FDA Approves Tislelizumab for Advanced or Metastatic ESCC After Chemotherapy

FDA

The FDA has approved tislelizumab-jsgr (Tevimbra) for single-agent use in adult patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC) following prior systemic chemotherapy that did not include a PD-1/PD-L1 inhibitor.

The regulatory decision was supported by data from the phase 3 RATIONALE 302 study (NCT03430843) in which tislelizumab (n = 256) significantly improved overall survival (OS) vs chemotherapy (n = 256), at a median of 8.6 months (95% CI, 7.5-10.4) vs 6.3 months (95% CI, 5.3-7.0), respectively (HR, 0.70; 95% CI, 0.57-0.85; P = .0001). The 6-month OS rate with tislelizumab was 62.3% vs 51.8% with chemotherapy; the respective 12-month OS rates were 37.4% and 23.7%.

“Today’s FDA approval of Tevimbra for patients with ESCC who have previously received chemotherapy, along with its ongoing review of our BLA for first-line ESCC patients, represents a significant step in our commitment to bringing this therapy to more patients around the world,” Mark Lanasa, MD, PhD, chief medical officer of Solid Tumors at BeiGene, stated in a press release. “As BeiGene’s first drug candidate produced through our immuno-oncology program and second approved medicine in the United States, Tevimbra is poised to be a critical pillar of our solid tumor development program, which spans more than 17 registration-enabling clinical trials in more than 30 countries across regions globally.”

About RATIONALE 302

Patients with advanced or metastatic ESCC who experienced disease progression during or after first-line systemic treatment were enrolled in the phase 3 study.² Patients were required to have an ECOG performance status of 0 or 1.

Participants (n = 512) were were randomly assigned in a 1:1 fashion to intravenous (IV) tislelizumab at 200 mg every 3 weeks or investigator’s choice of chemotherapy. Those in the chemotherapy arm received one of the following regimens: 135 mg/m² to 175 mg/m² of IV paclitaxel given every 3 weeks or 80 mg/m² to 100 mg/m² given weekly; 75 mg/m² of IV docetaxel given every 3 weeks; or IV irinotecan given at 125 mg/m² on days 1 and 8 every 3 weeks.

Stratification factors included region (Asia [excluding Japan] vs Japan vs Europe/North America), ECOG performance status (0 vs 1), and choice of chemotherapy (paclitaxel vs docetaxel vs irinotecan).

OS in the all-randomized population served as the trial's primary end point. 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 an HR of 0.75 at a 0.025 significance level (1-sided) for the primary end point. If OS in the all-randomized population proved significant, OS in the subset of patients with a PD-L1 combined positive score (CPS) of at least 10% was evaluated sequentially.

Additional Data

Findings presented at the 2021 ASCO Annual Meeting showed that the survival benefit achieved with tislelizumab over chemotherapy was reported across the predefined subgroups, including PD-L1 status, race, and region.

In the subset of patients with a PD-L1 CPS of at least 10%, the median OS with tislelizumab was 10.3 months (95% CI, 8.5-16.1) vs 6.8 months (95% CI, 4.1-8.3) with chemotherapy (HR, 0.54; 95% CI, 0.36-0.79; P = .0006). Here, the 6-month OS rates in the tislelizumab and chemotherapy arms were 67.4% and 50.8%, respectively; the 12-month rates were 44.0% and 27.0%, respectively.

The median PFS reported 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 these respective arms were 21.7% and 14.9%, and the respective 12-month PFS rates were 12.7% and 1.9%. The PFS Kaplan-Meier curves began to separate about 3 months after randomization and favored tislelizumab.

Tislelizumab also elicited a higher ORR than that experienced with 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). Moreover, the median DOR was longer with tislelizumab vs chemotherapy, at 7.1 months (95% CI, 4.1-11.3) and 4.0 months (95% CI, 2.1-8.2), respectively. At the data cutoff date of December 1, 2020, 19.2% of patients in the tislelizumab arm were still responding to treatment vs no patients in the chemotherapy arm.

Safety

The most common toxicities experienced with the agent that occurred in at least 20% of patients included increased glucose, decreased hemoglobin, decreased lymphocytes, decreased sodium, decreased albumin, increased alkaline phosphatase, anemia, fatigue, increased aspartate aminotransferase, musculoskeletal pain, decreased weight, increased alanine aminotransferase, and cough.¹

The Road to Approval

In September 2021, the FDA accepted the biologics license application (BLA) for tislelizumab as a potential therapeutic option in patients with unresectable recurrent locally advanced or metastatic ESCC after prior systemic treatment.³ In July 2022, the agency deferred action on the BLA due to an inability to conduct the inspections required due to travel restrictions linked with COVID-19.⁴

In September 2023, the FDA accepted for review a BLA seeking the approval of tislelizumab in the first-line treatment of patients with unresectable, recurrent, locally advanced or metastatic ESCC based on data from the phase 3 RATIONALE 306 study (NCT03783442).⁵ Data indicated that the addition of tislelizumab to chemotherapy (n = 326) led to a median overall survival (OS) of 17.2 months (95% CI, 15.8-20.1) vs 10.6 months (95% CI, 9.3-12.1) with placebo plus chemotherapy (n = 323; stratified HR, 0.66; 95% CI, 0.54-0.80; P < .0001).⁶

In February 2024, the FDA accepted for review a BLA seeking the approval of the agent in combination with fluoropyrimidine- and platinum-containing chemotherapy in the frontline treatment of patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma.⁷ This application is supported by findings from the phase 3 RATIONALE 305 study (NCT03777657) in which the median OS with tislelizumab plus chemotherapy (n = 501) was 15.0 months (95% CI, 13.6-16.5) vs 12.9 months (95% CI, 12.1-14.1) with placebo plus chemotherapy (n = 496; HR, 0.80; 95% CI, 0.70-0.92; log-rank P = .0011).⁸ The target action date is expected in December 2024.

References

1. BeiGene receives FDA approval for Tevimbra for the treatment of advanced or metastatic esophageal squamous cell carcinoma after prior chemotherapy. News release. BeiGene, Ltd. March 14, 2024. Accessed March 14, 2024. https://ir.beigene.com/news/beigene-receives-fda-approval-for-tevimbra-for-the-treatment-of-advanced-or-metastatic-esophageal-squamous/20eb032c-15ce-456a-a852-39c88a28d811/
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
3. BeiGene announces US FDA acceptance of biologics license application for tislelizumab in esophageal squamous cell carcinoma. News release. BeiGene, Ltd. September 13, 2021. Accessed March 14, 2024. https://hkexir.beigene.com/news/beigene-announces-u-s-fda-acceptance-of-biologics-license-application-for-tislelizumab-in-esophageal-squamous-cell/5c97c078-8ee7-4a4e-aba3-19d5a9dac715/
4. 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 March 14, 2024. https://ir.beigene.com/news/beigene-provides-regulatory-update-on-the-u-s-biologics-license-application-bla-for-pd-1-inhibitor-tislelizumab/09127f95-fd94-4a1b-b215-3e356e5fcfd9/
5. BeiGene announces positive regulatory updates in Europe and the US after recently regaining global rights for Tevimbra. News release. BeiGene, Ltd. September 19, 2023. Accessed March 14, 2024. https://ir.beigene.com/news/beigene-announces-positive-regulatory-updates-in-europe-and-the-u-s-after-recently-regaining-global-rights/5e4692d6-d726-4989-a659-49dc97d4d7ed/
6. Xu J, Kato K, Raymond E, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023;24(5):483-495. doi:10.1016/S1470-2045(23)00108-0
7. BeiGene’s biologics license application for Tevimbra (tislelizumab) for first-line gastric or gastroesophageal junction cancers accepted by FDA. News release. BeiGene. February 27, 2024. Accessed March 14, 2024. https://ir.beigene.com/news/beigene-s-biologics-license-application-for-tevimbra-tislelizumab-for-first-line-gastric-or-gastroesophageal-junction-cancers-accepted/4cc83f12-9249-4984-9a2a-c607c8a6e879/
8. Xu RH, Oh DY, Kato K, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment of advanced gastric or gastroesophageal junction adenocarcinoma: final analysis results of the RATIONALE-305 study. Ann Oncol. 2023;34(suppl 2):S1281-S1282. doi:10.1016/S0923-7534(23)X0011-8