CHMP Grants Positive Opinion to Tislelizumab/Chemotherapy in Frontline ES-SCLC

The median overall survival was 15.5 months with tislelizumab vs 13.5 months with placebo in extensive-stage small cell lung cancer.

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has recommended approval for tislelizumab-jsgr (Tevimbra) combined with etoposide and platinum chemotherapy in the first-line treatment of adult patients with extensive-stage small cell lung cancer (SCLC), according to a press release from the developer, BeiGene.¹

The positive opinion is supported by data from the randomized, double-blind, phase 3 RATIONALE-312 trial (NCT04005716) that evaluated the efficacy and safety of either tislelizumab or placebo with cisplatin or carboplatin and etoposide in the indicated population.²

At the data cutoff of April 19, 2023, with a median follow-up of 14.2 months, the median overall survival (OS) was 15.5 months (95% CI, 13.5-17.1) with tislelizumab vs 13.5 months (95% CI, 12.1-14.9) with placebo (HR, 0.75; 95% CI, 0.61-0.93; P = .0040). Estimated OS rates at 1 year were 63% with tislelizumab and 58% with placebo; at 2 years, they were 33% and 22%, respectively; and at 3 years, they were 25% and 9%, respectively.

The median progression-free survival (PFS) was 4.7 months (95% CI, 4.3-5.5) with tislelizumab vs 4.3 months (95% CI, 4.2-4.4) with placebo, respectively (HR, 0.64; 95% CI, 0.52-0.78; P < .0001). The estimated 6-month PFS rates were 35% and 18%, respectively, and the 12-month PFS rates were 21% and 5%.

Currently, tislelizumab plus chemotherapy is approved in the European Union and by the FDA in first-line unresectable esophageal squamous cell carcinoma and gastric or gastroesophageal junction adenocarcinoma, among other indications.^3,4

“The aggressive nature of extensive-stage SCLC makes it an extremely difficult type of lung cancer to treat, and currently available treatments may not adequately control disease progression,” Silvia Novello, MD, PhD, president of Women Against Lung Cancer in Europe and head of the Medical Oncology Unit of San Luigi Hospital in Orbassano, Italy, stated in the press release.¹ “The compelling data from the RATIONALE-312 study demonstrate the potential of [tislelizumab] plus chemotherapy as a further first-line treatment option to extend overall survival for patients with [extensive-stage] SCLC.”

RATIONALE-312 enrolled a total of 457 patients who were randomly assigned, in a 1:1 ratio, to receive either four 21-day cycles with 200 mg of intravenous tislelizumab or matched placebo every 3 weeks plus 100 mg/m² of intravenous etoposide on days 1 to 3 of each 21-day cycle and platinum chemotherapy—75 mg/m² of cisplatin or serum concentration–time curve of 5 of carboplatin—intravenously on day 1 of each cycle.

Eligible patients were 18 years or older with histologically or cytologically confirmed extensive-stage SCLC who hadn’t received prior systemic treatment and who also had an ECOG performance status of 1 or less, at least 12 weeks of life expectancy, and adequate organ function.

Active leptomeningeal disease or uncontrolled brain metastasis, mixed histologic diagnosis, underlying medical conditions, and previous therapy with an antibody or drug against immune checkpoint pathways were all reasons patients were excluded from participation.

The trial’s primary end point was OS. Secondary end points included PFS, overall response rate (ORR), duration of response (DOR), disease control rate, safety, and tolerability.

The confirmed ORR was 68% (95% CI, 62%-74%) with tislelizumab vs 62% (95% CI, 55%-68%) with placebo, and the median DOR was 4.3 months (95% CI, 4.1-5.6) vs 3.7 months (95% CI, 3.0-4.1), respectively.

Regarding safety, treatment-related adverse events (TRAEs) occurred in more than 99% of both groups, with grade 3 or higher TRAEs occurring in 86% of the tislelizumab group and 86% of the placebo group. The most common TRAEs of any grade were alopecia (78% vs 79%), anemia (76% vs 79%), and neutropenia (69% vs 70%); of grade 3 or higher, the most common TRAEs were neutropenia (56% vs 55%), decreased white blood cell count (24% vs 27%), and thrombocytopenia (19% vs 25%). Treatment-related serious AEs occurred in 31% vs 18% of patients, respectively.

TRAEs led to discontinuation in 11% and 2% of patients, respectively, and 4% of patients (n = 8) in the tislelizumab arm experienced a TRAE leading to death, with 5 instances related to tislelizumab and chemotherapy (thrombocytopenia, acute cardiac failure, autoimmune myocarditis, respiratory failure, and death with unknown cause), 2 related only to tislelizumab (gastrointestinal hemorrhage and depressed level of consciousness), and 1 due to chemotherapy (neutropenia). No patients in the placebo arm experienced a TRAE leading to death.

“In conclusion, the addition of tislelizumab to standard first-line chemotherapy with platinum and etoposide exhibited a significant reduction in the risk of death for patients with ES-SCLC, which was further supported by improvements in PFS, ORR, and DOR and a manageable safety profile,” the study authors wrote in the paper.²

References

1. BeiGene receives positive CHMP opinion for TEVIMBRA as a first-line treatment for extensive-stage small cell lung cancer. News release. BeiGene. March 31, 2025. Accessed April 1, 2025. https://tinyurl.com/4rt9673a
2. Cheng Y, Fan Y, Zhao Y, et al. Tislelizumab plus platinum and etoposide versus placebo plus platinum and etoposide as first-line treatment for extensive-stage SCLC (RATIONALE-312): a multicenter, double-blind, placebo-controlled, randomized, phase 3 clinical trial. J Thorac Oncol. 2024;19(7):1073-1085. doi:10.1016/j.jtho.2024.03.008
3. TEVIMBRA approved in U.S. for first-line treatment of advanced esophageal squamous cell carcinoma in combination with chemotherapy. News release. BeiGene. March 4, 2025. Accessed April 1, 2025. https://tinyurl.com/4np7u39m
4. TEVIMBRA approved in U.S. for first-line treatment of gastric and gastroesophageal junction cancers in combination with chemotherapy. News release. BeiGene. December 27, 2024. Accessed April 1, 2025. https://tinyurl.com/rwaw5cee