FDA Defers Action on BLA for Tislelizumab in Second-Line Esophageal Squamous Cell Carcinoma

Special IssuesIO - Immuno-Oncology - July 2022 Issue
Volume 1
Issue 1

The FDA has deferred action on the biologics license application seeking the approval of tislelizumab as a second-line treatment in patients with unresectable or metastatic esophageal squamous cell carcinoma, citing the inability to conduct required inspections in China because of travel restrictions associated with COVID-19.

The FDA has deferred action on the biologics license application (BLA) seeking the approval of tislelizumab (BGB-A317) as a second-line treatment in patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC), citing the inability to conduct required inspections in China because of travel restrictions associated with COVID-19.1

Action on the application will be deferred until those inspections are completed, according to a press release issued by BeiGene. Although a new anticipated action date has not been announced, the BLA remains under review.

The BLA for the PD-1 inhibitor was filed in September 2021, and had a decision date of July 12, 2022, under the Prescription Drug User Fee Act. The application was supported by data yielded from the phase 3 RATIONALE-302 trial (NCT03430843), which showed that treatment with tislelizumab (n = 256) resulted in a 30% reduction in the risk of death vs chemotherapy (n = 256) in this patient population (HR, 0.70; 95% CI, 0.57-0.85; P = .0001).2,3 The median overall survival (OS) with tislelizumab was 8.6 months (95% CI, 7.5-10.4) vs 6.3 months (95% CI, 5.3-7.0) with chemotherapy.

“We are working with our partner, Novartis, to facilitate the required inspections and bring tislelizumab to patients with second-line esophageal cancer in the United States following regulatory approval,” John V. Oyler, co-founder, chairman, and chief executive officer of BeiGene, stated in a press release.

The open-label, randomized, multicenter, phase 3 trial enrolled patients with histologically confirmed ESCC who had advanced or metastatic disease and who had experienced disease progression within 6 months of definitive chemoradiation, neoadjuvant, or adjuvant treatment.

To be eligible for enrollment, patients were required to be at least 18 years of age, have an ECOG performance status of 0 or 1, at least 1 measurable lesion per RECIST v1.1 criteria, and acceptable hematologic, renal, and coagulation function.

Patients could not have previously received PD-1/PD-L1 therapies, nor could they have active brain or leptomeningeal metastasis, active autoimmune disease, or other previous malignancies within 2 years before randomization on the trial.

Study participants were randomized 1:1 to receive intravenous (IV) tislelizumab at 200 mg once every 3 weeks or investigator’s choice of single-agent paclitaxel, docetaxel, or irinotecan. Specifically, IV paclitaxel was given once every 3 weeks at doses ranging from 135 mg/m2 to 175 mg/m2 or at once-weekly doses ranging from 80 mg/m2 to 100 mg/m2. Docetaxel was administered at 75 mg/m2 once every 3 weeks, and irinotecan was given at 125 mg/m2 on days 1 and 8, every 21 days.

Treatment was administered until progressive disease, intolerable toxicity, or withdrawal for other reasons. Patients were permitted to continue to receive tislelizumab after disease progression per investigator discretion.

Key stratification factors included region (Asia [excluding Japan] vs Japan vs Europe/North America), performance status (0 vs 1), and selected chemotherapy (paclitaxel vs docetaxel vs irinotecan).

The primary end point of the trial was OS in the intention-to-treat population, and a key secondary end point was OS in the subset of patients with a PD-L1 TAP of 10% or higher. Other secondary end points included PFS, ORR, and DOR per investigator assessment and RECIST v1.1 criteria in both populations, as well as safety and tolerability.

Across the treatment arms, the median age of patients was 62.5 years (range, 35-86), with most patients under the age of 65 years. The majority of patients in the investigative and control arms, respectively, were male (84.8% vs 84.0%), Asian (78.5% vs 80.9%), from Asia (78.5% vs 79.3%), had an ECOG performance status of 1 (74.2% vs 76.6%), former or current smokers (73.4% vs 75.0%), had metastatic disease at study entry (98.0% vs 92.2%), and received prior radiotherapy (66.0% vs 63.7%) or platinum-based chemotherapy (97.3% vs 98.4%).

Additional data published in the Journal of Clinical Oncology showed that the 12-month OS rate achieved with tislelizumab was 37.4% (95% CI, 31.4%-43.4%) vs 23.7% (95% CI, 18.5%-29.3%) with chemotherapy.

In patients with a PD-L1 tumor area positivity (TAP) of 10% or higher, tislelizumab (n = 89) was found to significantly improve OS over chemotherapy (n = 68), with a median OS of 10.3 months (95% CI, 8.5-16.1) and 6.8 months (95% CI, 4.1-8.3), respectively (HR, 0.54; 95% CI, 0.36-0.79; P = .0006). Tislelizumab (n = 116) also provided survival benefits over chemotherapy (n = 140) in those with a PD-L1 TAP of less than 10% (HR, 0.82; 95% CI, 0.62-1.09).

The median PFS in the tislelizumab and chemotherapy arms was 1.6 months (95% CI, 1.4-2.7) and 2.1 months (95% CI, 1.5-2.7), respectively (HR, 0.83; 95% CI, 0.67-1.01), although PFS Kaplan-Meier curves began to separate at about 3 months in favor of the immunotherapy. The estimated 6-month PFS rates in the investigative and control arms are 21.7% and 14.7%, respectively; the estimated 12-month rates are 12.7% and 1.9%, respectively.

Moreover, tislelizumab elicited an ORR of 20.3% (95% CI, 15.6%-25.8%) vs 9.8% (95% CI, 6.4%-14.1%) with chemotherapy (odds ratio, 2.39; 95% CI, 1.42-4.01). Of those who responded to treatment in the immunotherapy arm, 2.0% achieved a complete response, 18.4% experienced a partial response, and 26.6% had stable disease. Just under half, or 45.3%, had progressive disease. The median DOR with tislelizumab was 7.1 months (95% CI, 4.1-11.3) vs 4.0 months (95% CI, 2.1-8.2) with chemotherapy.

Fewer patients who received the immunotherapy reported treatment-related adverse effects (TRAEs) than those who were given chemotherapy, at 73.3% and 93.8%, respectively. The TRAEs that were most frequently experienced with tislelizumab were increased aspartate aminotransferase (11.4%), anemia (11.0%), and hypothyroidism (10.2%).

Fewer grade 3 or higher TRAEs were reported with tislelizumab vs chemotherapy, at 18.8% and 55.8%, respectively. Serious TRAEs were experienced by 14.1% of those who received tislelizumab vs 19.6% of those given chemotherapy. Moreover, 6.7% vs 13.8% of patients in the investigative and control arms, respectively, discontinued treatment.


  1. BeiGene provides regulatory update on the US biologics license application (BLA) for PD-1 inhibitor tislelizumab in 2L ESCC. News release. BeiGene. July 14, 2022. Accessed July 14, 2022. https://bit.ly/3ccOQGW
  2. BeiGene announces US FDA acceptance of biologics license application for tislelizumab in esophageal squamous cell carcinoma. News release. BeiGene, Ltd. September 13, 2021. Accessed July 14, 2022. https://bit.ly/2YJw17s
  3. Shen Li, KatoK, Kim S-B, et al. Tislelizumab versus chemotherapy as second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-302): a randomized phase III study. J Clin Oncol. Published online April 20, 2022. doi:10.1200/JCO.21.01926
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