Frontline Tislelizumab/Chemo Combo Improves OS in Advanced Esophageal Squamous Cell Carcinoma

The combination of tislelizumab and chemotherapy resulted in a significant improvement in overall survival compared with chemotherapy alone in patients with locally advanced, recurrent or metastatic esophageal squamous cell carcinoma, irrespective of PD-L1 expression.

The combination of tislelizumab (BGB-A317) and chemotherapy resulted in a significant improvement in overall survival (OS) compared with chemotherapy alone in patients with locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC), irrespective of PD-L1 expression, according to topline data from an interim analysis of the phase 3 RATIONALE 306 trial (NCT03783442).1

Novartis shared plans to collaborate with BeiGene to present these data at an upcoming medical meeting, and to submit the findings to regulatory authorities.

"People living with esophageal cancer experience painful everyday challenges and typically have a poor prognosis, with a 5-year survival rate of around 5% for metastatic cases, underscoring the urgency for more immunotherapy options,” Jeff Legos, PhD, MBA, executive vice president of Global Head of Oncology & Hematology Development at Novartis, stated in a press release. “We plan to discuss these data with health authorities, and we will continue to expand our tislelizumab clinical development program in pursuit of novel, synergistic combinations with the ultimate goal of extending survival for more patients.”

Chemoradiotherapy is the current frontline standard of care for patients with advanced unresectable or metastatic ESCC. However, PD-1 inhibition has demonstrated antitumor activity with acceptable tolerability in this patient population.2,3 Tislelizumab was designed to minimize binding to FcyR on macrophages to repeal antibody-dependent phagocytosis. Data from a phase 1 trial (NCT02407990) demonstrated that single-agent tislelizumab was generally well tolerated and had activity in patients with solid tumors, including those with ESCC.

RATIONALE 306 included patients with histologically confirmed ESCC and who were at least 18 years of age. To be eligible for enrollment, patients needed to have stage IV unresectable ESCC at first diagnosis or unresectable, locally advanced, recurrent or metastatic disease with a treatment-free interval of at least 6 months following definitive treatment.4 Patients were also required to have an ECOG performance status of 0 or 1.

Key exclusion criteria included palliative radiation treatment for ESCC within 4 weeks of initiation of study treatment; prior systemic therapy for unresectable, locally advanced, recurrent or metastatic ESCC; and prior anti–PD-1/PD-L1/PD-L2 therapies.

Approximately 649 participants were randomized 1:1 to receive intravenous (IV) tislelizumab at 200 mg every 3 weeks plus investigator’s choice of chemotherapy doublet or chemotherapy alone. Chemotherapy options included IV cisplatin at 60 mg/m2 to 80 mg/m2 on day 1 once every 3 weeks, oral capecitabine at a twice-daily dose of 1000 mg/m2 on days 1 to 14 every 3 weeks, IV paclitaxel at 175 mg/m2 on day 1 every 3 weeks, IV 5-fluorouracil at 750 mg/m2 to 800 mg/m2 via continuous infusion on days 1 to 5 every 3 weeks, or IV oxaliplatin at 30 mg/m2 on day 1 every 3 weeks.

OS and progression-free survival serve as the co-primary end points of the trial. Other end points include objective response rate, duration of response, and health-related quality-of-life, and safety. Safety will be assessed through the monitoring of adverse effects, physical examinations, vital signs, and electrocardiograms.

In September 2021, the FDA accepted for review a biologics license application for tislelizumab as a potential therapeutic option in patients with unresectable recurrent locally advanced or metastatic ESCC following previous systemic therapy.5 The application was supported by data from the phase 3 RATIONALE 302 trial (NCT03430843), which showed that the agent improved OS over chemotherapy in this patient population.6


  1. Novartis tislelizumab plus chemotherapy significantly improved overall survival as first-line treatment for advanced esophageal cancer in phase III study. News release. Novartis. April 27, 2022. Accessed April 27, 2022.
  2. Nakajima M, Kato H. Treatment options for esophageal squamous cell carcinoma. Expert Opin Pharmacother. 2013;14(10):1345-1354. doi:10.1517/14656566.2013.801454
  3. Xu J-M, Kato K, Hubner R, et al. A randomized, placebo-controlled, phase III trial-in-progress to evaluate the efficacy and safety of tislelizumab plus chemotherapy as first-line treatment for unresectable, locally advanced recurrent/metastatic esophageal squamous cell carcinoma (ESCC). J Clin Oncol. 2019;37(suppl 15):TPS2656. doi:10.1200/JCO.2019.37.15_suppl.TPS2656
  4. A study of tislelizumab (BGB-A317) in combination with chemotherapy as first line treatment in participants with advanced esophageal squamous cell carcinoma. Updated April 21, 2022. Accessed April 27, 2022.
  5. BeiGene announces US FDA acceptance of biologics license application for tislelizumab in esophageal squamous cell carcinoma. News release. BeiGene, Ltd. September 13, 2021. Accessed April 27, 2022.
  6. Shen L, Kato K, Kim S-B, et al. RATIONALE 302: randomized, phase 3 study of tislelizumab versus chemotherapy as second-line treatment for advanced unresectable/metastatic esophageal squamous cell carcinoma. J Clin Oncol. 2021;39(suppl 15):4012. doi:10.1200/JCO.2021.39.15_suppl.4012