Neoadjuvant cobimetinib and atezolizumab with or without vemurafenib for high-risk operable Stage III melanoma: the Phase II NeoACTIVATE trial

Tina J. Hieken, Garth D. Nelson, Thomas J. Flotte, Eric P. Grewal, Jun Chen, Robert R. McWilliams, Lisa A. Kottschade, Lu Yang, Evidio Domingo-Musibay, Roxana S. Dronca, Yiyi Yan, Svetomir N. Markovic, Anastasios Dimou, Heather N. Montane, Courtney L. Erskine, Mara A. Piltin, Daniel L. Price, Samir S. Khariwala, Jane Hui, Carrie A. Strand, Susan M. Harrington, Vera J. Suman, Haidong Dong and Matthew S. Block ()
Additional contact information
Tina J. Hieken: Department of Surgery, Mayo Clinic
Garth D. Nelson: Mayo Clinic
Thomas J. Flotte: Mayo Clinic
Eric P. Grewal: Mayo Clinic
Jun Chen: Mayo Clinic
Robert R. McWilliams: Mayo Clinic
Lisa A. Kottschade: Mayo Clinic
Lu Yang: Mayo Clinic
Evidio Domingo-Musibay: University of Minnesota
Roxana S. Dronca: Mayo Clinic
Yiyi Yan: Mayo Clinic
Svetomir N. Markovic: Mayo Clinic
Anastasios Dimou: Mayo Clinic
Heather N. Montane: Mayo Clinic
Courtney L. Erskine: Mayo Clinic
Mara A. Piltin: Department of Surgery, Mayo Clinic
Daniel L. Price: Mayo Clinic
Samir S. Khariwala: University of Minnesota
Jane Hui: University of Minnesota
Carrie A. Strand: Mayo Clinic
Susan M. Harrington: Mayo Clinic
Vera J. Suman: Mayo Clinic
Haidong Dong: Mayo Clinic
Matthew S. Block: Mayo Clinic

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Both targeted therapies and immunotherapies provide benefit in resected Stage III melanoma. We hypothesized that the combination of targeted and immunotherapy given prior to therapeutic lymph node dissection (TLND) would be tolerable and drive robust pathologic responses. In NeoACTIVATE (NCT03554083), a Phase II trial, patients with clinically evident resectable Stage III melanoma received either 12 weeks of neoadjuvant vemurafenib, cobimetinib, and atezolizumab (BRAF-mutated, Cohort A, n = 15), or cobimetinib and atezolizumab (BRAF-wild-type, Cohort B, n = 15) followed by TLND and 24 weeks of adjuvant atezolizumab. Here, we report outcomes from the neoadjuvant portion of the trial. Based on intent to treat analysis, pathologic response (≤50% viable tumor) and major pathologic response (complete or near-complete, ≤10% viable tumor) were observed in 86.7% and 66.7% of BRAF-mutated and 53.3% and 33.3% of BRAF-wild-type patients, respectively (primary outcome); these exceeded pre-specified benchmarks of 50% and 30% for major pathologic response. Grade 3 and higher toxicities, primarily dermatologic, occurred in 63% during neoadjuvant treatment (secondary outcome). No surgical delays nor progression to regional unresectability occurred (secondary outcome). Peripheral blood CD8 + TCM cell expansion associated with favorable pathologic responses (exploratory outcome).

Date: 2024
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DOI: 10.1038/s41467-024-45798-8

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