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PURPOSE Donafenib, a novel multikinase inhibitor and a deuterated sorafenib derivative, has shown efficacy in phase Ia and Ib hepatocellular carcinoma (HCC) studies. This study compared the efficacy and safety of donafenib versus sorafenib as first-line therapy for advanced HCC. PATIENTS AND METHODS This open-label, randomized, parallel-controlled, multicenter phase II-III trial enrolled patients with unresectable or metastatic HCC, a Child-Pugh score ≤ 7, and no prior systemic therapy from 37 sites across China. Patients were randomly assigned (1:1) to receive oral donafenib (0.2 g) or sorafenib (0.4 g) twice daily until intolerable toxicity or disease progression. The primary end point was overall survival (OS), tested for noninferiority and superiority. Efficacy was primarily assessed in the full analysis set (FAS), and safety was assessed in all treated patients. RESULTS Between March 21, 2016, and April 16, 2018, 668 patients (intention-to-treat) were randomly assigned to donafenib and sorafenib treatment arms; the FAS included 328 and 331 patients, respectively. Median OS was significantly longer with donafenib than sorafenib treatment (FAS; 12.1 v 10.3 months; hazard ratio, 0.831; 95% CI, 0.699 to 0.988; P = .0245); donafenib also exhibited superior OS outcomes versus sorafenib in the intention-to-treat population. The median progression-free survival was 3.7 v 3.6 months ( P = .0570). The objective response rate was 4.6% v 2.7% ( P = .2448), and the disease control rate was 30.8% v 28.7% (FAS; P = .5532). Drug-related grade ≥ 3 adverse events occurred in significantly fewer patients receiving donafenib than sorafenib (125 [38%] v 165 [50%]; P = .0018). CONCLUSION Donafenib showed superiority over sorafenib in improving OS and has favorable safety and tolerability in Chinese patients with advanced HCC, showing promise as a potential first-line monotherapy for these patients.

This randomized, open-label, multi-center phase 2 study (NCT03116152) assessed sintilimab, a PD-1 inhibitor, versus chemotherapy in patients with esophageal squamous cell carcinoma after first-line chemotherapy. The primary endpoint was overall survival (OS), while exploratory endpoint was the association of biomarkers with efficacy. The median OS in the sintilimab group was significantly improved compared with the chemotherapy group (median OS 7.2 vs.6.2 months; P = 0.032; HR = 0.70; 95% CI, 0.50–0.97). Incidence of treatment-related adverse events of grade 3–5 was lower with sintilimab than with chemotherapy (20.2 vs. 39.1%). Patients with high T-cell receptor (TCR) clonality and low molecular tumor burden index (mTBI) showed the longest median OS (15.0 months). Patients with NLR < 3 at 6 weeks post-treatment had a significantly prolonged median OS (16.6 months) compared with NLR ≥ 3. The results demonstrate a significant improvement in OS of sintilimab compared to chemotherapy as second-line treatment for advanced or metastatic ESCC.

4511 Background: Patients (pts) with advanced esophageal squamous cell carcinoma (ESCC) refractory to first-line chemotherapy have limited treatment options. The study aims to evaluate the efficacy and safety of sintilimab, a PD-1 inhibitor, versus chemotherapy in these pts, and explore predictive value of PD-L1 and neutrophil-to-lymphocyte ratio (NLR) on efficacy of sintilimab. Methods: The open-label, multi-center phase 2 trial (NCT03116152) enrolled advanced ESCC pts refractory to first-line chemotherapy, and randomly assigned (1:1) them to receive sintilimab (200mg, Q3W) or chemotherapy (paclitaxel, 175mg/m2, Q3W; or irinotecan, 180mg/m2, Q2W), intravenously. The primary endpoint was overall survival (OS). Explorative endpoint were effects of PD-L1 and NLR on efficacy of sintilimab. Results: From May 16, 2017 to Aug 30, 2018, 190 pts were randomly assigned to sintilimab or chemotherapy (n = 95 per group). With the median follow-up of 7.2 months for sintilimab group and 6.2 months for chemotherapy group, the median OS in sintilimab was significantly higher than chemotherapy (7.2m vs. 6.2m, hazard ratio [HR] 0.70, P = 0.034). The objective response rate (ORR) was greater in sintilimab than chemotherapy with 12.6% vs. 6.3%, and the median duration of response was longer (8.3m vs. 6.2m). Incidences of treatment-related adverse events (TRAEs) of any grade (54.3% vs. 90.8%) and of grade 3-5 (20.2% vs. 39.1%) were both numerically less in sintilimab than in chemotherapy. The ORR in sintilimab versus chemotherapy in pts with tumor PD-L1 tumor proportion score (TPS) ≥1% and with TPS ≥10% were 20.2% vs. 0%, and 35.7% vs. 0%, respectively. In sintilimab group, pts with low NLR ( < 3) had a significant longer median OS (HR 0.54, P = 0.019) than with high NLR. Conclusions: Sintilimab was superior to chemotherapy with a significantly prolonged survival benefit and a favorable safety profile in pts with advanced ESCC refractory to first-line chemotherapy. High tumor PD-L1 expression (TPS ≥1% or ≥10%) might indicate more response benefit to sintilimab for these pts, and low NLR might be a positive predictive factor for sintilimab. Clinical trial information: NCT03116152 .

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