S1801: A randomized trial of adjuvant versus neoadjuvant pembrolizumab for melanoma.
Authors: Patel Sapna Pradyuman , Othus Megan , Moon James , Tetzlaff Michael , Buchbinder Elizabeth Iannotti , Sondak Vernon K. , Lowe Michael C. , Mireles Catrina , Sharon Elad , Korde Larissa A. , Guild Samantha , Carson William Edgar , Ribas Antoni , Grossmann Kenneth F. 
Published: June 2021

TPS9585 Background: Although long term outcomes for most patients with early-stage melanoma is excellent following surgery, patients who have high-risk features such as lymph node involvement have poorer outcomes. Adjuvant therapy (AT) is currently considered for patients with stage III melanoma and selected patients with resected stage IV melanoma. Currently, AT for melanoma is anti-PD-1 or targeted therapy in the presence of a BRAF mutation. At this time, we are not able to predict which patients will derive benefit from AT and experience cure. While curative intent is the goal of treatment for primary melanoma, patients with bulky nodal involvement are at high risk of local or distant recurrence despite upfront surgery. Neoadjuvant treatment (NAT) offers the benefit of an early on-treatment pathological sample that can be profiled for biomarkers and correlated with response and survival. Treating with anti-PD1 while tumor remains visible in the body may generate a stronger immune response against in vivo tumor antigens compared to the traditional adjuvant setting where antigen is presented by microscopic residual tumor burden. Pilot studies of NAT with anti-PD-1 therapy have been initiated in melanoma. Multidisciplinary coordination in these cases is paramount. In these studies, an improvement in relapse-free survival and overall survival has been observed; additionally, pathologic response rates to NAT have been estimated in small studies. Methods: S1801 is a randomized phase II study of AT versus NAT with pembrolizumab (PEM, NCT03698019). Patients with measurable, clinically detectable and resectable cutaneous, acral, and mucosal melanomas without brain metastasis are eligible. Patients with Stage IIIB to oligometastatic, resectable Stage IV are randomized 1:1 to AT or NAT. Patients getting AT undergo surgery first followed by 18 doses of PEM 200 mg IV every 3 weeks. Patients getting NAT receive 3 doses of pre-operative PEM followed by surgery and then 15 doses of adjuvant PEM. Radiation may be given on either arm after surgery, at the investigator’s discretion. Primary endpoint is event-free survival measured from the date of randomization to the date of first documented progression that renders the patient unable to receive planned protocol surgery, failure to begin adjuvant therapy within 84 days of surgery, relapse after surgery, or death due to any cause. Secondary endpoints include RECIST and iRECIST response rates, as well as a number of surgical outcomes. Safety monitoring is conducted with disease progression and toxicity thresholds. The key Translational Medicine objective of this trial is to determine the pathologic response rate to NAT after 3 doses of PEM. Surgical pathology grossing instructions to ensure readout for pathologic response are provided in the form of training slides. Enrollment is at 40% of a planned 500 patients. Clinical trial information: NCT03698019.