Tislelizumab/Chemo Combo Takes Step Toward Chinese Approval for Unresectable ESCC


The China National Medical Products Administration’s Center for Drug Evaluation has accepted for review a supplemental biologics application seeking the approval of tislelizumab plus chemotherapy in the first-line treatment of patients with unresectable, locally advanced, recurrent, or metastatic esophageal squamous cell carcinoma.

The China National Medical Products Administration’s Center for Drug Evaluation has accepted for review a supplemental biologics application seeking the approval of tislelizumab (BGB-A317) plus chemotherapy in the first-line treatment of patients with unresectable, locally advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC).1

The application is supported by findings from the phase 3 RATIONALE-306 trial (NCT03783442), in which the frontline combination (n = 326) significantly improved overall survival (OS) over chemotherapy alone (n = 323) in this patient population, at a median of 17.2 months (95% CI, 15.8-20.1) and 10.6 months (95% CI, 9.3-12.1), respectively (HR, 0.66; 95% CI, 0.54-0.80; P < .0001).

“Our global clinical development program for tislelizumab encompasses more than 20 registration-enabling trials and we are pleased that our robust clinical data for tislelizumab are contributing to advancing the treatment landscape for solid tumors in China,” Lai Wang, PhD, global head of R&D at BeiGene, stated in a press release. “We look forward to working with NMPA on this submission and to progressing global regulatory submissions based on the clinically meaningful OS benefit seen in the RATIONALE-306 trial.”

The randomized, placebo-controlled, double-blind, global phase 3 trial enrolled patients with unresectable locally advanced or metastatic ESCC who had an ECOG performance status of 0 or 1 and measurable or evaluable disease per RECIST v1.1 criteria. Patients could not have previously received treatment for advanced disease.

A total of 649 study participants were randomly assigned 1:1 to receive intravenous (IV) tislelizumab at a dose of 200 mg every 3 weeks in combination with investigator’s choice of chemotherapy or matching IV placebo every 3 weeks and chemotherapy. Chemotherapy regimens consisted of cisplatin or oxaliplatin with fluoropyrimidine (option A), or cisplatin or oxaliplatin plus paclitaxel (option B). Treatment was given until progressive disease, unacceptable toxicity, or withdrawal due to other reasons.

Patients were stratified based on geographic region (Asia except for Japan vs Japan vs rest of the world), previous definitive therapy (yes vs no), and investigator-chosen chemotherapy (option A vs option B).

The primary end point of the trial was OS in all randomized patients, and key secondary end points comprised progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) per investigator assessment, as well as OS in the subset of patients with a PD-L1 expression of at least 10%, health-related quality of life, and safety.

Across the investigative and control arms, the median age was 64.5 years (range, 26-84), most patients were from Asia (64.4% vs 65.0%, respectively), were Asian (74.5% vs 75.2%), had an ECOG performance status of 1 (66.6% vs 67.8%), were current or former smokers (75.7% vs 71.5%), had squamous cell histology (99.7% vs 100.0%), and had metastatic disease at baseline (85.6% vs 87.3%). Moreover, 32.8% of those in the investigative arm and 33.1% of those in the control arm received prior definitive therapy.

Regarding PD-L1 status, in the tislelizumab/chemotherapy arm, 37.7% of patients had a PD-L1 score of at least 10%, 50.6% had a score of less than 10%, and 11.7% had unknown status; these rates were 35.0%, 54.5%, and 10.5%, respectively, in the chemotherapy-alone arm. In the investigative arm, 45.1% of patients received option A with regard to investigator-selected chemotherapy and 54.9% received option B; these rates were 45.2% and 54.8%, respectively, in the control arm.

Additional findings presented during the 2022 ESMO World Congress on Gastrointestinal Cancer showed that in all-randomized patients, the OS rates in the tislelizumab/chemotherapy and chemotherapy-alone arms at 6 months were 84.3% and 77.3%, respectively; at 12 months, these rates were 65.0% and 44.9%, respectively; and at 18 months, these rates were 48.6% and 34.5%, respectively.

The OS benefit derived with the addition of tislelizumab to chemotherapy was noted irrespective of baseline PD-L1 expression.

In those with a PD-L1 of at least 10% who received tislelizumab/chemotherapy (n = 123), the median OS was 16.6 months (95% CI, 15.3-24.4) vs 10.0 months (95% CI, 8.6-13.0) with chemotherapy alone (n = 113; HR, 0.62; 95% CI, 0.44-0.86; P = .0020). In those with a PD-L1 score of less than 10%, the median OS with tislelizumab/chemotherapy (n = 165) was 16.7 months (95% CI, 13.0-20.1) vs 10.4 months (95% CI, 9.1-13.0) with chemotherapy alone (n = 176; HR, 0.72; 95% CI, 0.55-0.94).

The median PFS in the investigative arm was 7.3 months (95% CI, 6.9-8.3) vs 5.6 months (95% CI, 4.9-6.0) in the control arm (HR, 0.62; 95% CI, 0.52-0.75; P < .0001). The 6-month PFS rates in the investigative and control arms were 61.1% and 44.5%, respectively, and the 12-month PFS rates were 30.0% and 15.7%, respectively.

The addition of tislelizumab to chemotherapy elicited an ORR of 63.5% (95% CI, 58.0%-68.7%) vs 42.4% (95% CI, 37.0%-48.0%) with chemotherapy alone (odds ratio, 2.36; 95% CI, 1.73-3.27; P < .0001). In the investigative arm, the best overall response was a complete response in 4.6% of patients, a partial response in 58.9% of patients, and stable disease in 25.5% of patients. Four percent of patients experienced progressive disease.

The median DOR in the investigative arm was 7.1 months (95% CI, 6.1-8.1) vs 5.7 months (95% CI, 4.4-7.1) in the control arm, with 19.3% and 9.5% of patients, respectively, still experiencing a response to treatment.

Tislelizumab plus chemotherapy was found to have an acceptable toxicity profile in this patient population, with no new signals reported.

Grade 3 or higher effects were experienced by 66.7% of those in the investigative arm vs 64.5% of those in the control arm; serious toxicities occurred in 28.7% and 64.5% of patients, respectively.

The most common treatment-related toxicities included anemia, decreased neutrophil count, decreased white blood cell count, decreased appetite, nausea, and peripheral sensory neuropathy. Moreover, 31.8% of those in the tislelizumab/chemotherapy arm experienced at least 1 toxicity that resulted in discontinuation vs 22.4% of those on the chemotherapy-alone arm. Six patients on the tislelizumab/chemotherapy arm died vs 4 patients on the chemotherapy-alone arm.


  1. BeiGene announces acceptance of 11th regulatory submission for PD-1 inhibitor tislelizumab in China. News release. BeiGene. August 23, 2022. Accessed August 23, 2022.
  2. Yoon HH, Kato K, Raymond E, et al. RATIONALE 306: randomized, global, placebo-controlled, double-blind phase 3 study of tislelizumab plus chemotherapy versus chemotherapy as first-line treatment for advanced or metastatic esophageal squamous cell carcinoma. Ann Oncol. 2022;33(suppl 4):S375. doi:10.1016/j.annonc.2022.04.439
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