positive disease. I suspect we’re going to continue to tackle that because those therapies are well tolerated compared to chemotherapies and even antibody-drug conjugates. Once those stop working for our patients, it’s very easy to think how we’ll be reaching for trastuzumab deruxtecan for those patients. Within that trial, they also studied what we call triple-negative disease that’s HER2-low. For those patients, there are now a couple of options. We have sacituzumab govitecan, which is formally evaluated in a robust dataset and [has been] shown to benefit those patients, but we also have this very active molecule, trastuzumab deruxtecan. If you notice how I’m saying these words, govitecan [and] deruxtecan, they end in the same terminal 5 letters. These are all Topo1 inhibitors, so there may be cross-resistance. Our ability to use these drugs one after the other isn’t assumed. We have to test that formally to see if that’s even possible. I think, in the triple-negative space, [it’s] a little murky. For those HER2-low [cases], you have a couple of options, and for those that don’t make HER2 at any level, the so-called HER2-0 [cases], I think sacituzumab govitecan might be the choice for those patients.

Thank you very much for listening to my ramblings about HER2-positive metastatic breast cancer. It’s a rapidly changing field. If you took boards just a few years ago, you’ve go5t to know a lot going forward to make sure you do well on the boards in the future. Fortunately, for our patients, this innovation is really making an impact for them, so thank you to the patients who’ve also participated on these studies to help the patients coming down the pipe.

Transcript has been edited for clarity.