Abstract PD13-04: Activity of patritumab deruxtecan, a HER3-directed antibody drug conjugate, in early breast cancer according to ERBB3 expression: Interim analysis results of a window-of-opportunity study (SOLTI-1805 TOT-HER3)

Abstract Introduction Patritumab deruxtecan (U3-1402; HER3-DXd) is a HER3-directed antibody drug conjugate with demonstrated clinically meaningful antitumor activity and acceptable safety profile in heavily pre-treated metastatic breast cancer (BC) with high or low HER3 expression levels (Masuda et al. Cancer Res. 2019; Krop et al. SABCS 2020). Here, we report the interim efficacy and safety data of the TOT-HER3 trial (NCT04610528), the first window-of-opportunity study designed to assess whether a single dose of HER3-DXd may increase immune infiltration during short-term preoperative treatment in early BC. Methods This is a prospective, phase 0, multicenter, single arm trial planned to enroll 80 patients with treatment naïve hormone receptor positive, HER2 negative primary operable BC ≥1 cm by ultrasound. Patients are allocated to one of 4 cohorts based on centrally assessed levels of ERBB3 mRNA by the nCounter platform in a pre-treatment biopsy and receive HER3-DXd administered as a single dose of 6.4 mg/kg. Post-treatment biopsy at C1D21 is obtained to explore primary and correlative endpoints. The primary objective is to evaluate the median change in the CelTIL score (-0.8*tumor cellularity% + 1.3*tumor-infiltrating lymphocytes%) (Nuciforo et al. Ann Oncol. 2018) in paired pre- and post-treatment samples in the overall cohort. Change in CelTIL score and the expression of 67 genes across ERBB3 cohorts and PAM50 subtypes is also explored. Adverse events (AEs) are graded according to CTCAE v 5.0. Results As of April 21 2021, 30 patients (all women) received the study treatment and were evaluable for the primary endpoint. Mean age was 52 years (range 35-77 years); 19 patients were pre- and 11 were post-menopausal. Median tumor size was 20 mm (range 10-60 mm); cN0 70%; mean Ki67 35% (range 10-90%); grade 1-2 67%. According to ERBB3 expression, 6 (20%), 13 (43%), 5 (17%) and 6 (20%) patients were categorized as high, medium, low and ultra-low, respectively. CelTIL score increased, was stable and decreased in 17 (57%), 3 (10%) and 10 (33%) patients, respectively. Overall, a statistically significant increase in CelTIL was observed between paired samples (p=0.028). At C1D21, a total of 12 (44%) patients experienced a response (7 complete and 5 partial response) by clinical palpation. CelTIL significantly changed in responders (p=0.006) but not in patients with stable disease (p=0.61). Baseline ERBB3 levels did not correlate with CelTIL change or clinical response. Moreover, PAM50 subtype distribution was as follows: Luminal A 15 (50%), Luminal B 13 (43%), HER2-Enriched 1 (3.5%), Basal-like 1 (3.5%). CelTIL score did not change significantly between Luminal A and Luminal B tumors. Five (38.5%) Luminal B tumors switched to Luminal A at C1D21. Interestingly, baseline high PAM50 risk-of-recurrence was associated with higher CelTIL score at C1D21 (p=0.002). Patritumab deruxtecan induced high expression of immune-related genes including PD1, CD8a and CD19 and Luminal A signature and suppressed proliferation-related genes. Overall, 29 (97%) patients reported at least one AE and 98% of AEs were grade 1 or 2. The most common AEs were nausea, asthenia, abdominal pain, alopecia, vomiting, diarrhea, neutropenia, increased liver enzymes. A grade 3 treatment-related reversible AST increase occurred in 1 patient. Conclusion In this interim trial analysis, a single dose of patritumab deruxtecan was associated with clinical response and important biological changes irrespective of baseline ERBB3 expression. The safety profile was consistent with that previously reported for the drug. Citation Format: Aleix Prat, Juan M. Cejalvo, Laia Pare, Olga Martínez-Sáez, Mireia Margelí Vila, Claudette Falato, Josefina Cruz, Miriam Arumí de Dios, Maria J Vidal, Juan Antonio Guerra, Ana Maria Luna Barrera, Pablo Tolosa, Francisco Javier Salvador-Bofill, Sonia Pernas, Blanca Gonzáles-Farré, Esther Sanfeliu, Eva Ciruelos, Violeta Serra, Martin Espinosa-Bravo, Yann Izarzugaza, Stephen Esker, Pang-Dian Fan, Guillermo Villacampa, Juan M Ferrero-Cafiero, Tomás Pascual, Mafalda Oliveira. Activity of patritumab deruxtecan, a HER3-directed antibody drug conjugate, in early breast cancer according to ERBB3 expression: Interim analysis results of a window-of-opportunity study (SOLTI-1805 TOT-HER3) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD13-04.