LBA3 - Patritumab deruxtecan (HER3-DXd) in early-stage HR+/HER2- breast cancer: final results of the SOLTI TOT-HER3 window of opportunity trial

Background

SOLTI TOT-HER3 study (NCT04610528) previously reported the biologic and clinical activity of HER3-DXd, a HER3 directed antibody drug conjugate, across the first 30 patients (Prat A, SABCS 2021). Here, we present the efficacy and safety results across all patients in the initial study cohort.

Methods

This window of opportunity, multicenter, pre-operative trial enrolled patients with untreated HR+/HER2- operable (≥1 cm) breast cancer (BC). Patients were categorized based on pre-treatment (pre-) ERBB3 mRNA levels and received a single dose of HER3-DXd (6.4 mg/kg). Primary objective was to evaluate the CelTIL score (Nuciforo P, Ann Oncol 2018) variation between pre- and post-treatment (C1D21) samples. Clinical, proteomic and genomic variables were associated with CelTIL changes. Adverse events (AEs) were graded according to CTCAE v5.0.

Results

Overall, 78 patients were enrolled and 77 were evaluable for the primary endpoint. Baseline characteristics were: mean age 53 years; median tumor size 21 mm; cN0 71%; mean Ki67 27%. Based on pre-ERBB3, tumors were classified as high (n=21), medium (n=21), low (n=21) and ultralow (n=14). All PAM50 subtypes were identified: Luminal (Lum) A 52%, LumB 41%, HER2-Enriched 3% and Basal-like 4%. The overall response rate was 45%. CelTIL increased significantly at C1D21 (mean diff.+6.8, p<0.001). This increase was observed among responders (p<0.001) but not in patients with stable disease (p=0.135). Non-Lum subtypes and high Risk Of Recurrence score were associated with high CelTIL response. Pre-ERBB3 was not associated with CelTIL change or clinical response. Paired Ki67 significantly decreased (p<0.001), while ERBB3 mRNA did not (p=0.13). At C1D21, immune genes were induced and proliferation genes were suppressed (False Discovery Rate=5%). Overall, 74 (95%) patients reported any grade AEs. Most common grade 3-4 AEs were: neutropenia (n=6), ALT increase (n=2) and diarrhea (n=1).

Conclusions

In untreated early HR+/HER2- BC, a single dose of HER3-DXd led to clinically meaningful response, increased immune infiltration and suppression of proliferation across varied levels of baseline ERBB3 mRNA. The safety profile was consistent with that previously reported.

Clinical trial identification

NCT04610528, released on October 30th 2020.

Legal entity responsible for the study

SOLTI Cancer Research Group.

Funding

Daiichi Sankyo.

Disclosure

A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Other, Contracted research: Roche, Nanostring, Novartis, Roche, Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Pfizer, Novartis, Amgen, BMS, Nanostring, Contracted research, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Amgen, BMS, Puma, Oncolytics, MSD, Guardant Health, Lilly; Financial Interests, Institutional, Invited Speaker, Lecture fees: Nanostring; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Personal, Expert Testimony, Advisory role/consultancy: Peptomyc; Financial Interests, Institutional, Other, Clinical trials: Lilly, Roche, Amgen, Boehringer; Financial Interests, Institutional, Other, Contracted research: Boehringer, Sysmex Europa GmbH, Medica Scientia inno. Research, Celgene, Astellas; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation. O. Martinez Saez: Financial Interests, Personal, Invited Speaker: Novartis, Eisai; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Other, Travel expenses: Roche. J.M. Cejalvo Andujar: Financial Interests, Personal, Speaker’s Bureau: Novartis, Pfizer, Roche. M. Margeli Vila: Financial Interests, Personal, Advisory Board: Novartis, Roche, Pfizer; Financial Interests, Personal, Research Grant: Roche, AstraZeneca, Eisai, Novartis, Pfizer. P. Tolosa: Financial Interests, Personal, Speaker’s Bureau: Pfizer, Novartis, Roche, Eli Lilly, AstraZeneca. J. Cruz Jurado: Financial Interests, Personal, Advisory Role: AstraZeneca, Roche, Novartis, PharmaMar, Eisai, Lilly, Amgen, GlaxoSmithKline, Seagen, Daiichi Sankyo, Pfizer; Financial Interests, Personal, Speaker’s Bureau: GlaxoSmithKline, AstraZeneca, Roche, Novartis, PharmaMar, Eisai, Lilly, Celgene, Astellas, Amgen, Pfizer. E.M. Ciruelos: Financial Interests, Personal, Other, Speakers Bureau, Educational activities: Roche, Lilly; Financial Interests, Personal, Invited Speaker, Symposia and Educational activities: Roche; Financial Interests, Personal, Advisory Board, Non-permanent advisor: Roche, Lilly, Novartis, Pfizer, AstraZeneca, Daiichi Sankyo, MSD; Financial Interests, Personal, Invited Speaker, Symposia and Education: Lilly; Financial Interests, Personal, Invited Speaker, Educational activities: Pfizer; Financial Interests, Institutional, Funding, PI for Patricia 2 trial (sponsor: SOLTI Group): Pfizer; Financial Interests, Institutional, Funding, PI for Prometeo 2 trial (sponsor: SOLTI Group): Pfizer; Financial Interests, Institutional, Funding, PI for TATEN trial (sponsor: SOLTI Group): MSD; Financial Interests, Institutional, Funding, PI for NEREA trial (sponsor: SOLTI Group): PUMA; Financial Interests, Institutional, Funding, PI for ATREZZO trial (sponsor: SOLTI Group): Roche; Non-Financial Interests, Invited Speaker, Non-profit organization dedicated to breast cancer research: SOLTI Cooperative Group; Non-Financial Interests, Advisory Role, Scientific Evaluator at ISCIII (Spanish Government Academic Research Platform): Instituto de Salud Carlos III. S. Pernas Simon: Financial Interests, Personal, Advisory Role: AstraZeneca, Daiichi Sankyo, Polyphor, Novartis, Seattle Genetics, Roche, Eisai, Pierre Fabre, Lilly. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca, Lilly. M. Oliveira: Financial Interests, Personal, Other: Roche, Pierre Fabre, Novartis, Eisai, Immunomedics, AstraZeneca, Genentech, Seagen, Boehringer Ingelheim, PUMA Biotechnology, GSK, Zenith Epigenetics. Financial Interests, Personal, Advisory Role: Roche, GSK, PUMA Biotechnology, AstraZeneca, Pierre Fabre iTEOS. All other authors have declared no conflicts of interest.