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BACKGROUNDFirst-line chemotherapy for advanced esophageal squamous-cell carcinoma results in poor outcomes. The monoclonal antibody nivolumab has shown an overall survival benefit over chemotherapy in previously treated patients with advanced esophageal squamous-cell carcinoma. METHODSIn this open-label, phase 3 trial, we randomly assigned adults with previously untreated, unresectable advanced, recurrent, or metastatic esophageal squamouscell carcinoma in a 1:1:1 ratio to receive nivolumab plus chemotherapy, nivolumab plus the monoclonal antibody ipilimumab, or chemotherapy. The primary end points were overall survival and progression-free survival, as determined by blinded independent central review. Hierarchical testing was performed first in patients with tumor-cell programmed death ligand 1 (PD-L1) expression of 1% or greater and then in the overall population (all randomly assigned patients). RESULTSA total of 970 patients underwent randomization. At a 13-month minimum followup, overall survival was significantly longer with nivolumab plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of 1% or greater (median, 15.4 vs. 9.1 months; hazard ratio, 0.54; 99.5% confidence interval [CI], 0.37 to 0.80; P<0.001) and in the overall population (median, 13.2 vs. 10.7 months; hazard ratio, 0.74; 99.1% CI, 0.58 to 0.96; P = 0.002). Overall survival was also significantly longer with nivolumab plus ipilimumab than with chemotherapy among patients with tumor-cell PD-L1 expression of 1% or greater (median, 13.7 vs. 9.1 months; hazard ratio, 0.64; 98.6% CI, 0.46 to 0.90; P = 0.001) and in the overall population (median, 12.7 vs. 10.7 months; hazard ratio, 0.78; 98.2% CI, 0.62 to 0.98; P = 0.01). Among patients with tumor-cell PD-L1 expression of 1% or greater, a significant progression-free survival benefit was also seen with nivolumab plus chemotherapy over chemotherapy alone (hazard ratio for disease progression or death, 0.65; 98.5% CI, 0.46 to 0.92; P = 0.002) but not with nivolumab plus ipilimumab as compared with chemotherapy. The incidence of treatment-related adverse events of grade 3 or 4 was 47% with nivolumab plus chemotherapy, 32% with nivolumab plus ipilimumab, and 36% with chemotherapy alone. CONCLUSIONSBoth first-line treatment with nivolumab plus chemotherapy and first-line treatment with nivolumab plus ipilimumab resulted in significantly longer overall survival than chemotherapy alone in patients with advanced esophageal squamous-cell carcinoma, with no new safety signals identified. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 648 ClinicalTrials.gov number, NCT03143153.

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LBA4001 Background: NIVO demonstrated superior overall survival (OS) vs chemo in previously treated patients (pts) with ESCC (ATTRACTION-3). We report OS and progression-free survival (PFS) from CheckMate 648, the first global phase III study to evaluate both an immuno-oncology (I-O)/chemo combination and an I-O/I-O combination in advanced ESCC. Methods: Adults with previously untreated, unresectable advanced, recurrent or metastatic ESCC were enrolled regardless of tumor cell PD-L1 expression. Pts were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), or chemo alone. Primary endpoints for both comparisons were OS and PFS per blinded independent central review (BICR) in pts with tumor cell PD-L1 ≥ 1%. Hierarchically tested secondary endpoints included OS and PFS in all randomized pts. Results: 970 pts were randomized to NIVO + chemo, NIVO + IPI, and chemo arms (49% with tumor cell PD-L1 ≥ 1%). With 13 months (mo) minimum follow-up, NIVO + chemo and NIVO + IPI led to statistically significant improvement in OS vs chemo in pts with tumor cell PD-L1 ≥ 1% and all randomized pts (Table). Statistically significant PFS benefit was also observed for NIVO + chemo vs chemo (HR 0.65 [98.5% CI 0.46–0.92]; P = 0.0023) in pts with tumor cell PD-L1 ≥ 1%. PFS in NIVO + IPI vs chemo in pts with tumor cell PD-L1 ≥ 1% did not meet the prespecified boundary for significance. The objective response rate (per BICR) was 53% (NIVO + chemo), 35% (NIVO + IPI), and 20% (chemo) in pts with tumor cell PD-L1 ≥ 1% and in all randomized pts was 47%, 28%, and 27%, respectively; longer median (95% CI) duration of response was observed vs chemo for pts with tumor cell PD-L1 ≥ 1%: 8.4 (6.9–12.4), 11.8 (7.1–27.4), and 5.7 (4.4–8.7) mo and for all randomized pts: 8.2 (6.9–9.7), 11.1 (8.3–14.0), and 7.1 (5.7–8.2) mo, respectively. No new safety signals were identified (Table). Conclusions: NIVO plus chemo and NIVO plus IPI both demonstrated superior OS vs chemo, along with durable objective responses and acceptable safety, in pts with advanced ESCC, and each represents a potential new 1L treatment option. Clinical trial information: NCT03143153. [Table: see text]

Purpose: Human papillomavirus (HPV) is found in 90% of squamous cell carcinomas of the anal canal (SCCA). We investigated the clinical validity of HPV circulating tumor DNA (ctDNA) detection in patients enrolled in the Epitopes-HPV02 trial that demonstrated the efficacy of docetaxel, cisplatin, and 5-FU as first-line chemotherapy in advanced SCCA.Experimental Design: According to the protocol, serum samples were collected before chemotherapy and on completion of chemotherapy. HPV16 ctDNA was quantified by droplet digital PCR (ddPCR) and correlated with prospectively registered patient characteristics and outcomes. A landmark was set at the time of chemotherapy completion for postchemotherapy progression-free survival (PFS) analyses.Results: Among 57 patients with HPV16-related advanced SCCA, HPV ctDNA was detected in 91.1% (95% confidence interval, 81.1-96.2) of baseline samples. Baseline HPV ctDNA levels were not associated with any patient characteristics; baseline ctDNA level below the cutoff obtained by AUC (area under the curve) was associated with a longer PFS (HR ¼ 2.1; P ¼ 0.04). Among the 36 patients who completed 5 months of chemotherapy, residual HPV ctDNA was detected after chemotherapy in 38.9% of patients. Residual HPV ctDNA detected at chemotherapy completion was associated with shorter postchemotherapy PFS (median PFS 3.4 months vs. not reached; HR ¼ 5.5; P < 0.001) and a reduction of 1-year overall survival rate (OR ¼ 7.0; P ¼ 0.02).Conclusions: This prospective study in advanced SCCA demonstrated a significant prognostic impact of HPV ctDNA level before first-line chemotherapy and HPV ctDNA negativity after chemotherapy completion. With a limited cost and short turnaround, this assay is a promising tool to optimize the therapeutic management of SCCA.See related commentary by Morris, p. 2030