Background: Pembro, a PD-1 inhibitor, has shown effective antitumor activity, deep and durable responses, and survival benefit in treatment-naive pts and those with previously treated metastatic melanoma. Len, a potent inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT, combined with a PD-1 inhibitor showed antitumor activity superior to either agent alone in preclinical models of colorectal and lung cancer. Additionally, len plus pembro showed anti-tumor activity and was well-tolerated (24-wk ORR, 47.6%; TRAE: gr 3/4, 67%; gr 5, 0%) in pts with advanced melanoma previously treated with 0-2 therapies in the phase 1b/2 KEYNOTE-146 trial. The efficacy and safety of len plus pembro combination therapy will be evaluated in an open-label, phase 2 trial of pts with advanced melanoma that progressed on PD-1/PD-L1 inhibitor therapy (NCT03776136). Methods: Key inclusion criteria: age ≥18 years, histologically/cytologically confirmed unresectable stage III-IV melanoma that progressed (per iRECIST) within 12 weeks of last dose of an approved PD-1/PD-L1 inhibitor therapy (≥2 doses as monotherapy or combined with other therapies), measurable disease, ECOG PS 0/1, no active autoimmune disease, and adequate organ function. Pts must provide a baseline tumor sample. Pts will receive len 20 mg/day orally plus pembro 200 mg IV Q3W for approximately 2 years (35 doses of pembro), after which they may receive len alone until PD or unacceptable toxicity. Response will be assessed per RECIST v1.1 based on blinded independent central review (BICR) Q9W until week 54, Q12W until week 102, and Q24W thereafter. Pts with CR may discontinue treatment after ≥24 weeks of therapy; eligible pts may continue treatment beyond initial RECIST- or iRECIST-defined PD. AEs will be assessed throughout treatment and for 90 days (120 days for serious AEs) after last dose and graded per NCI CTCAE v4.0. Pts will be followed-up for survival status Q12W. The primary efficacy end point is ORR per modified RECIST v1.1 (BICR). Key secondary end points are PFS and DOR per modified RECIST v1.1 (BICR), OS, and safety; an exploratory biomarker analysis is planned. Clinical trial information: NCT03776136