The clinical algorithm for HER2+ metastatic breast cancer (MBC) includes a taxane plus trastuzumab and pertuzumab as first-line therapy, with the addition of ado-trastuzumab emtansine (T-DM1) in the second line (2L), according to guidelines from the National Comprehensive Cancer Network and American Society of Clinical Oncology. However, it is unclear what therapy or therapies can be used when these patients progress with conventional 2L therapy. At SABCS, Shanu Modi, MD, reviewed recent clinical data with emerging treatments for HER2+ MBC, including new antibody-drug conjugates (ADCs), novel anti-HER2 antibodies, potent tyrosine kinase inhibitors (TKIs), and promising combination therapies, including immune therapies and CDK 4/6 inhibitors.
Trastuzumab deruxtecan (TD) is a novel ADC composed of 3 components: a humanized anti-HER2 monoclonal antibody, a topoisomerase I inhibitor payload, and a tetrapeptide-based cleavable linker. In the DESTINY-Breast01 phase 2 trial in T-DM1–refractory or –intolerant HER2+ MBC patients, TD demonstrated a 61% confirmed overall response rate (ORR) with a 7% complete response rate, and 97% disease control rate. Median duration of response (DOR) was 14.8 months, with an estimated 86% 1-year overall survival (OS). There are currently 3 phase 3 trials with TD: DESTINY-Breast02 (TD vs investigator’s choice in T-DM1–treated MBC), DESTINY-Breast03 (TD vs T-DM1 in trastuzumab/taxane-treated MBC), and DESTINY-Breast04 (TD vs physician’s choice in HER2-low MBC).
Small molecule TKIs are also being studied. NALA is a phase 3 trial of neratinib plus capecitabine versus lapatinib plus capecitabine in patients with HER2+ MBC with asymptomatic and stable brain metastases. Compared with lapatinib, neratinib demonstrated a 2.2-month benefit in progression-free survival (PFS) and a 1.8-month benefit in OS, with a significantly higher median DOR (8.5 months vs 5.6 months; P = .0004) and a significantly lower cumulative incidence of central nervous system metastases.
Tucatinib is an HER2-selective TKI. The exciting results of the HER2CLIMB study were already reviewed in this publication. Briefly, the combination of tucatinib, trastuzumab, and capecitabine demonstrated a significantly higher median PFS, OS, and ORR than placebo, trastuzumab, and capecitabine in patients with HER2+ MBC with or without brain metastases. Importantly, patients with brain metastases in the tucatinib arm demonstrated a significantly higher PFS than those in the control arm (25% vs 0%). The phase 3 HER2CLIMB-02 study, in which patients will be treated with tucatinib plus T-DM1 versus placebo plus T-DM1, is underway.
Margetuximab is an anti-HER2 monoclonal antibody that has been engineered to have a higher Fc affinity for the activating FCƳ RIIIA (CD16A) receptor and lower affinity for the inhibitory FCƳ RIIIB (CD32B) receptor. The results of the SOPHIA study have also been reported in this publication, and showed a numerical, but not statistically significant, improvement in OS in HER2+ MBC patients treated with margetuximab plus chemotherapy versus trastuzumab plus chemotherapy. Even in those with CD16A, the margetuximab improvement in OS was numerically but not statistically significant.
Other studies were reviewed, including the monarchHER trial (the CD4/6 inhibitor abemaciclib plus trastuzumab vs trastuzumab plus investigator’s choice); the abemaciclib arm showed a significant improvement in ORR, leading to the ongoing phase 2 PATRICIA trial and the phase 3 PATINA trial of CDK4/6 inhibitors.
Finally, the PANACEA trial is a phase 1 trial of pembrolizumab plus trastuzumab in HER2+ MBC, which demonstrated a benefit of the immune checkpoint inhibitor in increasing OS in PD-L1–positive patients. Other studies with immunotherapy are underway.
Dr Modi concluded that the data from these studies suggest potential new lines of therapy in the future after failure of T-DM1, including TD, tucatinib triplet therapy, neratinib plus capecitabine, and margetuximab plus chemotherapy.
Modi S. SABCS 2019. Presentation CS1-2.