Sequencing Therapy for HER2-Positive Metastatic Breast Cancer: Emerging Strategies

Since the initial approval of trastuzumab (Herceptin) in 1998, the armamentarium for HER2-positive (HER2+) metastatic breast cancer has expanded substantially to include lapatinib (Tykerb), pertuzumab (Perjeta), trastuzumab emtansine (T-DM1; Kadcyla), the subcutaneous pertuzumab-trastuzumab fixed-dose combination (Phesgo), tucatinib (Tukysa), and trastuzumab deruxtecan (T-DXd; Enhertu). Most recently, T-DXd in combination with pertuzumab received regulatory consideration in 2025, reflecting a paradigm shift toward earlier use of antibody-drug conjugate (ADC) therapy. During his presentation at the 43rd Annual Miami Breast Cancer Conference® in March 2026, Giuseppe Curigliano, MD, PhD, of the University of Milano and Istituto Europeo di Oncologia in Milan, Italy, discussed the challenges of sequencing with the options currently available.¹

First-Line Treatment: Current Recommendations

Current European Society for Medical Oncology guidelines recommend taxane plus trastuzumab-pertuzumab as the standard first-line regimen for both hormone receptor–positive (HR+) and HR-negative (HR–), HER2+ metastatic breast cancer, followed by trastuzumab-pertuzumab maintenance.² The phase 3 CLEOPATRA trial (NCT00567190) established this approach, demonstrating a statistically significant progression-free survival (PFS) benefit (median 18.5 vs 12.4 months; hazard ratio, 0.62; 95% CI, 0.51-0.75; P < .001) and a meaningful overall survival (OS) advantage (median 57.1 vs 40.8 months; hazard ratio, 0.69; 95% CI, 0.58-0.82) compared with placebo plus trastuzumab and docetaxel after nearly 100 months of follow-up.³

Results from the phase 3 PERUSE single-arm study (NCT01572038) confirmed that the safety and efficacy of pertuzumab plus trastuzumab are maintained regardless of the investigator-selected taxane backbone: docetaxel, paclitaxel, or nab-paclitaxel. The study yielded a median PFS of 20.7 months and a median OS of 65.3 months.⁴

For patients with HR+/HER2+ metastatic breast cancer who were candidates for chemotherapy-free induction, the phase 2 PERTAIN study (NCT01491737) demonstrated that adding pertuzumab to trastuzumab plus an aromatase inhibitor improved PFS (median 20.6 vs 15.8 months; hazard ratio, 0.67; 95% CI, 0.50-0.89; P = .006), but did not have a significant OS benefit.⁵

Second-Line Treatment: T-DXd vs T-DM1

In the second-line setting, T-DXd has supplanted T-DM1 as the preferred therapy following the landmark phase 3 DESTINY-Breast03 (NCT03529110) trial.⁶ At a median follow-up of approximately 28 months, T-DXd demonstrated superior PFS compared with T-DM1 (median 28.8 vs 6.8 months; hazard ratio, 0.33; 95% CI, 0.26-0.43; P < .0001) and a clinically meaningful OS benefit (median 52.6 vs 42.7 months; hazard ratio, 0.73; 95% CI, 0.56-0.94) at a median follow-up of 43 months.⁷ The most clinically relevant adverse event of special interest with T-DXd was interstitial lung disease/pneumonitis, which occurred in 16.7% of patients vs 3.4% with T-DM1. For patients with active brain metastases who are not candidates for immediate local intervention, tucatinib combined with capecitabine and trastuzumab remains an evidence-based alternative.

T-DXd in the First-Line Setting: DESTINY-Breast07 and DESTINY-Breast09

The phase 1b/2 DESTINY-Breast07 trial (NCT04538742) evaluated T-DXd monotherapy (n = 75) and T-DXd plus pertuzumab (T-DXd+P; n = 50) as first-line therapy for HER2+ metastatic breast cancer.⁸ At a median follow-up of approximately 31 to 33 months (data cutoff: August 2024), confirmed objective response rates (ORR) were 77.3% and 84.0%, respectively, with median PFS not yet reached. PFS rates at 12 and 18 months were 82.6% and 78.2% for T-DXd monotherapy and 87.5% and 78.8% for T-DXd+P. Efficacy was consistent regardless of stromal tumor-infiltrating lymphocyte levels, and the safety profile was consistent with prior experience for each agent.

These encouraging data provided the rationale for the phase 3 DESTINY-Breast09 (NCT04784715) trial, which randomly assigned 1157 patients with treatment-naive HER2+ metastatic breast cancer 1:1:1 to T-DXd plus placebo, T-DXd+P, or the standard taxane plus trastuzumab-pertuzumab (THP) regimen.⁹ At the prespecified interim analysis (data cutoff: February 2025), T-DXd+P demonstrated a statistically significant and clinically meaningful improvement in PFS by blinded independent central review compared with THP (median 40.7 vs 26.9 months; hazard ratio, 0.56; 95% CI, 0.44-0.71; P < .00001). A consistent PFS benefit was observed across all prespecified subgroups, including de novo vs recurrent disease, HR+ vs HR– status, and PIK3CA-mutated vs wild-type tumors. Complete response rates were substantially higher with T-DXd+P (13.7%-16.5%) than with THP (4.1%-10.7%) across all subgroups, and the median duration of response with T-DXd+P approached 3 years. Early OS data showed a positive trend favoring T-DXd+P (hazard ratio, 0.60 for time to second progression [PFS2]), and the safety profile was consistent with the known profiles of each agent.¹⁰

Maintenance Therapy Strategies: PATINA and HER2CLIMB-05

Beyond induction strategies, several trials are redefining first-line maintenance. The phase 3 PATINA trial (NCT02947685) evaluated the addition of palbociclib (Ibrance) to anti-HER2 therapy plus endocrine therapy as maintenance for HR+/HER2+ metastatic breast cancer following induction chemotherapy. With a median follow-up of 53.5 months, palbociclib extended investigator-assessed PFS (median 44.3 vs 29.1 months; hazard ratio, 0.74; 95% CI, 0.58-0.94; 1-sided P = .011).¹¹ Although not yet approved by the European Medicines Agency for this indication, these findings support further evaluation of CDK4/6 inhibition in the HER2+ context.

The phase 3 HER2CLIMB-05 trial (NCT05132582) randomly assigned 654 patients who had not progressed after THP induction to tucatinib or placebo, each combined with trastuzumab and pertuzumab.¹² The addition of tucatinib extended investigator-assessed PFS to 24.9 months compared with 16.3 months for placebo plus HP (hazard ratio, 0.641; 95% CI, 0.514-0.799; P < .0001), with a numerical OS trend favoring tucatinib (hazard ratio, 0.539; 95% CI, 0.303-0.957). Notable adverse events in the tucatinib arm included hepatic events (grade ≥3, 15.3%) and diarrhea (any grade, 72.7%), with hepatic toxicity leading to treatment discontinuation in 7.7% of patients.

Additional ongoing maintenance studies include phase 3 heredERA (NCT05296798; giredestrant plus pertuzumab-trastuzumab in estrogen receptor–positive/HER2+ metastatic breast cancer), phase 3 INAVO122 (NCT05894239; inavolisib [Itovebi] plus pertuzumab-trastuzumab in PIK3CA-mutated tumors), and phase 2 DEMETHER (NCT06172127; T-DXd induction followed by pertuzumab-trastuzumab subcutaneous maintenance), each targeting distinct biological subsets and collectively aiming to individualize maintenance therapy.

The Case for Treatment Sequencing Trials With ADCs

As ADCs move into earlier lines of therapy, the design of rigorous sequencing trials becomes increasingly important. Sequencing decisions are not clinically neutral: ADCs share overlapping targets (HER2, TROP2, HER3), payloads (topoisomerase I inhibitors), and toxicity profiles, making the sequencing order biologically consequential. Cross-resistance, cumulative toxicity, and high real-world attrition rates—estimated below 5% for the shift from first-line to subsequent therapy in HER2+ metastatic breast cancer—must be incorporated into trial designs.

A true sequence trial must be distinguished from a standard first-line superiority study. Sequence-type trials require prespecified decision rules for treatment switching, a primary or key secondary end point capturing outcomes beyond first progression (such as PFS2 or OS), protocol-governed access to second-line therapy, and formal assessment of cumulative toxicity and patient-reported outcomes. The phase 3 SONIA trial (NCT03425838) in HR+/HER2– metastatic breast cancer provides an illustrative archetype: Using a treatment-strategy estimand with PFS2 as the primary end point, it demonstrated noninferiority of deferred vs upfront CDK4/6 inhibition, informing sequencing practice without moving to a superior first-line agent.¹³

For HER2+ metastatic breast cancer specifically, the most clinically meaningful sequencing question may not be ADC vs ADC but rather upfront ADC vs chemotherapy-first followed by ADC, a strategy that may spare patients from early ADC-related toxicities while preserving second-line efficacy. Researchers should also prioritize studies designed to understand and overcome resistance mechanisms following prior ADC exposure, as post-ADC PFS with a subsequent ADC is typically limited to 2 to 3 months in unselected populations.

Conclusions

The HER2+ metastatic breast cancer landscape is at an inflection point. T-DXd+P demonstrated superior PFS over the established THP standard in the DESTINY-Breast09 trial, positioning ADC-based regimens as a potential new first-line standard. Alongside this, novel maintenance strategies with tucatinib, palbociclib, and selective estrogen receptor degraders are expanding options for disease control following induction chemotherapy. As these treatments are integrated into clinical practice, Curigliano urged the oncology community to invest in rigorously designed sequencing and strategy trials, guided by robust estimands, protocol-governed postprogression management, and biomarker-driven patient selection, to ensure that advances in first-line efficacy translate into meaningful, durable benefit across the full treatment continuum.

DISCLOSURES: Curigliano reports serving as a board member for Ellipses Pharma; serving as a consultant for Lilly, Novartis, Roche-Genentech, and Seattle Genetics; receiving research grants to his institution from AstraZeneca and MSD; and participating in speakers’ bureaus for Celltrion, Lilly, Novartis, Pfizer, Roche-Genentech, and Samsung. No stock ownership was reported.

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