LAUSR

Background: Standard treatment for stage III melanoma is surgery followed by consideration of adjuvant therapy. This strategy is inadequate for high-risk stage III patients who have a substantial risk of subsequent relapse and distant metastasis. The goals of this trial are to improve oncologic outcomes, assess treatment response and spare patients with poorly responsive, rapidly metastatic disease from a futile operation. This protocol based on the hypothesis that treatment before surgery will immunize patients against his or her own unique tumor. While new drugs are now FDA-approved for adjuvant treatment of stage III melanoma, outcomes are still suboptimal in high-risk patients. The neoadjuvant approach is largely untested and preclinical data suggest neoadjuvant therapy is more effective than adjuvant immunotherapy. While targeted therapies can be rapidly effective, immunotherapy responses, when they occur, tend to be much more durable, prompting this study. Our specific strategy is based on the fact that BRAFm melanoma patients benefit both from BRAF/MEK inhibition (vemurafenib/cobimetinib) and PD-1 axis inhibition (atezolizumab) while patients with BRAFwt melanoma benefit from PD-1 axis inhibition (atezolizumab) and intermittent MEKi (cobimetinib) may increase effector function in tumor-infiltrating T cells. A second component of the study is robust evaluation of biomarkers of response, toxicity and outcome. Specific correlatives include assessment of the predictive value of Bim levels in tumor-related T cells, correlation of sPD-L1 with efficacy and toxicity, correlation of PD-L1 expression with efficacy, and determination of key relationships between tumor and immune cells via mIHC spatial analysis, gene expression profiles and microbiome associations with clinical response. Methods: The NeoACTIVATE trial enrolls melanoma patients with resectable clinically detectable nodal metastases (by physical examination or imaging), dual nodal basin disease or nodal recurrence of melanoma. Neoadjuvant systemic therapy is based on BRAF mutation status; participants receive either vemurafenib, cobimetinib and atezolizumab (vem/cobi/atezo), or cobimetinib and atezolizumab (cobi/atezo) before surgery. Following surgery, all patients receive atezo immunotherapy. The primary aim of the study is RFS estimates for each cohort. Secondary aims are safety/toxicity, pathologic complete response rate and prospective evaluation of biomarkers of treatment response and toxicity. This study is significant in that it is the first to test 1) combined of targeted and immunotherapy in the neoadjuvant setting for patients with resectable Stage III melanoma and 2) the novel combination of MEK-inhibition with immunotherapy in the neoadjuvant setting for resectable Stage III melanoma. As of January 1, 2019, 10% of planned patients have been enrolled and enrollment continues. Citation Format: Tina J. Hieken, Vera J. Suman, Shernan G. Holtan, Thomas J. Flotte, Lisa A. Kottschade, Matthew S. Block. Neoadjuvant combination targeted and immunotherapy for high-risk resectable stage III melanoma (NeoACTIVATE), NCT03554083 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT121.