Tislelizumab Receives Israeli Approval in Unresectable or Metastatic ESCC

The Israeli Ministry of Health (IL MOH) has approved tislelizumab-jsgr (Tevimbra) as monotherapy for the treatment of adult patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC) following prior systemic chemotherapy.¹

The anti–PD-1 antibody was compared with investigator’s choice of chemotherapy as second-line treatment in patients with unresectable, locally advanced, or metastatic ESCC in the phase 3 RATIONALE 302 trial (NCT03430843). Results demonstrated that tislelizumab (n = 256) led to a statistically significant improvement in median overall survival (OS) vs chemotherapy (n = 256) in the intention-to-treat population (ITT), at 8.6 months (95% CI, 7.5-10.4) vs 6.3 months (95% CI, 5.3-7.0), respectively, meeting the primary end point of the study (HR, 0.70; 95% CI, 0.57-0.85; P =.0001). The 12-month OS rates were 37.4% and 23.7% with tislelizumab and chemotherapy, respectively.²

“In Israel, the incidence of cancer continues to rise, with solid tumors representing a substantial health burden and where access to these inhibitors remains limited for the patients. The recent approval of [tislelizumab] by the Israeli Ministry of Health provides a new, innovative treatment for patients with ESCC, offering renewed hope and potentially improved outcomes for those affected by these challenging malignancies,” Itzik Mizrahi, country general manager of BeiGene Israel, said in a news release.¹ “We are pleased to have received approval in Israel, which represents a significant step forward in our mission to bring innovative treatments to cancer patients around the world.”

In September 2023, the European Commission approved tislelizumab as monotherapy for the treatment of adult patients with unresectable, locally advanced or metastatic ESCC after prior platinum-based chemotherapy.³ In March 2024, the FDA approved tislelizumab as a single agent in adult patients with unresectable or metastatic ESCC following prior systemic chemotherapy that did not include a PD-1/PD-L1 inhibitor.⁴ Both regulatory decisions were based on data from RATIONALE-302.

RATIONALE-302 Overview

The open-label, randomized, active-controlled, multicenter, phase 3 trial enrolled patients at least 18 years of age with histologically confirmed, advanced or metastatic ESCC that had progressed after first-line treatment. Patients who had tumor progression within 6 months after receiving definitive chemoradiotherapy, neoadjuvant, or adjuvant therapy were eligible. Patients were also required to have an ECOG performance status of 0 or 1, at least 1 measurable or evaluable lesion by RECIST 1.1, and adequate hematologic, hepatic, renal, and coagulation function.²

Patients were excluded if they had received prior PD-1/PD-L1–targeting therapies, or had active brain or leptomeningeal metastasis, active autoimmune disease, or other prior malignancies active within 2 years before random assignment.²

Patients were randomly assigned 1:1 to receive 200 mg of intravenous (IV) tislelizumab every 3 weeks or investigator’s choice of chemotherapy, which included either 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.²

OS in the ITT population served as the trial’s primary end point. Secondary end points included OS in patients with a PD-L1 tumor area positivity score (TAP) of at least 10%, progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and safety. Per the study design, OS would be evaluated in the subset of patients with a PD-L1 TAP score of at least 10% if deemed significant in the ITT population.²

Additional Efficacy and Safety Data for Tislelizumab

Further efficacy results from RATIONALE-302 demonstrated that patients with a TAP score of at least 10% also experienced a statistically significant improvement in median OS with tislelizumab vs chemotherapy, at 10.3 months (95% CI, 8.5-16.1) vs 6.8 months (95% CI, 4.1-8.3), respectively (HR, 0.54; 95% CI, 0.36-0.79; one-sided P = .0006).²

Median PFS in the ITT population was 1.6 months (95% CI, 1.4-2.7) with tislelizumab vs 2.1 months (95% CI, 1.5-2.7) with chemotherapy (HR, 0.83; 95% CI, 0.67-1.01). The ORR was 20.3% (95% CI, 15.6%-25.8%) vs 9.8% (95% CI, 6.4%-14.1%) with tislelizumab and chemotherapy, respectively. The median DOR in the tislelizumab and chemotherapy arms was 7.1 months (95% CI, 4.1-11.3) and 4.0 months (95% CI, 2.1-8.2), respectively.²

Furthermore, data from a prespecified exploratory analysis of the agent’s activity in the European/North American subgroup (n = 108) demonstrated that tislelizumab upheld its OS benefit vs chemotherapy, with a median OS of 11.2 months (95% CI, 5.9-14.8) vs 6.3 months (95% CI, 4.6-7.7), respectively (HR, 0.55; 95% CI, 0.35-0.87). The 12-month OS rates were 42.7% and 17.6% with tislelizumab and chemotherapy, respectively. Similar benefits in OS were seen regardless of PD-L1 TAP score (≥10%: HR, 0.47; 95% CI, 0.18-1.21; <10%: HR, 0.55; 95% CI, 0.30-1.01).⁵

Additionally, the median PFS was 2.3 months (95% CI, 1.5-2.8) with tislelizumab vs 2.7 months (95% CI, 1.4-3.9) with chemotherapy (HR, 0.97; 95% CI, 0.64-1.47). The ORR was also higher with tislelizumab, at 20.0% (95% CI, 10.4%-33.0%) vs 11.3% (95% CI, 4.3%-23.0%) with chemotherapy. Patients in the tislelizumab arm were also more likely to experience a prolonged response, with a median DOR of 5.1 months (95% CI, 1.6-not evaluable) vs 2.1 months (95% CI, 1.3-6.3) with chemotherapy.⁵

Regarding safety, the most common adverse effects that occurred in at least 20% of patients in the tislelizumab arm were 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.⁴

References

1. BeiGene receives Israeli Ministry of Health approval for Tevimbra for the treatment of oesophageal squamous cell carcinoma (OSCC) after prior chemotherapy. News release. BeiGene, Ltd. September 17, 2024. Accessed September 17, 2024. https://ir.beigene.com/news/beigene-receives-israeli-ministry-of-health-approval-for-tevimbra-for-the-treatment-of-oesophageal-squamous/dc2e4d21-42f4-4545-af69-ba4e09a40194/
2. Shen L, Kato K, Kim SB, et al. Tislelizumab vs chemotherapy as second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-302): a randomized phase III study. J Clin Oncol. 2022;40(26):3065-3076. doi:10.1200/JCO.21.01926
3. BeiGene announces positive regulatory updates in Europe and the U.S. after recently regaining global rights for Tevimbra. News release. BeiGene. September 19, 2023. Accessed September 17, 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/
4. 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 September 17, 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/
5. Ajani J, Hajbi FE, Cunningham D, et al. Tislelizumab versus chemotherapy as second-line treatment for European and North American patients with advanced or metastatic esophageal squamous cell carcinoma: a subgroup analysis of the randomized phase III RATIONALE-302 study. ESMO Open. 2024;9(1):102202. doi:10.1016/j.esmoop.2023.102202