Abraham J, Montero AJ, Jankowitz RC, et al. - Given that eventually, resistance to dual-antibody therapy with trastuzumab plus pertuzumab develops among patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer, researchers sought to assess whether ado-trastuzumab emtansine (T-DM1) plus neratinib is safe, tolerable, and efficacious in patients who progressed on trastuzumab plus pertuzumab. In this 3 + 3 dose-escalation study, treatment was provided with T-DM1 at 3.6 mg/kg intravenously every 3 weeks and dose-escalating neratinib at 120, 160, 200, or 240 mg/d orally to patients with metastatic breast cancer who progressed on trastuzumab, pertuzumab, and a taxane. Twenty-seven patients received treatment across four dose-levels of neratinib. Six patients experienced grade 3 diarrhea as dose-limiting toxicity in cycle 1 which was manageable with primary antidiarrheal prophylaxis; one patient experienced grade 3 nausea. Based on outcomes, the recommended phase 2 dose (RP2D) of neratinib with full-dose T-DM1 was determined to be 160 mg/d. Across all dose levels, responses were evident. Historical data suggest more activity of the combination of T-DM1 plus neratinib vs either agent alone. Further, results emphasize cell-free DNA (cfDNA) as potentially beneficial in personalizing the selection of cancer treatment and in monitoring response as well as genomic evolution under pressure of therapy (eg, eight of 27 patients had a phosphatidylinositol 3-kinase pathway aberration detected in cfDNA). In addition, findings suggest the therapeutic implications of alterations in the expression of specific HER2 species in ERBB2-amplified cancers, including p95HER2.