Research Propels Additional Options into the Advanced HER2+ Breast Cancer Armamentarium

Since the initial FDA approval of trastuzumab (Herceptin) in 1998, treatment options for patients with HER2-positive advanced breast cancer have rapidly expanded. Now, the continued emergence of novel agents and clinical trials evaluating drugs such as fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in earlier settings could continue to alter this treatment paradigm, according to Sarah Sammons, MD.

“[In] an incredibly short period of time, we've made such substantial progress,” Sammons stated during a presentation at the 23rd Annual International Congress on the Future of Breast Cancer® East.1 “We still have a long way to go, but we have a lot of options.”

Sammons is the associate director of the Metastatic Breast Cancer Program at Dana-Farber Cancer Institute in Boston, Massachusetts.

Optimizing First-Line Treatment Options

Despite numerous advances in the development of treatments for patients with HER2-positive advanced breast cancer, the standard of care (SOC) in the frontline setting remained consistent, Sammons said.

“The first line has gone unchallenged for over 10 years now, and we're on the precipice of a movement there,” Sammons continued. “The first-line SOC for metastatic HER2-positive disease remains, in 2024, a taxane plus trastuzumab and pertuzumab [Perjeta], based on [data from] the landmark phase 3 CLEOPATRA study [NCT00567190].”

CLEOPATRA evaluated the efficacy and safety of combining pertuzumab, trastuzumab, and docetaxel vs placebo, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer. Initial analyses and subsequent reports demonstrated significant improvements in both progression-free survival (PFS) and overall survival (OS) in patients receiving the pertuzumab regimen compared with those given placebo plus trastuzumab and docetaxel.2

In the end-of-study analysis, the median OS for patients in the pertuzumab arm (n = 402) was 57.1 months (95% CI, 50-72) vs 40.8 months (95% CI, 36-48) for the placebo group (n = 406; HR, 0.69; 95% CI, 0.58-0.82). Additionally, the 8-year landmark OS rates were 37% (95% CI, 31%-42%) for the pertuzumab group vs 23% (95% CI, 19%-28%) for the placebo group.

Beyond on these results, Sammons highlighted the goal of developing maintenance regimens to boost the durability of this first-line regimen. “There are several ongoing clinical trials that are looking at adding targeted therapeutics to that maintenance trastuzumab/pertuzumab,” she stated. These trials include the phase 3 HER2CLIMB-05 (NCT05132582), PATINA (NCT02947685), and INAVO122 (NCT05894239) studies, as well as the phase 2 DEMETHER study (NCT06172127).

Sammons also highlighted the ongoing phase 3 DESTINY-Breast09 trial (NCT04784715), which she said is poised to challenge the current first-line CLEOPATRA regimen. The trial, which has completed accrual, enrolled 1134 patients with advanced or metastatic HER2-positive breast cancer who have not received prior chemotherapy or HER2-targeted therapy for advanced or metastatic disease.

Enrolled patients were randomly assigned 1:1:1 to receive T-DXd plus placebo; T-DXd plus pertuzumab; or SOC trastuzumab plus pertuzumab and docetaxel. The study stratified patients by prior treatment status (de novo vs recurrent), hormone receptor status (positive vs negative), and PIK3CA mutation status (detected vs not detected).

Initial data from DESTINYBreast-09 are anticipated to read out in 2025, and Sammons said this trial has the potential to establish new first-line SOC for patients with HER2-positive metastatic breast cancer.

T-DXd Emerges in the Second Line

The potential for T-DXd to disrupt the SOC in the first-line setting has already been realized in the second-line setting after displacing ado-trastuzumab emtansine (T-DM1; Kadcyla), Sammons continued.

"For almost 10 years, the SOC [in the second line] was T-DM1, and that was based on the results of the [phase 3] EMILIA trial [NCT00829166], which [randomly assigned] patients to lapatinib [Tykerb] plus capecitabine or T-DM1 [alone]; there was an advantage in both PFS and OS with TDM-1 vs lapatinib/capecitabine,” Sammons explained “However, the second-line space is now dominated by T-DXd.”

Both T-DM1 and T-DXd are HER2-targeting antibody-drug conjugates with similar monoclonal antibody backbones. T-DXd employs a topoisomerase I inhibitor as its payload, with a drug-to-antibody ratio of 8:1, and it has a tumor-selective cleavable linker that enables a bystander anti-tumor effect. Contrarily, T-DM1 utilizes an anti-microtubule agent, has a drug-to-antibody ratio of 3.5:1, and lacks both a tumor-selective cleavable linker and evidence of a bystander antitumor effect.

T-DXd is now an established SOC in the second-line setting based on data from the phase 3 DESTINY-Breast03 trial (NCT03529110), which was a multicenter study that enrolled patients with unresectable or metastatic HER2-positive breast cancer who had previously been treated with trastuzumab and a taxane. The study included patients with clinically stable, treated brain metastases, and at least 2 weeks were required between the end of whole brain radiotherapy and study enrollment. Participants were stratified based on hormone receptor status, prior treatment with pertuzumab, and history of visceral disease.

The trial randomly assigned patients in a 1:1 ratio to receive either T-DXd at 5.4 mg/kg once every 3 weeks or T-DM1 at 3.6 mg/kg once every three weeks. The primary end point was PFS with OS serving as a key secondary end point. Additional secondary end points included objective response rate, duration of response, investigator-assessed PFS, and safety.

In data presented at the 2024 ASCO Annual Meeting, T-DXd continued to demonstrate sustained improvement in PFS and OS vs T-DM1 in DESTINY-Breast03, according to updated findings from an exploratory analysis of the trial.³ The median PFS per investigator assessment was 29.0 months (95% CI, 23.7-40.0) with T-DXd (n = 261) vs 7.2 months (95% CI, 6.8-8.3) with T-DM1 (n = 263; HR, 0.30; 95% CI, 0.24-0.38).

"There was not a [subgroup of] patients that did not derive benefits from T-DXd vs T-DM1, [including those who had] prior pertuzumab, visceral disease, number of prior lines of therapy, or brain metastases. All patients derived benefit,” Sammons emphasized.

Sammons also explained that T-DXd has demonstrated intracranial activity in patients with HER2-positive breast cancer across multiple trials, which she notes is important for a patient population associated with a prevalence for developing brain metastases.,

"The intracranial response rate across trials varies somewhere between 45% and 73%, [which] is actually quite striking,” she expanded.

Furthermore, T-DXd has demonstrated improved outcomes in central nervous system (CNS) PFS, according to results from a retrospective, exploratory pooled analysis of patients that had brain metastasis from the phase 2 DESTINY-Breast01 trial (NCT03248492), the phase 3 DESTINY-Breast02 trial (NCT03523585), and the phase 3 DESTINY-Breast03 trial; these data were shared at the 2023 ESMO Annual Congress.⁴

Innovative Approaches and Emerging Therapies in the Third Line and Beyond

"Moving onto the third line and beyond, this is a space where we have more work to do; however, we have several compelling options,” Sammons said.

Regarding SOC within this line of treatment, the most recent and "probably the most common third-line option," according to Sammons, is the phase 3 HER2CLIMB trial (NCT02614794) regimen of tucatinib (Tukysa) plus capecitabine and trastuzumab.

HER2CLIMB evaluated patients with HER2-positive metastatic breast cancer, all of whom had previously received treatment with trastuzumab plus pertuzumab or T-DM1, making this a heavily pretreated population, Sammons said. Notably, the trial also included patients with brain metastases. In HER2CLIMB, patients were randomly assigned 2:1 to receive the triplet therapy or placebo plus capecitabine and trastuzumab.

Among the 612 patients enrolled in the trial, 291 had brain metastases, including 174 patients who had active brain metastases, which was unprecedented for a phase 3 clinical trial, according to Sammons. Despite the heavily pretreated population, the intention-to-treat patients experienced improvements in both PFS and OS with the tucatinib-based regimen. Specifically, the PFS in the tucatinib arm was 7.8 months (95% CI, 7.5-9.6) compared with 5.6 months (95% CI, 4.2-7.1) in the placebo arm (HR, 0.54; 95% CI, 0.42-0.71; P < .001). Additionally, there was a statistically significant improvement in OS (HR, 0.66; 95% CI, 0.50-0.88; P = .005).⁵

“[The HER2CLIMB regimen] is a nice option for patients with either stable or active brain metastases, and it has the highest level of data—phase 3 prospective data—for patients with active brain metastases, which we've never had before,” she stated.

Later, the phase 3 HER2CLIMB-02 trial (NCT03975647) investigated the combination of T-DM1 and tucatinib, and data were shared at the 2023 San Antonio Breast Cancer Symposium. HER2CLIMB-02 was a randomized, double-blind, placebo-controlled study in which patients were randomly assigned in a 1:1 ratio to receive 21-day cycles of tucatinib at 300 mg twice per day or placebo in combination with T-DM1 at 3.6 mg/kg once every 3 weeks.

The addition of T-DM1 significantly improved PFS in patients with previously treated HER2-positive locally advanced or metastatic breast cancer, with a median PFS of 9.5 months (95% CI, 7.4-10.9) with the triplet vs 7.4 months (95% CI, 5.6-8.1) with the placebo (HR, 0.76; 95% CI, 0.61-0.95; P = .0163).⁶

"We do still want OS data. We also await the nitty, gritty intracranial data, intrapreneurial response rates, and CNS PFS, which can help us make decisions for our patients,” Sammons said.

Although neratinib (Nerlynx) could also be considered in the third-line setting for patients with HER2-positive breast cancer, Sammons explained that this agent is “a little challenging to use” due to certain adverse effects (AEs). However, with AE management, neratinib can be an option, and “we need options,” she said.

Combatting Brain Metastases and Understanding the Current SOC

It remains important to understand the issue of brain metastases, Sammons continued, citing an analysis that examined the incidence of brain metastases by line of therapy in HER2-positive metastatic breast cancer. She shared that the incidence of brain metastases increases with the progression through lines of therapy.

Local therapy, although not common, can be considered to address solitary lesions, she said. However, for patients with a small number of brain metastases, stereotactic radiosurgery is preferred to spare them from whole-brain radiation. However, for patients with extensive brain metastases, the treatment approach varies, Sammons said. In the United States, hippocampal-sparing techniques are often used, along with memantine for memory preservation in patients requiring whole-brain radiation.

"The clinical goals of active vs stable brain metastases are a bit different, in my mind. For an active brain metastasis, we really need an intracranial response. We want to try to control the intracranial disease to avoid the morbidity of local therapies like whole brain radiation or repeat stereotactic radiation,” Sammons shared. “Of course, we want to try to improve survival. Therefore, I'm prioritizing agents that have a high intracranial response rate and have a CNS PFS benefit.”

References

1. Sammons S. HER2+ Metastatic breast cancer systemic therapy options. Presented at: 23rd Annual International Congress on the Future of Breast Cancer East; July 19-20, 2024; New York, NY.
2. Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(4):519-530. doi:10.1016/S1470-2045(19)30863-0
3. Hamilton EP, Hurvitz SA, Im SA, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated survival results of DESTINY-Breast03. J Clin Oncol. 2024;42(suppl 16):1025. doi:10.1200/JCO.2024.42.16_suppl.1025
4. Hurvitz SA, Modi S, Li W, et al. A pooled analysis of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-positive (HER2+) metastatic breast cancer (mBC) with brain metastases (BMs) from DESTINY-Breast (DB) -01, -02, and -03. Ann Oncol. 2023;34(suppl 2):S335-S336. doi:10.1016/j.annonc.2023.09.554
5. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609
6. Hurvitz S, Loi S, O’Shaughnessy J, et al. HER2CLIMB-02: Primary analysis of a 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.