Waisman Walks Through Sequencing Strategy in Metastatic HER2-Positive Breast Cancer

James R. Waisman, MD

Sorting out optimal treatment sequencing remains a top priority as the treatment arsenal continues to expand for patients with metastatic HER2- positive breast cancer, according to James R. Waisman, MD.

“I’m an orthodox person and I try not to deviate. It’s my responsibility in a major comprehensive cancer center to not be anecdotal,” said Waisman. “I use tucatinib [Tukysa] plus capecitabine [Xeloda] plus trastuzumab [Herceptin], and I’ve had colleagues say they drop the capecitabine quickly because they don’t think it’s a big contributor; I don’t do that.”

In an interview with OncLive^® during a 2020 Institutional Perspectives in Cancer webinar on breast cancer, Waisman, the medical director of Duarte Clinics, as well as a clinical professor in the Department of Medical Oncology and Therapeutics Research at City of Hope, shared his process for matching patients with the right treatment in the metastatic setting and discussed areas for future exploration.

OncLive^®: How do you approach sequencing for patients with metastatic HER2-positive disease?

[For] the first-line metastatic setting is pertuzumab [Perjeta], trastuzumab, and a taxane. Sometimes, an elderly patient is going to experience a lot more difficulty with [the] CLEOPATRA [(NCT00567190) regimen], meaning [pertuzumab, trastuzumab, and] docetaxel. As such, I will use paclitaxel in some patients, but I still believe that [the] CLEOPATRA [regimen] is the standard; I pretty much try to stick to that. I use 8 cycles, because that was the average in CLEOPATRA, but some people stop at 6. Then, if [patients are] doing well and they’re having a good remission, I like to get them to antibody therapy only because it’s a major quality-of-life change. However, if they have high-risk disease, chemotherapy is important.

Then there’s the second-line [setting], which currently is trastuzumab emtansine [Kadcyla; T-DM1], [but] it would depend on the population. Obviously, if [patients] have brain metastases I would use tucatinib, trastuzumab, and capecitabine. If they don’t, and let’s say they’re not progressing in certain disease sites—maybe their burden is primarily node or bone, [and] there’s a lot of tumor heterogeneity, particularly under the pressures of therapy— they go several years into treatment after [the] CLEOPATRA [regimen] or after first-line therapy, and you rebiopsy them. Some of the old literature says that HER2 doesn’t change that often, maybe 10% of the time, but that’s not our experience. With further and further lines of therapy, you biopsy, and HER2 loses its amplification and becomes either 2-plus or 1-plus; that’s where the trastuzumab deruxtecan molecule really has some advantages, because of the efficacy in [patients with] HER2-low [expression]—not 0, but 1-plus and 2-plus.

Could you speak to the excitement surrounding the antibody-drug conjugate?

It’s very exciting because then you don’t have to worry as much about [having] lost [the] HER2 target and [figuring out what to do]. You either have a triple-negative disease or endocrine-positive disease, and you very much worry that the HER2 expression will make them endocrine resistant. Unless you use HER2 targeting, you’re going to have that problem. Therefore, the addition of trastuzumab deruxtecan [to the arsenal] has really made a major impact, and that drug is really going to gain favor. It’s given every 3 weeks; [it doesn’t come with the] adverse effects of capecitabine. [Some patients] do experience hair loss and fatigue. Also, interstitial lung disease is a problem that you have to watch for [with this agent].

What do you use for later lines of treatment?

I use tucatinib or trastuzumab deruxtecan in the second or third [line of treatment]. For the fourth-line setting, it is usually T-DM1, and [then the] fifth is neratinib [Nerlynx] and capecitabine. Then, it’s dealer’s choice regarding what kind of chemotherapy you want to use. We don’t tend to get [that far] anymore because the drugs [we are using] work [so well].

What is your advice to your colleagues?

We have to be careful about dismissing any drugs that may be negative early on. [We need to look] at the data carefully, be data driven, as we all like to think we are, and be interested in not only survival but also quality of life for our patients.

We’ve gained a lot in de-escalation. We have to be careful that if we see a patient with a [tumor that is] 2 cm, node negative, HER2 positive on imaging, that we don’t just jump to neoadjuvant chemotherapy. Maybe we go to surgery f irst and just use a de-escalated, [effective] good regimen. The de-escalation space is really one of great interest. I’m interested to know how T-DM1 and tucatinib will do, as well as in combination and [approaches] like that.