Irene Morae Kang, MD

The panel addresses one of the field's most pressing practical questions: what to offer after a first-line ADC, acknowledging that no prospective data yet exist to guide the decision.

The panel explores how to assign value to different trial endpoints in an aggressive disease, discussing overall survival as the gold standard while considering how crossover and confounding factors complicate its interpretation, and where PFS2 fits as a measure that reflects benefit across lines of therapy.

With both pivotal trials reviewed, the panel discusses how to reconcile the data when counseling an individual patient.

The panel reviews the TROPION-Breast02 findings, offering equipoise alongside the prior discussion of ASCENT-03.

The panel takes a closer look at ASCENT-03, framing it as a study designed to test whether a TROP2-directed ADC could serve as a first-line alternative to chemotherapy.

The panel turns to the design of two pivotal first-line trials, framing the discussion not as a head-to-head comparison but as a way to inform patient selection in clinic.

The panel addresses one of the more difficult challenges in metastatic TNBC: central nervous system involvement.

The panel discusses the rationale for using effective agents in the first-line metastatic setting rather than reserving them for later lines, considering the disease's aggressive course and limited expected survival alongside the trajectories seen in other breast cancer subtypes.

The panel reviews how the metastatic TNBC treatment paradigm has evolved, tracing TROP2-directed ADCs from later-line use into the first-line setting.

The panel grounds the discussion in the biology and natural history of metastatic triple-negative breast cancer, framing it as a high-proliferation subtype prone to rapid resistance, in which the first-line setting offers an important opportunity to influence outcomes. Panelists outline a biomarker-driven treatment algorithm stratified by PD-L1 status, germline BRCA status, and prior early-stage therapy, touching on immune checkpoint inhibition, PARP inhibitors, platinum-based chemotherapy, and the role of antibody-drug conjugates across lines of therapy.

Drs Nunnery and Kang discuss the rapidly evolving treatment paradigm for first-line metastatic TNBC, including the emergence of novel ADCs.

Dr. Kruse reviews ASCENT-03 and TROPION-Breast02 data for PD-L1-negative or checkpoint inhibitor-ineligible metastatic TNBC, noting unsurprising ADC superiority in first-line treatment.

Dr. Kang describes ASCENT-04 results as logical and practice-changing for PD-L1-positive metastatic TNBC.

Dr. Kruse discusses Dato-DXd placement in hormone receptor-positive, HER2-negative metastatic disease following TROPION-Breast01 results.

Dr. Kruse addresses the complexity introduced by simultaneous release of DESTINY-Breast05 and -11 data, requiring contextualization of both neoadjuvant and adjuvant approaches.

Dr. Kruse describes DESTINY-Breast12 as providing crucial reassuring data regarding T-DXd activity in patients with brain metastases.

Dr. Kruse discusses DESTINY-Breast09 as a transformative study challenging the long-standing CLEOPATRA regimen (docetaxel, trastuzumab, pertuzumab) for first-line HER2-positive metastatic breast cancer.

Dr. Kruse addresses patient selection for TROP2-targeted ADC therapy, noting that TROP2 expression intensity does not correlate with therapeutic efficacy. The current therapeutic landscape includes datopotamab deruxtecan (Dato-DXd) and SG, each with distinct toxicity profiles. Selection decisions involve multifactorial considerations including disease progression patterns, prior progression-free survival (PFS) duration, disease location (visceral versus bone-only), and individual patient preferences regarding treatment scheduling and toxicity management.

Dr. Irene Kang from City of Hope Orange County and Dr. Megan Kruse from Cleveland Clinic introduce this OncLive Insights program reviewing HER2 and TROP2-directed antibody drug conjugates (ADCs) in breast cancer. Dr. Kruse emphasizes that 2025 and 2026 represent a transformative period for ADCs, with expanding utility across all breast cancer subtypes and treatment settings. Previously confined to later-line therapy or HER2-positive disease, ADCs now have indications spanning hormone receptor-positive, HER2-positive, and triple-negative breast cancer (TNBC) across first-line, second-line, and later-line settings, with increasing penetration into early-stage disease.

Irene Morae Kang, MD, discusses key overall survival data from the phase 3 PALOMA-2 and PALOMA-3 trials, which evaluated the addition of palbociclib to standard endocrine therapy for patients with advanced breast cancer.