CheckMate 648: A randomized phase 3 study of nivolumab plus ipilimumab or nivolumab combined with fluorouracil plus cisplatin versus fluorouracil plus cisplatin in patients with unresectable advanced, recurrent, or metastatic previously untreated esophageal squamous cell carcinoma.

TPS193 Background: Esophageal cancer (EC) is the sixth most common cause of cancer-related death worldwide, with a 5-y survival rate of 5%–8% in pts with metastatic disease. First–line platinum-based doublet chemotherapy (CTX) provides a modest survival benefit in pts with metastatic squamous cell EC (mESCC), with a median OS of 7.6 months. Over 40% of pts with EC have PD-L1 + tumors, which are associated with worse OS outcomes. Nivolumab (NIVO), an anti–PD-1 mAb, demonstrated efficacy and a manageable safety profile in pts with ESCC. In the phase 2 ATTRACTION-1 trial, NIVO 3 mg/kg produced an ORR of 17% and median OS of 10.8 months in heavily pretreated pts with ESCC (Kudo T et al Lancet Oncol 2017). NIVO + ipilimumab (IPI) yielded enhanced responses with a manageable safety profile in multiple tumor types. Similarly, NIVO + platinum-based CTX resulted in encouraging clinical activity and an acceptable safety profile in pts with metastatic gastric cancer and SCC NSCLC. This randomized phase 3 study will evaluate the efficacy and safety of NIVO + IPI or NIVO + fluorouracil (5-FU)/cisplatin (Cis) vs 5-FU/Cis as first-line treatment (Tx) in pts with advanced (adv) or mESCC (CheckMate 648; NCT03143153). Methods: 939 pts aged ≥ 18 y with histologically confirmed unresectable advanced, recurrent or mESCC, not amenable to curative approaches, and no prior systemic therapy for advanced/metastatic disease, with adequate organ function and ECOG PS 0 or 1 will be randomized 1:1:1 to NIVO + IPI, NIVO + 5-FU/Cis or 5-FU/Cis. Pts with autoimmune diseases, serious or uncontrolled medical disorders; active infections or positive for HIV, AIDS, or hepatitis B/C, indicating acute or chronic infection and/or detectable virus; and previous Tx with other therapy targeting T-cell co-stimulation or immune checkpoint pathways are excluded. Primary endpoints are OS and PFS by central assessment in pts with a PD-L1 + tumor (defined as PD-L1 expression on ≥ 1% of tumor cells). Secondary endpoints include ORR, PFS, and OS in all pts, as well as ORR in pts with PD-L1 + tumors. Clinical trial information: NCT03143153.