Pembrolizumab and Paclitaxel in HR+/HER2- Breast Cancer with HER2-Enriched or Basal-Like Subtypes

Purpose: Hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) is biologically distinct from early-stage disease, with a higher prevalence of genomically defined non-luminal subtypes, particularly the HER2-enriched (HER2-E) and Basal-like subtypes. These tumors are highly proliferative, less dependent on hormone signaling, and associated with poor outcomes and early resistance to endocrine therapy and CDK4/6 inhibition (CDK4/6i). This biological shift highlights the need for biomarker-driven strategies in the CDK4/6i-resistant setting. Methods: SOLTI-1716 TATEN trial (NCT04251169) is a phase II, single-arm study evaluating the combination of pembrolizumab and paclitaxel in patients with HR+/HER2- mBC classified as HER2-Enriched or Basal-like by PAM50 following progression on CDK4/6i. A total of 126 patients were screened using the PAM50 genomic assay; 20 with HER2-Enriched or Basal-like subtypes were enrolled and received pembrolizumab (200 mg every 3 weeks) and paclitaxel (80 mg/m² weekly). Results: The primary endpoint, overall response rate (ORR), was 61.1% (95% CI: 35.7-82.7), and the clinical benefit rate (CBR) was 94.4% (95% CI: 72.7-99.9). Median progression-free survival (PFS) was 8.1 months (95% CI 5.9-10.4), and median overall survival (OS) was 26.0 months (95% CI 18-NR). Three patients achieved durable responses lasting ≥24 months. Gene expression analyses revealed that high expression of proliferation- and immune-related genes predicted improved ORR and survival, while luminal-related gene expression was associated with lower clinical benefit. Conclusions: These results suggest that chemo-immunotherapy may be an effective strategy in genomically defined non-luminal subtypes of HR+/HER2- mBC following CDK4/6i resistance and highlight the value of molecular subtyping to guide post-endocrine treatment decisions.