Recent developments in HER2-targeted therapy for patients with HER2-positive metastatic breast cancer: insights from the latest DESTINY-Breast12 trial results

About 15–20% of all patients with breast cancer have an intratumoral amplification of the v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2) gene. This amplification leads to overexpression of the human epidermal growth factor receptor 2 (HER2) protein, which accelerates tumor growth, increases aggressiveness, and predisposes the cancer cells to metastasize, particularly to the brain (1).

Metastatic breast cancer in the central nervous system (CNS) has the poorest prognosis among patients with breast cancer.

In fact, between 30% and 50% of patients with HER2-positive metastatic breast cancer will develop brain metastases in the course of their disease (2,3).

Over the past 15–20 years, significant progress has been made in the development of HER2-targeted therapies, which have shown promising improvements in progression-free survival (PFS) and overall survival (OS) for patients with metastatic HER2-positive breast cancer.

A common challenge in managing HER2-positive metastatic breast cancer is the emergence of CNS metastases, despite stable systemic disease during antibody maintenance therapy. Treatment guidelines typically recommend surgical resection followed by radiotherapy for solitary CNS lesions. For a limited number of metastases, stereotactic radiotherapy is often used, while whole-brain radiotherapy is indicated for more widespread CNS involvement (4). These approaches aim to extend the effectiveness of ongoing systemic therapies.

Tyrosine kinase inhibitors targeting HER2 and epidermal growth factor receptor (EGFR), such as lapatinib, pirotinib or neratinib have been investigated in patients with CNS metastasis of HER2 positive breast cancer.

Lapatinib has demonstrated evidence of CNS penetration, as detected after radioactive labeling through positron emission tomography-computer tomography (PET-CT) scan analysis (5). However, as a single agent, lapatinib did not show a significant response rate into the brain (6,7). A better effect was observed when capecitabine was added to lapatinib in the phase II LANDSCAPE trial, which involved patients with HER2-amplified metastatic breast cancer and untreated brain metastases, showing a 65.9% rate of partial response in the brain. However, with a PFS of 5.5 months and no influence on OS, the treatment is not considered clinically useful (8).

Pirotinib (9) demonstrated promising results in the Phase 2 PERMEATE trial, when combined with capecitabine, in a cohort of patients without prior radiotherapy. The treatment yielded a PFS of 10.9 months. Notably, the trial included only patients with measurable CNS metastases.

Neratinib was evaluated in combination with capecitabine in the Phase 2 TBCRC 022 trial (10), and further tested in a Phase 3 study comparing it to lapatinib plus capecitabine (11). In the Phase 3 trial, both tyrosine kinase inhibitors demonstrated similar PFS and OS outcomes in patients with CNS metastases. In the group of patients receiving the combination therapy with lapatinib, a higher proportion of interventions due to CNS progression was observed, along with a shorter duration of response. However, these differences were not statistically significant.

Another tyrosine kinase inhibitor selective for HER2 is tucatinib. In the dose escalation trial (12) tucatinib was combined with trastuzumab and capecitabine in patients with HER2-positive metastatic breast cancer. In the trial patients with brain metastasis could be included. Preliminary activity of the drug was seen in this subgroup of patients resulting in a partial response or stable disease.

Motivated by these results, the phase III HER2CLIMB trial was developed, including up to 48% of patients with brain metastases. The trial explored the efficacy of HER2-targeted therapy in patients with metastatic HER2-positive (HER2 3⁺ by immunohistochemistry or ERBB2 gene amplification by in situ hybridization) breast cancer and active (untreated or treated and now progressing) or stable brain metastases (13). Patients were treated with capecitabine, a drug known to penetrate brain metastases (14), combined with trastuzumab and tucatinib or placebo after failure of prior treatment with trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1).

HER2CLIMB was the first randomized study to include patients with untreated or relapsing brain metastases prior to surgery or radiotherapy. The 2:1 randomized phase 3 trial demonstrated a significantly better intracranial response in the experimental vs. the comparator arm (47.3% vs. 20%) with trastuzumab and capecitabine as well as an improvement in OS (21.9 vs. 17.4 months) in the group of patients treated with the triple combination (tucatinib, trastuzumab, and capecitabine) (15). Among patients with brain metastases, the one-year PFS rate was 24.9% in those treated with the tucatinib combination, whereas all patients receiving trastuzumab and capecitabine alone experienced disease progression within one year.

We are now in the era of antibody-drug conjugates (ADCs). These antibodies target a specific molecule on the cell surface and locally release their cytotoxic payload. In the case of HER2-positive metastatic breast cancer, the first developed ADC commonly used by oncologists is T-DM1. T-DM1 targets the HER2 protein and is linked to the microtubule disrupting agent emtansine.

Since the publication of the phase 2 trial DESTINY-Breast01 (16) a new ADC has been introduced into everyday clinical practice in many countries: trastuzumab deruxtecan (T-DXd).

T-DXd targets HER2 with the monoclonal antibody trastuzumab. The antibody is linked via a cleavable tetrapeptide to a topoisomerase I inhibitor (the so-called payload) deruxtecan (17).

After the dose escalation trial, T-DXd was tested within the DESTINY-Breast01 in patients with HER2-positive metastatic breast cancer. In this trial, 24 patients with stable or treated brain metastases were included. The group of these patients showed similar PFS of 18.1 months compared to the patients without brain metastasis, who had a PFS of 16.4 months (16).

In the DESTINY-Breast03 multicenter phase 3 trial T-DXd challenged T-DM1 in second line in the metastatic setting after therapy with trastuzumab and pertuzumab demonstrating a clinically relevant better PFS and OS benefits in favor of T-DXd (18).

In the DESTINY-Breast03 trial 62 patients with clinically stable asymptomatic and/or treated and stable brain metastasis were included in the T-DXd group as also 52 in the TDM1 group. Although usually patients with CNS metastasis respond poorly to systemic treatment, here there was no difference in time to progression nor in PFS.

In 2022, the small TUXEDO1 phase II trial evaluated 15 patients with metastatic HER2-positive breast cancer and newly diagnosed or progressing brain metastases either after radiotherapy or newly identified but not requiring immediate treatment (19). T-DXd demonstrated an intracranial response in the majority of patients (11/15) and a PFS of 21 months.

Building on the proven efficacy of T-DXd as a systemic treatment in patients previously treated with trastuzumab and pertuzumab, the DESTINY-Breast12 phase 3b/4 trial was designed to assess the safety and efficacy of T-DXd in patients with HER2-positive metastatic breast cancer. The trial consisted of two cohorts: one with, the other without brain metastases. Notably, the cohort with brain metastases included both stable (60%) and active (40%) brain metastases, comprising a total of 263 patients.

At 12 months, the PFS in patients with active brain metastases treated with T-DXd was 59.6%, while those with stable brain metastases had a PFS of 62.9%. The overall response rate (ORR) was approximately 50%, and a CNS-specific response rate was evaluated in 52% of patients with measurable disease. Most patients showed an intracranial tumor response within 6 months of starting therapy (20).

The group without brain metastases showed similar results to the active metastasis cohort. The ORR was 62.7%, with most responses occurring within the first 6 months of treatment, and 72.1% of patients had no progression after 12 months on T-DXd (20).

Interestingly, patients with brain metastases responded similarly to those who had previously received radiotherapy as compared to patients without CNS metastases. In a relatively short 2-year period, there was no significant difference in OS between patients with CNS metastases and those without.

The efficacy of T-DXd has been well-established, but its impact on patients with brain metastases is proving to open a new treatment aera in the field.

In both patient groups, a decrease in left ventricular ejection fraction was observed in approximately 11% of cases. The known side-effect of inflammatory lung disease (ILD) occurred in 16% of patients with brain metastasis and 12.9% of those without. ILD proved fatal in 2.7% of participants.

The treatment burden for patients with brain metastasis included opportunistic infections in 2.7% of cases, most notably due to Pneumocystis jirovecii. Given these findings, clinicians should be vigilant and consider prophylactic treatment with trimethoprim/sulfamethoxazole three times per week for patients with brain metastasis, particularly those on corticosteroids or who have recently undergone radiotherapy following the initiation of T-DXd. In the DESTINY-Breast12 trial, 11.8% of patients with CNS metastasis discontinued treatment due to adverse events.

T-DXd demonstrated a significant OS benefit in second line therapy within the Destiny Breast03 trial (18). In the most recent analysis after a median follow-up of 41 months, the median PFS was 29 months for T-DXd vs. 7.2 months for TDM1 and median OS was 52.6 vs. 42.7 months in T-DXd and TDM1 groups respectively. T-DXd has now become the preferred standard second-line systemic therapy for patients with HER2-positive metastatic breast cancer.

Before the publication of the DESTINY-Breast12 trial, patients with brain metastasis from HER2-amplified breast cancer were typically treated with a combination of tucatinib, trastuzumab, and capecitabine.

However, a direct comparison between these two regimens (tucatinib, trastuzumab, capecitabine vs. T-DXd) would not be entirely appropriate. The HER2CLIMB trial primarily involved patients who were in the third or later lines of therapy (up to 14 lines). In both the HER2CLIMB and DESTINY-Breast12 trials, the ORR was around 40%. A key difference lies in PFS, which was significantly shorter with tucatinib (9.9 months) compared to T-DXd, where PFS has yet to be reached at the time of analysis.

It would be valuable to conduct a randomized clinical trial comparing head-to-head the HER2CLIMB and the DESTINY-Breast12 regimens.

In the future, perhaps not only patients with amplification of HER2 breast cancer but also HER2-low with brain metastases could have a more favorable outcome with T-DXd. This will be investigated within the DEBBRAH Phase II trial (21) treating patients with brain metastasis and HER2-positive or HER2-low metastatic breast cancer. The recently published small group of 7 patients with leptomeningeal disease (Cohort 5) with a median follow-up of 12 months experienced median PFS of 8.9 months and a median OS of 13.3 months (22). This time is longer than expected. Once leptomeningeal disease due to metastatic breast cancer is diagnosed, the reported median OS is below 6 months (23). Leptomeningeal metastases, which are challenging to treat, remain underrepresented in clinical trials due to their historical exclusion from such studies. Currently, there is a significant gap in evidence regarding the optimal treatment strategies for this condition, which is associated with a poor prognosis. There is an urgent need for more clinical trials involving patients with leptomeningeal disease to address this critical gap in therapeutic knowledge.

Would it be meaningful to introduce T-DXd for patients with locally advanced HER2-positive breast cancer or those who do not achieve complete remission after neoadjuvant immunochemotherapy?

The DESTINY-Breast05 will give the answer to this question comparing TDM1 against T-DXd in patients without complete pathological remission after neo-adjuvant immunchemotherapy.

If the goal is to reduce the incidence of CNS metastasis, the number needed to treat would be very high, as only 2% of patients experience a first relapse exclusively within the CNS (24).

Moreover, the higher toxicity profile of T-DXd, which includes pneumonitis, prolonged nausea and vomiting, and an increased risk of opportunistic infections such as Pneumocystis jirovecii in patients receiving glucocorticosteroids or CNS radiotherapy, must be considered.

An interesting avenue for future research will be the trial comparing T-DXd in the first-line treatment of metastatic HER2-amplified breast cancer to the standard first-line therapy from the CLEOPATRA trial, which involves docetaxel, trastuzumab, and pertuzumab (25). Such a trial could assess whether T-DXd might prevent CNS spread and improve OS compared to the conventional regimen.

An interdisciplinary approach to manage CNS metastatic disease remains key to make best use of our currently available armamentarium. T-DXd is an important contribution to maintain CNS control and to prolong time without whole brain radiation.

Acknowledgments

Professor Stefan Paul Aebi, MD (for the constructive discussion during the writing process).

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-25-24/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-24/coif). B.C. reports receiving payments from Daiichi Sankyo for serving on the advisory board. B.T. reports owning stock in Roche. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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