Tislelizumab Plus Chemo Expands First-Line ESCC Treatment Paradigm

Nataliya Uboha, MD, PhD

Results from the phase 3 RATIONALE-306 trial (NCT03783442), as well as its unique mechanism of action, have positioned tislelizumab-jsgr (Tevimbra) to alter the frontline treatment armamentarium for patients with treatment-naive esophageal squamous cell carcinoma (ESCC), according to Nataliya Uboha, MD, PhD.

In March 2025, the FDA approved first-line tislelizumab in combination with platinum-containing chemotherapy for the treatment of adult patients with unresectable or metastatic ESCC with a tumor PD-L1 expression of at least 1.1 This regulatory decision was backed by data from RATIONALE-306, where findings showed that in the population of patients with disease with a PD-L1 tumor area positivity (TAP) score of at least 1, the median overall survial (OS) was 16.8 months (95% CI, 15.3-20.8) among those who received tislelizumab plus chemotherapy (n = 231) vs 9.6 months (95% CI, 8.9-11.8) among those who received placebo plus chemotherapy (n = 250; HR, 0.66; 95% CI, 0.53-0.82).1,2

Additionally, in patients with a PD-L1 combined positive score of at least 1, the median OS was 16.8 months (95% CI, 15.3-20.8) for those in the tislelizumab arm (n = 233) vs 9.6 months (95% CI, 8.9-11.8) for patients in the placebo arm (n = 247; HR, 0.65; 95% CI, 0.52-0.81).2

“We should be able to easily incorporate this [regimen] into our treatment paradigms,” Uboha said in an interview with OncLive®. “Tislelizumab can be combined with different chemotherapy backbones and should be built into treatment guidelines for patients with ESCC.”

In the interview, Uboha discussed the benefits of expanding the ESCC treatment paradigm with tislelizumab plus chemotherapy, key findings from RATIONALE-306, and considerations for managing toxicities with the use of PD-1 inhibitors in patients with ESCC.

Uboha is a faculty leader for the Early Phase Oncology Therapeutics Program at the University of Wisconsin Carbone Cancer Center, as well as an associate professor and researcher in the Department of Medicine at the University of Wisconsin School of Medicine and Public Health in Madison.

OncLive: What is the significance of the FDA approval of frontline tislelizumab plus chemotherapy in PD-L1–positive advanced ESCC?

Uboha: This approval allows patients to have access to additional options for treatment. ESCC is an aggressive malignancy; patients with this disease have a poor prognosis. It’s incurable in the metastatic setting, and we need more and better treatment options for patients with this disease. In addition, many patients with ESCC are diagnosed with significant disease-related symptoms, and they have a lot of comorbidities. This approval will hopefully lead to better outcomes for patients with significant needs.

How does this approval address unmet needs for patients with ESCC?

Typically, we treat patients with this cancer with chemotherapy and immunotherapy. Tislelizumab is a new anti–PD-1 agent that has demonstrated activity in advanced ESCC. In [March 2024], it was FDA approved for patients with pretreated ESCC, and now we are seeing the approval of this agent in the first-line ESCC setting. This approval [is for tislelizumab] in combination with multiple different chemotherapy backbones. In the United States, we can combine this anti–PD-1 antibody with 5-fluorouracil [5-FU]–based chemotherapy or with taxane-based chemotherapy in the first-line setting, which are additional options for patients.

How does the mechanism of action of tislelizumab differ from other PD-1 inhibitors?

Tislelizumab is designed to optimize PD-1 binding, resulting in potent CD8-positive T-cell activation. It binds to PD-1 at a unique epitope, and this binding competitively blocks PD-1 interaction with both PD-L1 and PD-L2. A differentiating factor from other anti–PD-1 agents is that tislelizumab does not bind Fcγ receptors and macrophages; therefore, it does not induce antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity. In preclinical studies, this feature enhanced the functional activity of T cells.

What was the design of the RATIONALE-306 trial?

RATIONALE-306 was a global, double-blind, placebo-controlled study that enrolled 649 patients with advanced ESCC. These patients had not received prior treatment in the advanced setting. Patients were randomly assigned in a 1:1 fashion to receive either placebo plus chemotherapy or tislelizumab plus chemotherapy. The primary end point was OS in the intention-to-treat [ITT] population. The study also had several secondary end points, including progression-free survival, overall response rate, and OS in a biomarker-defined patient population of patients with a PD-L1 score of 10% or greater.

The study allowed investigators to choose the chemotherapy backbone. Patients could be treated with platinum—either cisplatin or oxaliplatin—plus either a fluoropyrimidine, such as 5-FU, capecitabine, or paclitaxel. The patient populations were well balanced between the treatment arms.

What were the key efficacy findings from this trial?

The median OS was improved with the addition of tislelizumab [to chemotherapy vs placebo plus chemotherapy]. In the ITT patient population, the median OS was 17.2 months [95% CI, 15.8-20.1] in the experimental arm [n = 326] vs 10.6 months [95% CI, 9.3-12.1] in the control arm [n = 323; HR, 0.66; 95% CI, 0.54-0.80].3 In the preplanned subgroup analysis, we saw a significant improvement in OS [with tislelizumab] in patients who had tumors with a PD-L1 score of 10% or higher.

We also saw improvements in OS across other subgroups. The only subgroup of patients not to derive benefit from the addition of tislelizumab [to chemotherapy] were patients with low PD-L1 scores, [defined as] less than 1%. Otherwise, at different PD-L1 score cutoffs—including 1%, 5%, and 10%—we saw significant improvements in OS with the addition of tislelizumab to chemotherapy.

What is the safety profile of tislelizumab? Are there any patients in whom you would hesitate to use this agent?

We did not see any new or unexpected safety signals when tislelizumab was used in this patient population. Tislelizumab has a similar safety profile to other anti–PD-1 agents, and we did not uncover any surprising findings in this study. I would hesitate to use this medication in patients who have any pre-existing or poorly controlled autoimmune conditions, or in patients with transplanted organs requiring immunosuppression. Otherwise, this agent should be offered to all patients with advanced PD-L1–positive ESCC.

What resources do you recommend for learning to manage the AEs that are commonly seen with the use of PD-1 inhibitors?

I typically refer to the National Comprehensive Cancer Network guidelines for the management of immune-mediated toxicities, as well as the ASCO guidelines. Both of those documents provide a good roadmap on how to manage immune-mediated toxicities [associated with] anti–PD-1 antibodies.

Based on this approval, where does tislelizumab fit into the current ESCC treatment paradigm?

Tislelizumab is another anti–PD-1 agent that we can use in combination with chemotherapy in the first-line setting. This antibody should be used in patients with ESCC who have tumors with a PD-L1 score of 1% or greater. This antibody can be combined with either 5-FU–based or taxane-based chemotherapy in the first-line setting. This is a great option for patients and expands their treatment possibilities.

References

1. Tevimbra approved in US for first-line treatment of advanced esophageal squamous cell carcinoma in combination with chemotherapy. News release. BeiGene, Ltd. March 4, 2025. Accessed March 26, 2025. https://hkexir.beigene.com/news/tevimbra-approved-in-u-s-for-first-line-treatment-of-advanced-esophageal-squamous-cell-carcinoma-in-combination/8379a7c3-35ce-45af-82d3-164c64ecf37c/
2. Tevimbra. Prescribing information. BeiGene. March 2025. Accessed March 26, 2025. https://www.beigene.com/PDF/TEVIMBRAUSPI.pdf
3. 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