Chemoradiation and Pembrolizumab Followed by Pembrolizumab and Lenvatinib Before Surgery for the Treatment of Non-metastatic Esophageal or Esophageal/Gastroesophageal Junction Cancer

This phase II trial studies the effect of chemoradiation and pembrolizumab followed by pembrolizumab and lenvatinib before surgery in treating patients with esophageal or esophageal/gastroesophageal junction cancer that has not spread to other places in the body (non-metastatic). Pembrolizumab is an immunotherapy drug that works by harnessing the immune system to attack cancer. Lenvatinib is an anti-cancer drug that works by stopping or slowing down the growth of cancer cells. Chemotherapy drugs, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving chemoradiation and pembrolizumab followed by pembrolizumab and lenvatinib before surgery may kill more tumor cells.

PRIMARY OBJECTIVE: I. To evaluate pathologic complete response rate (path CR) and complete clinical response rate (clinical CR) at 14 weeks after starting chemoradiotherapy. SECONDARY OBJECTIVES: I. To assess safety and tolerability of pembrolizumab and lenvatinib in this patient population. II. To establish that pembrolizumab + lenvatinib will increase immune response via increased expression of the 18 gene pro-immune response signature measured using the Nanostring platform on tumor tissue biopsies. III. To evaluate disease-free survival (DFS) and overall survival (OS) in this study population. EXPLORATORY OBJECTIVES: I. To identify through an integrated genomic sequencing approach (MHC-PepSeq) the presence of tumor mutations able to elicit neo-antigen-specific immunity in this population expected to be predominated by microsatellite stability (MSS) tumors. II. To correlate temporal variations in circulating tumor deoxyribonucleic acid (ctDNA) representing immunogenic and non-immunogenic mutations as pharmacodynamic immune markers. III. To correlate diversity in the gut microbiome with path CR and clinical CR in this study population. OUTLINE: CHEMORADIATION PHASE: Patients receive carboplatin intravenously (IV) and paclitaxel IV once a week (QW) for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo external beam radiation therapy (EBRT) over 6 weeks and receive pembrolizumab IV over 30 minutes on day 1 of radiation therapy in the absence of disease progression or unacceptable toxicity. WINDOW PERIOD: Patients receive pembrolizumab IV over 30 minutes on day 1 of week 3 and lenvatinib mesylate orally (PO) once daily (QD) at weeks 3-6 in the absence of disease progression or unacceptable toxicity. SURGERY/SURVEILLANCE: Patients without complete response undergo standard of care surgical resection. Patients with complete response/pursue non-operative management undergo surveillance via periodic endoscopic biopsy. After completion of study treatment, patients are followed up at 90 days, then for up to 3 years.