McAndrew Expands on the Evolving Treatment Armamentarium in HER2+ Breast Cancer

The emergence of new and updated research continues to shift the treatment paradigm in HER2-positive metastatic breast cancer, not only by providing long-term insights for established regimens, but by identifying new roles for these agents in various combinations or in earlier lines, according to Nicholas P. McAndrew, MD, MSCE.

At the 2023 San Antonio Breast Cancer Symposium, 7-year updated data from the phase 3 KATHERINE trial (NCT01772472) demonstrated sustained survival benefits with adjuvant ado-trastuzumab emtansine (T-DM1; Kadcyla) vs trastuzumab (Herceptin) after a median follow-up of 8.4 years in patients with HER2-positive breast cancer and residual invasive disease following neoadjuvant therapy (invasive disease-free survival [HR, 0.54; 95% CI, 0.44-0.66; P <.0001]; overall survival [HR, 0.66; 95% CI, 0.51-0.87; P =.0027]).¹

Findings from the phase 3 HER2CLIMB-02 trial (NCT03975647) were also presented during the meeting, and showed that tucatinib (Tukysa) plus T-DM1 significantly improved progression-free survival (PFS) vs placebo plus T-DM1 in patients with previously treated HER2-positive metastatic breast cancer, particularly those with brain metastases.² Based on this research, other studies will evaluate the addition of tucatinib to standard of care fam-trastuzumab-deruxtecan-nxki (Enhertu; T-DXd), as well as single-agent tucatinib’s efficacy in earlier lines, McAndrew detailed.

“The world of not just HER2-positive breast cancer but breast cancer in general is evolving all the time,” McAndrew said following his participation in an OncLive® State of the Science Summit on breast cancer. “We have new studies coming out and updated analyses of old studies. It’s important to try to stay up to date with these developments as they come out, and forums like this are perfect for doing that.”

In an interview with OncLive, McAndrew discussed the significance of practice-changing studies in HER2-positive breast cancer; ongoing research aiming to clarify the continued roles of T-DM1 and tucatinib in the evolving treatment paradigm; and how leveraging neoadjuvant trials such as the phase 2 PHERGain study (NCT03161353) could inform chemotherapy de-escalation in select patients.

McAndrew is an assistant clinical professor of medicine at the University of California, Los Angeles (UCLA) and a hematologist-oncologist at the UCLA David Geffen School of Medicine of UCLA Medical Center.

OncLive: Please detail the design and key objectives of the KATHERINE trial in HER2-positive breast cancer. Why are updated findings from this trial considered significant for the paradigm?

McAndrew: One study that was important to update was the phase 3 KATHERINE trial. This is an example of a study that many of us are very familiar with [because it] was immediately practice changing. What’s universal about early-stage breast cancer studies is that they are followed for many years, so we always get updates as time goes by. Part of the reason why KATHERINE was so practice changing is because it established a clinically meaningful rationale to use neoadjuvant therapy in HER2-positive breast cancer for a majority of patients, because you can select these high-risk patients who benefit from intensification of post-neoadjuvant therapy.

KATHERINE took patients who had neoadjuvant chemotherapy but did not have a pathologic complete response. They had residual disease after neoadjuvant chemotherapy. Based on prior analyses showing that these patients have a worse prognosis [for] IDFS, KATHERINE took these high-risk patients and randomly assigned them to receive either the SOC, which was adjuvant trastuzumab [Herceptin] for an additional 14 cycles, or adjuvant T-DM1, the first antibody-drug conjugate [ADC] approved in breast cancer.

Could you expand on some of the key updated efficacy findings from the KATHERINE trial? Why are these data significant?

The initial analysis showed that there was approximately an 11% benefit at 3 years [with T-DM1] for IDFS, which correlates to a relative 50% reduction in the risk of recurrence. At the 2023 San Antonio Breast Cancer Symposium, investigators presented an updated 7-year analysis with a median follow-up of 8.4 years. [In this analysis], that [IDFS] benefit [with T-DM1] grew to 13.7% with a similar relative risk reduction of 46%. [This was an] even more meaningful benefit. This does not suggest that these are just patients who were delaying metastases; it does seem to be a sustained benefit over time. OS benefit also continued to increase to 4.7% at 7 years. [Such findings] further underscore the importance of using this neoadjuvant approach.

What was the rationale for and importance of the HER2CLIMB-02 study of tucatinib plus T-DM1 in metastatic breast cancer?

The HER2CLIMB-02 study is further [assessing] whether there are different roles for drugs that we already have on hand. Tucatinib was approved [in HER2-positive breast cancer] based on data from the phase 2 HER2CLIMB study [NCT02614794], which showed that the addition of tucatinib to capecitabine [Xeloda] and trastuzumab was superior to capecitabine and trastuzumab alone in terms of PFS. That regimen also seemed to have benefit in patients with brain metastases.

Since then, several studies have explored the use of tucatinib in a variety of other combinations. The HER2CLIMB-02 study looked at using it in the second line or beyond in combination with T-DM1. Patients were randomly assigned in a 1:1 ratio to receive either T-DM1 plus placebo or tucatinib, with PFS as the primary end point and a host of secondary end points, including OS and PFS in patients with brain metastases. [In the tucatinib arm, 43.4%] of patients did have brain metastases and [45.2% had] de novo metastatic disease. The median number of prior lines of therapy was 1, so this was not an especially heavily pretreated population. This [regimen] was primarily [evaluated] in the second-line metastatic setting.

We did see a modest improvement in PFS of 9.5 months vs 7.4 months [with placebo], which was statistically significant with a hazard ratio of 0.76 [95% CI, 0.61-0.95; P = .0163]. Additionally, this very similar PFS was seen in patients with brain metastases, at 7.8 vs 5.7 [months, respectively]. [This shows a] shorter PFS in the placebo group of that arm, but somewhat similar survival [outcomes] in patients with and without brain metastases [with tucatinib].OS [data were] immature, but it’s so far favoring the tucatinib arm. The median OS was not yet reached [in the tucatinib arm] and was 38 months for patients in the placebo arm. [These are] promising data [indicating] that tucatinib does seem to be active in combination with other agents.

What other research will help contextualize the use and sequencing of tucatinib-based regimens?

Of course, the landscape of HER2-positive breast cancer is rapidly changing, and by the time the study was completed, the preferred ADC in the second-line setting had changed. Although these are clinically important results, they [may or may not] be immediately actionable in our population. The phase 3 DESTINY-Breast03 trial [NCT03529110] established T-DXd as a vastly more efficacious ADC than T-DM1, so that does seem to be the preferred second-line ADC in metastatic HER2-positive breast cancer.

There is the ongoing phase 2 single-arm HER2CLIMB-04 trial [NCT04539938] of T-DXd plus tucatinib in previously treated metastatic breast cancer. We look forward to the results of that. [We also have] the phase 3 HER2CLIMB-05 trial [NCT05132582], [which is] looking at adding tucatinib to maintenance trastuzumab and pertuzumab [Perjeta] in the first-line setting. These are patients who had initial induction therapy for untreated metastatic breast cancer with a taxane/trastuzumab/pertuzumab and had 6 cycles on average. When they go on to [receive] maintenance trastuzumab and pertuzumab, they are randomly assigned to either receive [additional] tucatinib or placebo. That trial is looking to move tucatinib into the first-line setting. These studies will help inform use of the best place to start using this drug.

How can ongoing or future neoadjuvant studies help address unmet needs and bolster efforts to personalize treatment approaches in early-stage breast cancer?

It’s important to try and harness the power of neoadjuvant studies to identify patients who need appropriate escalation of therapy, as well as identifying patients who need de-escalation of therapy. We know that not all breast cancers are the same, but not even all HER2-positive breast cancers are the same. Innovative studies like the PHERGain study attempt to [leverage these neoadjuvant studies.]

PHERGain used a response-adapted design where patients in the experimental arm were given the least toxic most effective therapy, which is just targeted therapy by itself. We know that in unselected patients, it’s not as good as chemotherapy on average. Multiple assessments [were conducted in the study] using PET scans after 2 cycles as well as response after surgery to try and select the patients who had a fantastic response to trastuzumab and pertuzumab [alone]. In the experimental arm, patients started off receiving just trastuzumab and pertuzumab. If they achieved a great response on [their] PET scans after 2 cycles, they continued to [receive that regimen]; if they didn’t, they went on to SOC chemotherapy plus targeted therapy. If they had a pathologic complete response [pCR], then they were able to achieve a well-established, meaningful end point that is associated with improved survival without the use of chemotherapy, which is groundbreaking. If they didn’t have a pCR, we can still give them chemotherapy.

[The study] showed that patients who were able to avoid chemotherapy, which was about one-third of patients, had just as good a rate of 3-year IDFS as patients who did end up receiving chemotherapy. Although this may not be the preferred standard approach in all patients, and I’m not using this approach in all my patients, it’s an innovative trial design. It’s trials like these that will help us personalize medicine in a way that maximizes effectiveness and minimizes toxicity for these patients.

References

1. Loibl S, Mano M, Untch M, et al. Phase III study of adjuvant ado-trastuzumab emtansine vs trastuzumab for residual invasive HER2-positive early breast cancer after neoadjuvant chemotherapy and HER2-targeted therapy: KATHERINE final IDFS and updated OS analysis. Presented at: 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX. Abstract GS03-12
2. Hurvitz S, Loi S, O’Shaughnessy J, et al. HER2CLIMB-02: randomized, double-blind phase 3 trial of tucatinib and trastuzumab emtansine for previously treated HER2-positive metastatic breast cancer. Presented at: 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, Texas. Abstract GS01-10.