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Mridula George, MD, discusses the variety of innovative HER2-positive breast cancer treatment options that have recently been approved or are undergoing investigation in clinical trials to broaden the standards of care for patients in this subgroup.
The regulatory approvals of fam-trastuzumab deruxtecan-nxki (Enhertu), tucatinib (Tukysa), and margetuximab-cmkb (Margenza), have altered the treatment paradigm for patients with HER2-positive breast cancer. As clinical trials continue to evaluate uses for these and other novel therapies, the question of finding the optimal sequencing approach has remained at the forefront of discussion, according to Mridula George, MD.
The phase 3 CLEOPATRA study (NCT00567190) and phase 3 EMILIA study (NCT00829166) set taxane-based chemotherapy with dual anti-HER2 therapy and ado-trastuzumab emtansine (Kadcyla; T-DM1), respectively, as current standards of care for patients with HER2-positive breast cancer, George said. However, new data from DESTINY-Breast03 (NCT03529110), the first global phase 3 study to compare trastuzumab deruxtecan with T-DM1, presented another efficacious therapy for patients in the second-line setting, George explained.
Furthermore, to better understand the potential role of combination trastuzumab (Herceptin) and pertuzumab (Perjeta) with or without tucatinib, the phase 3 HER2CLIMB-05 trial (NCT05132582), is investigating the triplet as a potential frontline strategy in HER2-positive breast cancer.
“A lot of change is happening, especially in the HER2-positive space,” George said, “It's very important to be aware of the new drugs, new drug approvals, and the changing indications for these drugs. We just must keep our eyes and ears open. These drugs are changing the outcomes in [the HER2-positive] disease population, and our patients are doing much better compared with even 5 or 10 years ago.
In an interview with OncLive®, George, medical oncologist, Stacy Goldstein Breast Cancer Center at Rutgers Cancer Institute of New Jersey, discussed the variety of innovative HER2-positive breast cancer treatment options that have recently been approved or are undergoing investigation in clinical trials to broaden the standards of care for patients in this subgroup.
George: There have been a lot of new drug approvals, especially in the last 3 years. HER2-positive breast cancer is one of the aggressive subtypes of breast cancer, and patients have poor survival [outcomes].
However, with the approval of trastuzumab, this has significantly changed treatment outcomes in patients with HER2-positive breast cancer. Previously, this subgroup of patients did worse than patients with metastatic triple-negative breast cancer in terms of survival. However, with the new drugs that are available, this has changed.
Since the approval of trastuzumab, there have been a slew of other new HER2-targeted therapies that have been approved, [including] antibody-drug conjugates and TKIs. In the first-line setting, based on the data from the CLEOPATRA study, the current standard is taxane-based chemotherapy with dual anti-HER2 therapy, [which is] routinely trastuzumab and pertuzumab after patients get at least 6 to 8 cycles of taxane. [CLEOPATRA] showed an improvement in progression-free survival [PFS] and overall survival [OS] of 57.1 months [with pertuzumab plus trastuzumab and docetaxel, vs 40.8 months with placebo plus trastuzumab and docetaxel].
In the second-line setting, the current standard of care is ado-trastuzumab [emtansine]. However, that will soon change based on the new data from DESTINY-Breast03 [and trastuzumab deruxtecan], which was recently presented at the 2021 ESMO Congress.
Trastuzumab deruxtecan was first approved by the FDA in 2019, based on the single-arm phase 2 study DESTINY-Breast01 [NCT03248492]. That study showed that patients who were heavily treated [with] at least 2 prior lines of chemotherapy had significant benefit with this agent.
DESTINY-Breast03 was the first global phase 3 head-to-head study, which compared trastuzumab deruxtecan with T-DM1. Patients got trastuzumab deruxtecan at 5.4 mg/kg, given every 3 weeks, or T-DM1 at 3.6 mg/kg every 3 weeks. The primary outcome was PFS assessed by blinded and independent review.
[Initial data showed] that at a median follow-up of 16 months, the median PFS by independent review] with trastuzumab deruxtecan was not reached. However, it was 6.8 months with T-DM1. By investigator review, the median PFS was about 25.1 months with trastuzumab deruxtecan, compared with 7.2 months with T-DM1.
There was a benefit seen across all subtypes, including patients with brain metastases. Patients with brain metastases could enroll in the study as long as there was a 2-week washout period from the completion of radiation. In those with brain metastases, the median PFS with trastuzumab deruxtecanwas 15 months compared with 3 months with T-DM1. The intracranial objective response was 33.4% with T-DM1 and 63.9% with trastuzumab deruxtecan. the complete response (CR) rate in the brain was 27.8% with trastuzumab deruxtecan compared with 2.8% in T-DM1.
T-DM1 has been the standard of care since the EMILIA study, after which it was approved in the second-line setting. Patients tolerated [T-DM1] well. But now, with the significant clinical benefit that we are seeing in [DESTINY-Breast03], trastuzumab deruxtecan is most likely going to replace T-DM1 in this setting. Especially in patients who have brain metastases, this would be a big benefit because trastuzumab deruxtecan is superior to T-DM1 in patients with brain metastases.
Then, an important question comes up: what is the role for T-DM1 in this space? Do we use T-DM1 in [the] third-line setting? We have other agents in the third-line setting. Tucatinib [Tukysa] is also approved in the second-line setting for patients with brain metastases. How to sequence these drugs [is going to be an interesting question for providers].
A very important study is the phase 3 DESTINY-Breast04 trial [NCT03734029], which showed there was benefit in the HER2-low subgroup. Right now, there is no treatment for the HER2-low subgroup. It’s not even characterized as a separate subgroup. However, with the data that we are seeing with trastuzumab deruxtecan, specifically in DESTINY-Breast04, we are going to focus on this subgroup, and it will be interesting to see how trastuzumab deruxtecanor any of the other anti–HER2-targeted therapies will show efficacy in this space.
The DESTINY-Breast04 study did meet its primary end point, which was PFS, [along with] secondary end points, such as OS in the hormone receptor–positive subgroup of patients.
Some interesting combinations [to explore] would be CDK4/6 inhibitors with trastuzumab deruxtecan. We will have to do a phase 1 study to see how the tolerability of this combination is going to be with hormonal therapy. There are a lot more interesting trials that will be coming out, looking at different combinations in this new subtype of breast cancer, the HER2-low tumors.
What's exciting is the number of new drugs that are getting approved. [In] 2019, we had trastuzumab deruxtecan and tucatinib. Margetuximab was approved [in 2020]. A lot of new drugs are being approved, and they're approved in the later settings in patients who are heavily pretreated, but they're moving up to frontline settings, so it will be interesting to see how that changes [the treatment paradigm].
Right now in the first-line setting, we are [incorporating] taxane. Is there a subgroup of patients [where] we could eliminate the use of [frontline] taxanes? There is taxane-based neuropathy associated with them. [There are] long-term [adverse effects], and it affects the quality of life for our patients.
It will be interesting to see if there is a subgroup where we could eliminate the taxanes. Can we add drugs like trastuzumab deruxtecan in the first-line setting, and also drugs like tucatinib? Since both tucatinib and trastuzumab deruxtecan have CNS penetration, does that delay the onset of CNS metastases, or does that completely eliminate it? Can we use that as a prophylaxis? We know that HER2-positive breast cancers have a high incidence of CNS metastases.
We currently have HER2CLIMB-05 ongoing, and is open at Rutgers, looking at the combination of trastuzumab and pertuzumab with or without tucatinib. Patients are treated with tucatinib in the first-line setting. It will be interesting to see what that shows.
Another important study that we'll be opening soon is cellular therapy. CAR T-cell therapy is being used in hematologic malignancies. We're trying to use adoptive T-cell therapy in patients with metastatic HER2-positive breast cancer. That's another emerging arena of treatment.
A lot of change is happening, especially in the HER2-positive space. It’s important to be aware of the new drug approvals and the changing indications for these drugs. We just have to keep our eyes and ears open. These drugs are changing the outcomes in [the HER2-positive] disease population, and our patients are doing much better compared to even 5 or 10 years ago.