PURPOSE: Patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) have poor prognosis. For these patients, treatment options are limited after first-line systemic therapy. PATIENTS AND METHODS: In this open-label phase III clinical study, patients with advanced or metastatic ESCC, whose tumor progressed after first-line systemic treatment, were randomly assigned (1:1) to receive intravenous tislelizumab, an anti–programmed cell death protein 1 antibody, 200 mg every 3 weeks or chemotherapy (investigator's choice of paclitaxel, docetaxel, or irinotecan). The primary end point was overall survival (OS) in all patients. The key secondary end point was OS in patients with programmed death-ligand 1 tumor area positivity (TAP) score ≥ 10%. RESULTS: In total, 512 patients across 11 countries/regions were randomly assigned. At final analysis, conducted after 410 death events occurred, OS was significantly longer with tislelizumab versus chemotherapy in all patients (median, 8.6 v 6.3 months; hazard ratio [HR], 0.70 [95% CI, 0.57 to 0.85]; one-sided P = .0001), and in patients with TAP ≥ 10% (median, 10.3 months v 6.8 months; HR, 0.54 [95% CI, 0.36 to 0.79]; one-sided P = .0006). Survival benefit was consistently observed across all predefined subgroups, including those defined by baseline TAP score, region, and race. Treatment with tislelizumab was associated with higher objective response rate (20.3% v 9.8%) and a more durable antitumor response (median, 7.1 months v 4.0 months) versus chemotherapy in all patients. Fewer patients experienced ≥ grade 3 treatment-related adverse events (18.8% v 55.8%) with tislelizumab versus chemotherapy. CONCLUSION: Tislelizumab significantly improved OS compared with chemotherapy as second-line therapy in patients with advanced or metastatic ESCC, with a tolerable safety profile. Patients with programmed death-ligand 1 TAP ≥ 10% also demonstrated statistically significant survival benefit with tislelizumab versus chemotherapy.

PURPOSE: The standard treatment for postoperative high-risk locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) is chemoradiotherapy with 3-weekly cisplatin (100 mg/m²). However, whether chemoradiotherapy with weekly cisplatin (40 mg/m²) yields comparable efficacy with 3-weekly cisplatin in postoperative high-risk LA-SCCHN is unknown. PATIENTS AND METHODS: In this multi-institutional open-label phase II/III trial, patients with postoperative high-risk LA-SCCHN were randomly assigned to receive either chemoradiotherapy with 3-weekly cisplatin (100 mg/m²) or with weekly cisplatin (40 mg/m²) to confirm the noninferiority of weekly cisplatin. The primary end point of phase II was the proportion of treatment completion, and that of phase III was overall survival. A noninferiority margin of hazard ratio was set at 1.32. RESULTS: Between October 2012 and December 2018, a total of 261 patients were enrolled (3-weekly cisplatin, 132 patients; weekly cisplatin, 129 patients). At the planned third interim analysis in the phase III part, after a median follow-up of 2.2 (interquartile range 1.19-3.56) years, chemoradiotherapy with weekly cisplatin was noninferior to 3-weekly cisplatin in terms of overall survival, with a hazard ratio of 0.69 (99.1% CI, 0.374 to 1.273 [< 1.32], one-sided P for noninferiority = .0027 < .0043). Grade 3 or more neutropenia and infection were less frequent in the weekly arm (3-weekly v weekly, 49% v 35% and 12% v 7%, respectively), as were renal impairment and hearing impairment. No treatment-related death was reported in the 3-weekly arm, and two (1.6%) in the weekly arm. CONCLUSION: Chemoradiotherapy with weekly cisplatin is noninferior to 3-weekly cisplatin for patients with postoperative high-risk LA-SCCHN. These findings suggest that chemoradiotherapy with weekly cisplatin can be a possible treatment option for these patients.

Purpose: This is a phase I/II trial to assess the efficacy and safety of napabucasin plus pembrolizumab for metastatic colorectal cancer (mCRC). Patients and Methods: Phase I was conducted to determine the recommended phase 2 dose (RP2D) in a dose escalation design of napabucasin (240 to 480 mg twice daily) with 200 mg pembrolizumab every 3 weeks. Phase II included cohort A (n = 10, microsatellite instability high, MSI-H) and cohort B (n = 40, microsatellite stable, MSS). The primary endpoint was immune-related objective response rate (irORR). PD-L1 combined positive score (CPS), genomic profiles, and the consensus molecular subtypes (CMS) of colorectal cancer were assessed. Results: A total of 55 patients were enrolled in this study. In phase I, no patients experienced dose-limiting toxicities, and napabucasin 480 mg was determined as RP2D. The irORR was 50.0% in cohort A and 10.0% in cohort B. In cohort B, the irORR was 0%, 5.3%, and 42.9% in CPS < 1, 1≤ CPS <10, and CPS ≥ 10, respectively. Patients with objective response tended to have higher tumor mutation burden than those without. Of evaluable 18 patients for CMS classification in cohort B, the irORR was 33.3%, 0%, 33.3%, and 33.3% in CMS1, CMS2, CMS3, and CMS4, respectively. The common grade 3 or higher treatment-related adverse events included fever (10.0%) in cohort A and decreased appetite (7.5%) and diarrhea (5.0%) in cohort B. Conclusions: Napabucasin with pembrolizumab showed antitumor activity with acceptable toxicities for patients with MSS mCRC as well as MSI-H mCRC, although it did not meet the primary end point. The impact of related biomarkers on the efficacy warrants further investigations in the additional cohort. See related commentary by Nusrat, p. 5775

The KEYNOTE-659 study evaluated the efficacy and safety of pembrolizumab in combination with chemotherapy as the first-line treatment in Japanese patients with advanced gastric/gastroesophageal junction (G/GEJ) cancer. In this paper, we report results from cohort 1 (S-1 plus oxaliplatin [SOX] with pembrolizumab). This was a non-randomised, multicentre, open-label phase IIb study in patients with advanced programmed death-ligand 1 (PD-L1)-positive, human epidermal growth factor receptor 2-negative G/GEJ tumours. The primary endpoint was the objective response rate (ORR) assessed by blinded independent central review (BICR). Secondary endpoints were duration of response (DOR), disease control rate (DCR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and safety. Exploratory analyses were performed based on the PD-L1 combined positive score (CPS) status. Fifty-four patients were evaluated. The median follow-up was 10.1 months. ORR and DCR by BICR were 72.2% (95% confidence interval [CI] 58.4-83.5) and 96.3% (95% CI 87.3-99.5), respectively. Median DOR, TTR, PFS and OS were as follows: not reached, 1.5 months, 9.4 months and not reached. The ORR was 73.9% in patients with CPS ≥1 to <10 and 71.0% in those with CPS ≥10. Grade ≥3 treatment-related adverse events (TRAEs) were reported by 57.4% of patients. The most common grade ≥3 TRAEs were decreased platelet count (14.8%), decreased neutrophil count (13.0%), colitis (5.6%) and adrenal insufficiency (5.6%). SOX with pembrolizumab showed encouraging efficacy and a manageable safety profile for the first-line treatment of advanced G/GEJ cancer. NCT03382600/JapicCTI-183829.

4012 Background: Preliminary analyses from the global, multicohort, phase 2 KEYNOTE-059 (NCT02335411) study suggested that safety of pembro + 5-FU + cisplatin is manageable as 1L therapy in pts with advanced gastric or gastroesophageal junction (G/GEJ) cancer (cohort 2). We present efficacy and updated safety data from KEYNOTE-059 cohort 2. Methods: Cohort 2 enrolled pts ≥18 y with HER2 ^– recurrent or metastatic G/GEJ adenocarcinoma, measurable disease, no prior therapy for metastatic/advanced disease, and ECOG PS 0-1. Pts received pembro 200 mg on day 1 of each 21-day cycle + cisplatin 80 mg/m² for 6 cycles + 5-FU 800 mg/m² (or capecitabine 1000 mg/m² in Japan) Q3W for up to 2 y or until disease progression, investigator/pt decision to withdrawal, or unacceptable toxicity. PD-L1⁺pts had expression in ≥1% tumor or stromal cells using IHC (22C3 antibody). End points were safety and tolerability (primary), ORR (RECIST v1.1, by central review), DOR, PFS, and OS (secondary). Results: Of 25 enrolled pts, 64% were men, 68% were Asian, and 64% had PD-L1⁺ tumors. Median age was 64 y. At data cutoff (Oct 19, 2016), median duration of follow-up was 12.2 mo (range, 1.8 to 19.6) and 84% of pts had discontinued treatment, mainly owing to clinical or radiologic disease progression (64%). ORR (CR + PR) was 60% (95% CI, 38.7-78.9) in all pts. Overall, 32% of pts had SD (95% CI, 14.9-53.5), 4% had PD (95% CI, 0.1-20.4), and 4% were not evaluable (95% CI, 0.1-20.4). ORR was 68.8% (95% CI, 41.3-89.0) in PD-L1⁺ pts and 37.5% (95% CI, 8.5-75.5) in PD-L1^– pts. Median DOR (range) was 4.6 mo (2.6 to 14.4+) in all pts, 4.6 mo (3.2 to 14.4+) in PD-L1⁺ pts, and 5.4 mo (2.8 to 8.3+) in PD-L1^–pts. Median PFS was 6.6 mo (95% CI, 5.9-10.6); median OS was 13.8 mo (95% CI, 7.3-not estimable). Grade 3-4 treatment-related adverse events (TRAEs) occurred in 76% of pts. TRAEs led to discontinuation in 3 pts (grade 3 stomatitis, grade 2 hypoacusis, and grade 1 creatinine increase). No TRAEs were fatal. Conclusions: Pembro + 5-FU + cisplatin showed manageable safety and encouraging antitumor activity as 1L therapy for pts with advanced G/GEJ cancer. Further exploration of pembro + 5-FU + cisplatin in this setting is warranted. Clinical trial information: NCT02335411.

PURPOSE: Although multiple agents targeting PD-1 have been approved as second-line treatment for esophageal squamous cell carcinoma (ESCC), only a fraction of patients derive long-term survival. Hence, reliable predictive biomarkers are urgently needed. METHODS: Comprehensive tumor genomic profiling and transcriptome sequencing were performed on samples from the RATIONALE-302 study. We also conducted single-cell RNA sequencing analysis on Notch1 knockdown ESCC murine models to further explore the potential molecular mechanisms underlying anti–PD-1 benefit. RESULTS: We identified NOTCH1 mutation as a potential predictive biomarker for longer overall survival (OS) with tislelizumab versus chemotherapy (18.4 months v 5.3 months; hazard ratio, 0.35 [95% CI, 0.17 to 0.71]). At the transcriptional level, type I IFN (IFN-I)/toll-like receptor expression signatures were positively associated with OS benefit of tislelizumab, whereas B-cell and neutrophil signatures predicted unfavorable OS. Exploratory analyses showed that the presence of NOTCH1 mutation correlated with enrichment of IFN-I signatures and reduced infiltration of B cells and neutrophils. In murine models, comparative single-cell transcriptome analyses further revealed that Notch1 deficiency facilitated a more immunologically activated tumor microenvironment which potentiated anti–PD-1 treatment. CONCLUSION: Our data provide novel insights for anti–PD-1 treatment selection using NOTCH1 mutations and may provide a rationale for combination therapy in ESCC.