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Clinical Trial
. 2025 Sep 9:227:115688.
doi: 10.1016/j.ejca.2025.115688. Epub 2025 Aug 6.

NeoACTIVATE Arm C: Phase II trial of neoadjuvant atezolizumab and tiragolumab for high-risk operable Stage III melanoma

Tina J Hieken  1 , David Zahrieh  2 , Thomas J Flotte  3 , Roxana S Dronca  4 , Evidio Domingo-Musibay  5 , Garth D Nelson  2 , Carrie A Strand  2 , Lisa A Kottschade  6 , Heather N Montane  6 , Mara A Piltin  1 , Ruqin Chen  7 , Robert R McWilliams  6 , James W Jakub  8 , Samir S Khariwala  9 , Arkadiusz Z Dudek  6 , Jeffrey E Johnson  1 , Svetomir N Markovic  6 , Anastasios Dimou  6 , Kendall K Tasche  10 , Matthew S Block  11
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Free article
Clinical Trial

NeoACTIVATE Arm C: Phase II trial of neoadjuvant atezolizumab and tiragolumab for high-risk operable Stage III melanoma

Tina J Hieken et al. Eur J Cancer. .
Free article

Abstract

Purpose: Neoadjuvant ± adjuvant immunotherapy improves event-free survival (EFS) versus adjuvant immunotherapy alone for high-risk resectable Stage III melanoma. However, the optimal regimen balancing efficacy and tolerability is unknown. T-cell immunoglobulin and ITIM domain (TIGIT) is a promising immune checkpoint whose therapeutic potential in Stage III melanoma is underexplored.

Methods: In this phase II trial, patients with resectable, macroscopic Stage III melanoma received four 21-day neoadjuvant cycles of 1200 mg IV atezolizumab (anti-PD-L1) + 600 mg IV tiragolumab (anti-TIGIT), therapeutic lymph node dissection (TLND) and eight adjuvant cycles of atezolizumab. Primary endpoints were pathologic response and recurrence-free survival (RFS) after TLND in patients receiving adjuvant therapy; secondary and exploratory endpoints included adverse events (AEs), EFS and distant metastasis-free survival (DMFS).

Results: Thirty-four patients initiated neoadjuvant atezolizumab/tiragolumab and were evaluable for AEs, pathologic response and EFS. 76.5 % had > 1 metastatic lymph node at baseline and 73.5 % were Stage IIIC. Thirty patients had per protocol TLND. Major pathologic responses (MPR, ≤10 % viable tumor) were observed in 16/34 patients (47.1 %). With 19.9 months median follow-up, 12-month EFS was 72.0 % (95 %CI 57.9-89.5 %), 12-month RFS was 73.3 % (95 %CI 56.9-94.5 %), and 12-month DMFS 86.0 % (95 %CI 72.2-100 %). 12-month RFS and DMFS for patients with an MPR were both 91.7 % (95 %CI: 77.3-100 %). Grade 3 + AEs at least possibly neoadjuvant treatment-related occurred in 2 patients (5.9 %).

Conclusion: Among patients with high-risk resectable Stage III melanoma, neoadjuvant atezolizumab/tiragolumab was a promising regimen with a favorable safety profile and warrants further study. A strategy to personalize neoadjuvant regimen selection is needed.

Keywords: Antibodies; Atezolizumab; Biomarkers; Clinical Trials; Humanized; Immunotherapy; Lymph Nodes; Melanoma; Monoclonal; Neoadjuvant Therapy; Phase II as Topic; Progression-Free Survival; Skin Neoplasms; T-Lymphocytes.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TJH: Research funding (institution) - Genentech/Roche, SkylineDx; DZ: Employment - Ultragenyx Pharmaceuticals, Stock - Ultragenyx Pharmaceuticals; Genentech and SkylineDx; TJF: Stock – Pramana; RSD: Consulting/Advisory Role – Eisai, EMD Serono, Genzyme, Elsevier, Natera, Bristol-Myers Squibb, Replimune, Travel Expense Support – BMSi, Replimune, Patents/Intellectual Property - Development of a Novel CAR-T Therapy to Tackle the Challenges of Immune Evasion, Honoraria – Eisai, EMD Serono, Natera, Elsevier, Bristol-Myers Squibb, Replimune, Research Funding (institution) – Merck Sharp & Dohme, BMSi Alkermes, Spirita Oncology, Emerson Collective, Regeneron, Sorrento Therapeutics, Phosplatin Therapeutics, E D-M: Research Funding (institution) – Iovance Biotherapeutics, Immunocore; LAK: Consulting/Advisory Role – Immunocore; Research Funding (institution) – Thermo Diagnostics; MAP: Research funding (institution) - Intuitive Surgical; Honoraria – OncLive/MJH Life Sciences, Kubtec Medical Imaging; Travel Expense Support – Intuitive Surgical; RC: Stock – Lilly; RRM: Research funding (institution) – Bristol-Myers Squibb, GlasoSmithKline; JWJ: Consulting/Advisory Role – Breathe BioMedical, Clarix Imaging; AZD: Consulting/Advisory Role – HiberCell; Patents/Intellectual Property – IGF Oncology; Stock – IGF Oncology; TTC Oncology, Squarex Pharma, Marell Diagnostic; SNM: Research funding (institution) - Bristol-Myers Squibb; Patents/Royalties/Intellectual Property – Nanoparticles – immunocongugates, Sorrento Therapeutics, Journey Therapeutics; AD: Research support (institution) - Syntrix Pharmaceuticals, Novartis, Merck, AnHearth Therapeutics, Sorrento Therapeutics, Guardant, Philogen, AstraZeneca, Consultant/Advisory Role - TP Therapeutics, Guardant Health, AnHeart Therapeutics, ChromaCode, Travel Expense Support – Guardant Health, Honoraria—Roche/Genentech, Intellisphere; MSB: Research support (institution) - Alkermes, Bristol-Myers Squibb, Genentech/Roche, Marker Inc., Merck, nFerence, Perspective Therapeutics, Pharmacyclics, Regeneron, Sorrento, TILT Biotherapeutics, Transgene; Consultant/Advisory Role - Perspective Therapeutics, Sorrento Therapeutics, TILT Biotherapeutics; Patents filed by employer: “Dendritic Cell-Based Vaccines and Uses Thereof”, and “Combinations of Dendritic Cell-Based Vaccines and Checkpoint Inhibitors.”

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