FDA Accepts BLA for Tislelizumab in Esophageal Squamous Cell Carcinoma

The FDA has accepted for review a biologics license application (BLA) for tislelizumab (BGB-A317) as a potential therapeutic option in patients with unresectable recurrent locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) following previous systemic therapy.¹

The BLA is supported by data from the phase 3 RATIONALE-302 trial (NCT03430843), which showed that the PD-1 monoclonal antibody resulted in a statistically significant and clinically meaningful improvement in overall survival (OS) compared with chemotherapy in patients with advanced or metastatic ESCC who experienced progression during or after frontline treatment.²

In the all-randomized patient population, the median OS in the investigative arm (n = 256) was 8.6 months (95% CI, 7.5-10.4) vs 6.3 months (95% CI, 5.3-7.0) in the control arm (n = 256; hazard ratio [HR], 0.70; 95% CI, 0.57-0.85; P = .0001). In a subset of patients with a PD-L1 combined positive score (CPS) of 10% or higher, the median OS with tislelizumab and chemotherapy was 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).

The application is also based on safety data yielded from 7 clinical trials that comprised 1972 patients who received the immunotherapy as a single agent.

The regulatory agency is expected to reach a decision on the BLA by July 12, 2022, under the Prescription Drug User Fee Act.

“Our uniquely designed anti–PD-1 antibody tislelizumab has been shown to significantly improve survival compared with chemotherapy for people with a variety of solid tumors and hematologic malignancies,” Yong (Ben) Ben, MD, chief medical officer, Immuno-Oncology, at BeiGene, Ltd. “…This BLA acceptance brings us closer to potentially providing tislelizumab as a treatment for these patients in the United States. Tislelizumab is already approved in 5 indications in China and has the potential to become a preferred immunotherapy option there.”

The global phase 3 RATIONALE-302 study enrolled patients with advanced or metastatic ESCC who experienced disease progression during or following frontline systemic treatment. To be eligible for enrollment, patients needed to have an ECOG performance status of 0 or 1.

A total of 512 participants were randomized 1:1 to receive either intravenous (IV) tislelizumab at a dose of 200 mg every 3 weeks (n = 256) or investigator’s choice of chemotherapy (n = 256). Those on the control arm could have received 1 of the following regimens: IV paclitaxel at 135 mg/m² to 175 mg/m² every 3 weeks or 80 mg/m² to 100 mg/m² weekly; IV docetaxel at 75 mg/m² every 3 weeks; or IV irinotecan at 125 mg/m² on days 1 and 8, given every 3 weeks.

Patients were stratified based on region (Asia [excluding Japan] vs Japan vs Europe/North America), performance status (0 vs 1), and chemotherapy option (paclitaxel vs docetaxel vs irinotecan).

The primary end point of the trial was OS in the all-randomized population, and key secondary end points comprised progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and safety.

The study required approximately 400 death events to achieve 82% power to detect a HR of 0.75 at 0.025 significance level (1-sided) for the primary end point of OS in the all-randomized population. If OS in the all-randomized population was found to be significant, the OS in the subset of patients with a PD-L1 CPS of 10% or higher was evaluated sequentially.

At a data cutoff of December 1, 2020, 99.6% (n = 255) of patients received treatment with tislelizumab and 93.8% (n = 240) received chemotherapy. The median follow-up was 8.5 months (range, 0.2-31.7) in the investigative arm and 5.8 months (range, 0-30.8) in the control arm. At the time of the cutoff, 16 patients vs only 1 patient, respectively, were still receiving treatment.

The median age of study participants across the 2 arms was 62.5 years, 84.4% were male, 78.9% were from Europe/North America, and 75.4% had an ECOG performance status of 1. Regarding PD-L1 status, 30.7% had a CPS of 10% or higher, 50% had a CPS less than 10%, and the remainder had unknown status. Most patients (95.1%) had metastatic disease at baseline.

Additionally, 64.9% of patients previously received radiotherapy, 37.7% had prior surgery, and 97.9% had previous platinum-based chemotherapy.

Additional data presented during the 2021 ASCO Annual Meeting showed that the 6-month OS rate with tislelizumab in the all-randomized population was 62.3% vs 51.8% with chemotherapy; at 12 months, these rates were 37.4% and 23.7%, respectively. In the subset of patients with a PD-L1 CPS of 10% or higher, the 6-month OS rates in the investigative and control arms were 67.4% and 50.8%, respectively; at 12 months, these rates were 44.0% and 27.0%, respectively.

Notably, survival benefit with tislelizumab over chemotherapy was noted across the predefined subgroups, including PD-L1 status, race, and region.

The median PFS with tislelizumab was 1.6 months (95% CI, 1.4-2.7) vs 2.1 months (95% CI, 1.5-2.7) with chemotherapy (HR, 0.83; 95% CI, 0.67-1.01). The 6-month PFS rates in the investigative and control arms were 21.7% and 14.9%, respectively; at 12 months, these rates were 12.7% and 1.9%, respectively. Notably, the PFS Kaplan-Meier curves began to separate about 3 months following randomization and favored tislelizumab.

The immunotherapy was also found to have a greater ORR vs chemotherapy, at 20.3% (95% CI, 15.6%-25.8%) and 9.8% (95% CI, 6.4%-14.1%), respectively (odds ratio, 2.4; 95% CI, 1.4-4.0). In the investigative arm, 2.0% of patients experienced a complete response, 18.4% had a partial response, and 26.6% achieved stable disease. Moreover, 45.3% of patients experienced disease progression.

Tislelizumab was also linked with a more durable tumor response, with a median DOR of 7.1 months (95% CI, 4.1-11.3) vs 4.0 months (95% CI, 2.1-8.2) with chemotherapy. At the time of the data cutoff, 19.2% of those in the investigative arm were still responding to treatment vs no patients on the control arm.

Regarding safety, tislelizumab had a favorable toxicity profile vs chemotherapy, with no new signals reported. In the investigative arm, 95.7% of patients experienced at least 1 treatment-emergent adverse effect (TEAE) and 73.3% experienced at least 1 treatment-related AE (TRAE); in the control arm, these rates were 98.3% and 93.8%, respectively. Grade 3 or higher TEAEs and TRAEs in the tislelizumab arm were experienced by 46.3% and 18.8% of patients, respectively; in the chemotherapy arm, these rates were 67.9% and 55.8%, respectively.

TEAEs and TRAEs resulted in treatment discontinuation in 19.2% and 6.7% of patients, respectively, who received tislelizumab; 26.7% and 13.8% of patients, respectively, who received chemotherapy discontinued treatment because of these toxicities. Moreover, 14 patients on the investigative arm experienced a TEAE that resulted in death, and 5 patients experienced a TRAE that resulted in death. In the control arm, 14 patients experienced a TEAE that led to death and 7 patients experienced a TRAE that led to death.

The most frequently reported treatment-related adverse effects in the investigative and control arms included aspartate aminotransferase increased (11.4% vs 3.8%, respectively), anemia (11.0% vs 34.6%), hypothyroidism (10.2% vs 0%), fatigue (7.5% vs 13.8%), decreased appetite (6.3% vs 31.3%), diarrhea (5.5% vs 27.5%), asthenia (4.7% vs 11.7%), malaise (3.9% vs 14.6%), and weight decrease (3.1% vs 10.4%), among others.

Tislelizumab is also under regulatory review in China as a potential treatment option for patients with locally advanced or metastatic ESCC who have progressive disease after, or are intolerant to, frontline standard chemotherapy.

References

1. BeiGene announces US FDA acceptance of biologics license application for tislelizumab in esophageal squamous cell carcinoma. News release. BeiGene, Ltd. September 13, 2021. Accessed September 13, 2021. https://bit.ly/2YJw17s
2. 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