PLUG-IN: Pembrolizumab Combined With Enfortumab Vedotin for Advanced Melanoma Patients

1. RATIONALE

There is a lack of strategies for patients who progress after responding to PD-1/l-1 in melanoma. High expression of Nectin4 in skin and melanomas may serve as a new target in advanced melanomas. The combination of enfortumab vedotin and pembrolizumab has shown synergistic effect in various solid tumors. Enfortumab vedotin and pembrolizumab may have a dual effect on clinical outcomes: 1. Enfortumab vedotin could induce a tumor response based on a high dose of the microtubule disruptor in tumor cells. 2. Enfortumab vedotin could enhance antitumor immunity and prolong the benefit of continuous PD1 therapy. 2. OBJECTIVE(S), HYPOTHESIS(ES), AND ENDPOINT(S)

2.1 Primary Objective(s), Hypothesis(es), and Endpoint(s) Objective: This study will evaluate the efficacy of EV plus pembrolizumab in advanced melanoma.

Hypothesis: 1) High expression of Nectin4 in skin and melanomas may serve as a new target in advanced melanomas; 2)EV+Pembrolizumab has shown synergistic effect in various solid tumors; 3) There is a lack of strategies for patients who respond to PD1-mAbs in melanoma.

The combination of EV+Pembrolizumab may have a dual effect on outcomes:

1. EV could induce a tumor response based on a high dose of the microtubule disruptor in tumor cells. 2. EV could enhance antitumor immunity and prolong the benefit of continuous PD1 therapy.

Primary Endpoint:

\- Objective Response Rate (ORR) as assessed by the investigator through Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). This will be considered as the percentage/proportion of patients with confirmed complete response (CR) or partial response (PR) as their overall best response throughout the study.

2.2 Secondary Objective(s), Hypothesis(es), and Endpoint(s)

Secondary Endpoint:

\- Progression-free Survival (PFS) as assessed by RECIST 1.1. PFS is defined as the time from first dose of study treatment to the date of the first documentation of progressive disease (PD) or death from any cause, whichever occurs first. * Overall Survival (OS), defined as the time from first dose of study treatment to the date of death from any cause. * Clinical Benefit Rate (CBR), defined as proportion of patients with complete response (CR) or partial response (PR), according to ORR definition for the trial, or maintained stable disease (SD) as their overall best response, assessed by imaging follow-up (CT scan/MRI) and RECIST V1.1 criteria. Stable disease should be maintained for at least 4 months to be considered as a CBR event. * Duration of Response (DoR) as Assessed by RECIST 1.1. DoR is considered an acceptable measure of clinical benefit when considered with ORR. * Treatment-free Survival (TFS), defined as the time from the end of study treatment until the start of subsequent treatment, progression or death, whichever occurs first. * Treatment-free Interval (TFI), defined as the time from the end study treatment until the start of subsequent treatment. * The safety objective for this study is to evaluate the safety of EV plus pembrolizumab on the basis of the following endpoints: