Abstract CT156: Novel neoadjuvant targeted therapy trial yields insight into molecular mechanisms of response
Authors: Woodman Scott E. , Prieto Peter , Andrews Miles C. , Amaria Rodabe N. , Tetzlaff Michael , Diab Adi , Patel Sapna P. , Wen-Jen Hwu , Glitza Isabella , Tawbi Hussein , Hwu Patrick , Cormier Janice , Lucci Anthony , Royal Richard , Lee Jeffrey , Bassett Roland , Simpson Lauren , Burton Elizabeth , Zhao Li , Grimm Elizabeth , Reuben Alexandre , Spencer Christine , Oba Junna , Ross Merrick , Gershenwald Jeffrey , Davies Michael , Wargo Jennifer A. 
Published: July 2017

Abstract
Background: Major advances have been made in the treatment of metastatic melanoma through the use of molecularly targeted therapy and immunotherapy, and trials incorporating these agents are now being extended to patients with earlier-stage disease. The current standard of care (SOC) therapy for high-risk resectable melanoma (stage IIIB/IIIC) is upfront surgery and SOC adjuvant therapy; however, relapse rates are high (~70%). We hypothesized that treatment with neoadjuvant + adjuvant targeted therapy (dabrafenib + trametinib) in this patient population would result in lower relapse rates and prolonged survival over SOC therapy.
Methods: To test this hypothesis, we designed a randomized clinical trial (NCT02231775) in patients with resectable Stage IIIB/C or oligometastatic stage IV BRAF-mutant melanoma. Patients were randomized 1:2 to SOC (Arm A) versus neoadjuvant + adjuvant D+T (Arm B, 8 wks neoadjuvant + 44 wks adjuvant). The primary endpoint was relapse-free survival (RFS) with additional secondary endpoints. Importantly longitudinal sampling of tumor tissue was obtained (at baseline, week 3, and surgery) and molecular profiling was performed to gain insights into mechanisms of therapeutic response.
Results: 21 of 84 patients were enrolled (arm A=7, arm B=14). Arms were well matched, and toxicity to targeted therapy was limited. RECIST response rate to 8 wks D+T was 77%, with a pathologic complete response rate (pCR) of 58%. Interim analysis revealed a significantly higher RFS in the D+T arm over SOC (p&lt;0.0001), substantiating early stoppage of the trial. Notably, achievement of a pCR correlated with durable clinical benefit. Tumor mutational load was similar in those achieving a pCR versus those who did not, however known recurrent gene alterations in melanoma were noted to be more abundant in those who failed to achieve a pCR. Transcriptomic profiling in longitudinal tumor samples revealed differentially expressed genes (DEGs) that were highly correlated with achieving a pCR. Initial functional analysis of DEGs implicate multiple cancer cell-intrinsic (differentiation, MAPK pathway and metabolic) features and immune microenvironmental factors to be associated with response to neoadjuvant targeted therapy.
Conclusion: Neoadjuvant + adjuvant D+T is associated with a high pCR rate and improved RFS over SOC in patients with high-risk resectable metastatic melanoma. Pathological and molecular correlative analysis revealed both pre- and on-treatment tumor features to be highly associated with the high pCR rate.
Citation Format: Scott E. Woodman, Peter Prieto, Miles C. Andrews, Rodabe N. Amaria, Michael Tetzlaff, Adi Diab, Sapna P. Patel, Hwu Wen-Jen, Isabella Glitza, Hussein Tawbi, Patrick Hwu, Janice Cormier, Anthony Lucci, Richard Royal, Jeffrey Lee, Roland Bassett, Lauren Simpson, Elizabeth Burton, Li Zhao, Elizabeth Grimm, Alexandre Reuben, Christine Spencer, Junna Oba, Merrick Ross, Jeffrey Gershenwald, Michael Davies, Jennifer A. Wargo. Novel neoadjuvant targeted therapy trial yields insight into molecular mechanisms of response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT156. doi:10.1158/1538-7445.AM2017-CT156