3 Things You Should Know About Frontline and Maintenance Therapy for HER2+ Metastatic Breast Cancer

Release Date: May 6, 2026

Expiration Date: May 6, 2027

Learning Objectives

Upon successful completion of this activity, you should be better prepared to:

• Assess emerging clinical evidence supporting current and novel treatment strategies in the frontline setting for HER2+ metastatic breast cancer
• Develop individually tailored induction and maintenance regimens based on patient and disease characteristics

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Physicians’ Education Resource®, LLC, is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Physicians’ Education Resource®, LLC, designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Acknowledgment of Commercial Support

This activity is supported by an educational grant from Pfizer, Inc.

Off-Label Disclosure/Disclaimer

This activity may or may not discuss investigational, unapproved, or off-label use of drugs. Learners are advised to consult prescribing information for any products discussed. The information provided in this activity is for accredited continuing education purposes only and is not meant to substitute for the independent clinical judgment of a health care professional relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER® or any company that provided commercial support for this activity.

How to Receive Credit

1. Read this activity in its entirety.
2. Go to https://www.gotoper.com/mbcc26her2maintenance-postref to access and complete the posttest.
3. Answer the evaluation questions.
4. Request credit using the drop-down menu.

You may immediately download your certificate.

Activity

HER2-positive (HER2+) metastatic breast cancer (MBC) is a fertile area for research and development, with 2 key new HER2-directed therapies introduced in recent years: antibody-drug conjugate trastuzumab deruxtecan (T-DXd) and tyrosine kinase inhibitor tucatinib. These agents have demonstrated efficacy initially in previously treated disease, and they are now moving into the frontline setting. Similarly, agents that have established themselves for HER2-negative disease, such as the CDK4/6 inhibitor palbociclib, are also moving into HER2+ MBC. Here are 3 things you should know about evolving paradigms in the frontline management of HER2+ MBC.

1. The DESTINY-Breast09 regimen beats the CLEOPATRA standard as first-line therapy for HER2+ MBC.

For more than a decade, a taxane backbone coupled with trastuzumab and pertuzumab (THP) has been the preferred first-line standard of care for most patients with HER2+ MBC, based on the pivotal phase 3 CLEOPATRA study (NCT00567190), which demonstrated both a progression-free survival (PFS) and an overall survival (OS) advantage for combined HER2 targeting vs trastuzumab only.^1,2 However, that standard has now been challenged by recently published data from the phase 3 DESTINY-Breast09 trial (NCT04784715).³

DESTINY-Breast09 enrolled 1157 patients with HER2+ MBC who had not received prior systemic cytotoxic therapy for metastatic disease (1 prior line of endocrine therapy [ET] was allowed).³ Patients were randomly assigned to treatment with T-DXd plus pertuzumab; T-DXd plus placebo; or THP. Only results from an interim analysis of the T-DXd plus pertuzumab vs the THP arms have been reported to date.

Median PFS was significantly longer with T-DXd plus pertuzumab than in the control arm (40.7 vs 26.9 months; hazard ratio, 0.56; 95% CI, 0.44-0.71; P < .00001), as seen in Table 1.³ Benefits were similar across preplanned subgroups, including hormone receptor status, PIK3CA mutation status, brain metastases at baseline, and prior exposure to anti-HER2 therapies. The hazard ratio was 0.49 (95% CI, 0.35-0.70) for patients with de novo HER2+MBC, and 0.63 (95% CI, 0.46-0.87) for those with recurrent disease, demonstrating a clinically meaningful benefit in both subsets. PFS after the next subsequent line of therapy was also significantly higher in the experimental arm (median not reached vs 36.5 months; hazard ratio, 0.60; 95% CI, 0.45-0.79; P = .00038). Overall response rates (ORRs) also favored the T-DXd plus pertuzumab arm (85.1%) vs 78.6% in the THP arm, with 73.3% and 54.9% in response at 24 months, respectively.

The most common grade 3 or higher treatment-related adverse events (TRAEs) were neutropenia (23.9%), hypokalemia (10.2%), and anemia (8.4%) with T-DXd plus pertuzumab.³ With THP, they were neutropenia (33.2%), leukopenia (17.5%), and diarrhea (5.2%). Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 12.1% of patients receiving T-DXd plus pertuzumab (all grade 1 or 2, with the exception of 2 grade 5 events) and in 1.0% of those receiving THP (all grade 1 or 2). Left ventricular dysfunction occurred in 11.0% of patients in the T-DXd plus pertuzumab arm (1.8%, grade 3; 0.3%, grade 4), compared with 7.1% in the control arm (1.8%, grade 3; no grade 4 events).

2. Inclusion of a CDK4/6 inhibitor to maintenance ET plus anti-HER2–targeted therapy improves outcomes in hormone receptor–positive (HR+)/HER2+ MBC.

Based on the significant improvement in outcomes seen with the addition of CDK4/6 inhibitors to ET for patients with HR+/HER2-negative MBC, the phase 3 PATINA trial (NCT02947685) was designed to test whether adding a CDK4/6 inhibitor to maintenance therapy with ET + trastuzumab and pertuzumab (HP) would similarly benefit patients with HR+/HER2+MBC.⁴

A total of 518 patients with HR+/HER2+MBC who did not have disease progression after 4-8 cycles of chemotherapy plus HER2-targeted therapy were randomly assigned to receive maintenance therapy with either ET + plus HER2-targeted therapy alone or in combination with palbociclib.⁴ Median PFS was significantly improved with palbociclib compared with control (44.3 vs 29.1 months; hazard ratio, 0.75; 95% CI, 0.59- 0.96; P = .02). Grade 3/4 neutropenia occurred in 10.0% of patients in the palbociclib arm vs 3.6% in the control arm.

A prespecified secondary analysis was conducted to evaluate the incidence and timing of central nervous system (CNS) progression, although baseline CNS imaging was not mandated.⁵ In the intent-to-treat population, CNS progression occurred in 13.4% of patients in the palbociclib arm and 19.5% of patients in the control arm. When the 20 patients with CNS metastases at baseline were excluded, the cumulative risk of CNS progression or death was 13.0% vs 19.2% at 36 months for palbociclib vs control (P=.0378), suggesting palbociclib may help to prevent or delay the development of CNS metastases in this setting (Table 2).

3. HER2CLIMB05 demonstrates the benefit of a HER2-directed tyrosine kinase inhibitor-based maintenance approach.

The phase 3 HER2CLIMB05 (NCT05132582) trial enrolled 654 patients with HER2+ MBC without evidence of progression following 4 to 8 cycles of induction therapy with THP.⁶ Eligibility criteria also required patients to have no or asymptomatic brain metastases at baseline, confirmed by MRI. Patients were randomly assigned to maintenance therapy with HP plus either tucatinib or placebo.

The inclusion of tucatinib in the maintenance regimen significantly increased median PFS vs HP alone (24.9 vs 16.3 months; hazard ratio, 0.641; 95% CI, 0.514-.799; P < .0001).⁶ Although benefit was observed regardless of HR status, magnitude appeared greater in the HR-negative subpopulation (hazard ratio, 0.554; 95% CI, 0.403-0.761; P = .0002) than in the HR+ subset (hazard ratio, 0.725; 95% CI, 0.535-0.983; P = .0389). The most common TRAEs (any grade) in the tucatinib arm were diarrhea (72.7%; grade ≥ 3, 6.1% ), nausea (33.1%; grade ≥ 3, 0.9%), and elevated liver enzymes (alanine aminotransferase: 28.2%; grade ≥ 3, 13.5%; and aspartate aminotransferase: 25.8%; grade ≥ 3, 7.1%). OS data were immature at this analysis.

Key References

3.Tolaney SM, Jiang Z, Zhang Q, et al. Trastuzumab deruxtecan plus pertuzumab for HER2-positive metastatic breast cancer. N Engl J Med. 2026;394(6):551-562. doi:10.1056/NEJMoa2508668.

4.Metzger O, Mandrekar S, Goel S, et al. Palbociclib for hormone-receptor-positive, HER2-positive advanced breast cancer. N Engl J Med. 2026;394(5):451-462. doi:10.1056/NEJMoa2511218.

6.Dieras V, Curigliano G, Martin M, et al. HER2CLIMB-05: a phase III study of tucatinib versus placebo in combination with trastuzumab and pertuzumab as first-line maintenance therapy for HER2+ metastatic breast cancer. J Clin Oncol. Published online December 10, 2025. doi:10.1200/JCO-25-02600

For a full list of references, go to https://www.gotoper.com/mbcc26her2maintenance-postref

CME POSTTEST QUESTIONS

A 46-year-old woman was diagnosed with hormone receptor–positive (HR+)/HER2-positive (HER2+) de novo metastatic breast cancer. Assuming availability and regulatory approval, which of the following options would you recommend for first-line therapy to optimize progression-free survival?

1. Taxane plustrastuzumab pluspertuzumab
2. Trastuzumab deruxtecan (T-DXd)
3. T-DXd pluspertuzumab
4. Ado-trastuzumab emtansine (T-DM1)
5. T-DM1 pluspertuzumab

A 55-year-old postmenopausal woman with HR+/HER2+ metastatic breast cancer has completed 6 cycles of trastuzumab and pertuzumab induction with a partial response. She would like to transition to maintenance therapy. Which of the following maintenance strategies is most appropriate for this patient?

1. Endocrine therapy (ET) plus palbociclib alone
2. Trastuzumab plus pertuzumab continuation alone
3. Trastuzumab plus pertuzumab plus ET
4. Trastuzumab plus pertuzumab plus ET plus palbociclib

A 51-year-old woman with HER2+ metastatic breast cancer has completed 6 cycles of docetaxel, trastuzumab, and pertuzumab with a confirmed partial response. She is transitioning to maintenance therapy. Based on phase 3 evidence, which of the following maintenance regimens has demonstrated superior progression-free survival compared with trastuzumab plus pertuzumab alone?

1. Neratinib plus trastuzumab
2. Trastuzumab emtansine
3. Trastuzumab deruxtecan
4. Tucatinib plus trastuzumab plus capecitabine
5. Tucatinib plus trastuzumab plus pertuzumab

Claim Your CME Credit at: https://www.gotoper.com/mbcc26her2maintenance-postref

To learn more about this topic, including information on the frontline management of HER2+ MBC, including perspectives from experts on how they are integrating these new data into their practices, go to https://www.gotoper.com/mbcc26her2maintenance-activity

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