792MO Neoadjuvant Pepinemab in Combination with Nivolumab And/or Ipilimumab in Resectable Stage III Melanoma

SEMA4D has broad immunomodulatory effects in the tumor microenvironment; blocking SEMA4D in combination with checkpoint inhibitors (CI) promotes immune infiltration, enhances T cell activity, and promotes tumor regression. We hypothesized that the combination of pepinemab (pepi), which targets SEMA4D, and CI will increase immunomodulatory effects and augment response to neoadjuvant therapy in stage III melanoma. Patients with resectable stage IIIB/C/D melanoma were sequentially enrolled on one of four treatment cohorts (n = 8 each): pepi/nivolumab (nivo), pepi/ipilimumab (ipi), pepi/nivo/ipi or nivo alone. Two doses were given on days 1 and 21; surgery occurred on day 42. Patients received adjuvant nivo q4w to complete one year of treatment. Primary clinical endpoint was major pathologic response (pMR), including complete and near complete responses (pCR). Secondary endpoints included safety, surgical delays, ORR, RFS, EFS, and OS. All 32 patients received both doses of neoadjuvant therapy; 31 patients safely proceeded to surgery without delay (1 patient is awaiting surgery). Thirteen (41.9%) patients had a pMR. Rates of pMR in the pepi/nivo, pepi/ipi, pepi/nivo/ipi, and nivo arms were 37.5% (2 pCR, 1 near pCR), 12.5% (1 pCR), 75.0% (5 pCR, 1 near pCR), and 42.9% (2 pCR, 1 near pCR), respectively. Three patients did not get adjuvant therapy due to treatment-related severe adverse events: 1 pepi/nivo and 2 pepi/nivo/ipi patients. Two patients had progression following surgery but prior to adjuvant therapy; both had no pathologic response. At median follow up of 19.6 months, 12 patients (38.7%) had recurred. Four patients died of disease; all had no pathologic response. All patients receiving pepi/nivo/ipi are free from recurrence at median follow up of 19.8 months, including two without major responses. We will update toxicities, RFS, EFS and OS at presentation. While neoadjuvant treatment is used routinely for resectable stage III melanoma, there is no consensus on the most appropriate regimen. The combination of pepi/nivo/ipi provides robust pathologic response, durable response, and suitable toxicity. Analysis of biomarker endpoints is ongoing and will inform further development of this regimen.