Kato Breaks Down FDA Approval of Tislelizumab in Esophageal Cancer

Ken Kato, MD, PhD

On March 4, 2025, the FDA approved the combination of tislelizumab-jsgr (Tevimbra) and platinum-containing chemotherapy as a frontline treatment for adult patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC) with a tumor PD-L1 expression of 1 or higher, based on data from the phase 3 RATIONALE-306 trial (NCT03783442).¹

This global trial demonstrated that adding tislelizumab to platinum-based chemotherapy significantly improved survival compared with chemotherapy alone, with a hazard ratio of 0.66 for the overall population (95% CI, 0.54-0.80; 1-sided P < .0001). At a median follow-up of 16.3 months (interquartile range [IQR], 8.6-21.8) in the tislelizumab plus chemotherapy group (n = 326) and 9.8 months (IQR, 5.8-19.0) in the placebo plus chemotherapy group (n = 323), the median OS was 17.2 months (95% CI, 15.8-20.1) vs 10.6 months (95% CI, 9.3-12.1), respectively.²

The benefit was consistent across PD-L1 expression levels, including patients with a PD-L1 combined positive score (CPS) of 5% to 10% and those with CPS <10%.

“Tislelizumab is the first PD-1 antibody developed in China to gain global approval, which is a significant milestone. Its efficacy and safety profile make it a unique and important addition to the treatment options for ESCC and potentially other cancers,” explained Ken Kato, MD, PhD, in an interview with Targeted Oncology^TM.

In the interview, Kato, chief of the department of head and neck, and esophageal medical oncology and gastrointestinal medical oncology at the National Cancer Center Hospital in Tokyo, Japan, further discussed this FDA approval of tislelizumab for the treatment of patients with ESCC.

Targeted Oncology: What was the background of the RATIONALE-306 trial?

Kato: The RATIONALE 306 trial was conducted globally, but mainly in China. Tislelizumab is a PD-1 antibody made in China. The trial evaluated tislelizumab in combination with platinum-containing chemotherapy regimens. The RATIONALE-306 trial aimed to validate the additive effect of tislelizumab to baseline chemotherapy and its role in the first-line treatment of esophageal squamous cell carcinoma.

3D rendered medically accurate illustration of esophagus cancer: © Sebastian Kaulitzki - stock.adobe.com

What were the key findings from the trial that led to this FDA approval?

Nivolumab [Opdivo] and pembrolizumab [Keytruda] have already shown survival benefits when combined with baseline chemotherapy for ESCC. In RATIONALE-306, the best chemotherapy regimens consisted of taxanes or fluorouracil with cisplatin or oxaliplatin. All combinations were adapted for the RATIONALE-306 trial. Compared with the nivolumab and pembrolizumab trials, RATIONALE-306 demonstrated a survival benefit for tislelizumab when added to baseline chemotherapy, with a hazard ratio of 0.66 for the entire population.

Could you elaborate on the primary results of the trial?

The primary result of RATIONALE-306 showed a hazard ratio of 0.66 for the entire population, regardless of PD-L1 positivity. The median survival time for the chemotherapy plus tislelizumab arm was 17.2 months, compared with 10.6 months for chemotherapy alone. For the population with a PD-L1 CPS of 10% or more, the hazard ratio improved to 0.62. Even in the population with a PD-L1 CPS of less than 10%, the hazard ratio was 0.77, which is still favorable compared to the chemotherapy-alone arm. This led to the FDA approval of tislelizumab in combination with platinum-based chemotherapy for the first-line treatment of ESCC.

How does this combination of tislelizumab and chemotherapy improve survival compared with chemotherapy alone? What should community oncologists know about this finding?

The RATIONALE-306 trial included various chemotherapy regimens, such as cisplatin with fluorouracil or paclitaxel. In China, paclitaxel-based regimens are standard, while in the rest of the world, fluorouracil with cisplatin or oxaliplatin is commonly used. Subgroup analysis showed that both combinations demonstrated favorable hazard ratios when tislelizumab was added to chemotherapy. This is different from the nivolumab and pembrolizumab trials, as tislelizumab showed positive results even with taxane-containing or fluorouracil-containing regimens. This is a unique point of the RATIONALE-306 trial.

How does this approval impact frontline treatment options for this patient population?

The hazard ratio is numerically better, but we believe the magnitude of benefit from adding tislelizumab to chemotherapy is similar to other PD-1 antibodies like nivolumab and pembrolizumab. In Japan and the US, nivolumab and pembrolizumab are already approved for first-line treatment. However, tislelizumab offers a slightly wider treatment window, especially for patients with a PD-L1 CPS of 5% to 10%. There is some preclinical data suggesting that tislelizumab binds more strongly to PD-1 compared with nivolumab and pembrolizumab, which may contribute to its efficacy. While the efficacy is similar, there is potential for tislelizumab to offer additional benefits in certain patient populations.

What were the most notable safety signals or adverse events observed in the trial, and how were they managed?

There were no obvious differences in safety signals between tislelizumab, nivolumab, and pembrolizumab. Immune-related adverse events were reported in less than 10% of patients, which is similar to the results from the CheckMate 648 [NCT03143153] and KEYNOTE-590 [NCT03189719] trials. Overall, the safety profile of tislelizumab does not differ significantly from other PD-1 antibodies.

How do you foresee this approval influencing future combination strategies in ESCC and beyond?

Of course, this approval opens the door for further research into combination therapies, such as combining tislelizumab with TKIs or other targeted therapies. Pembrolizumab has already been combined with lenvatinib (Lenvima), and we are waiting for results from other trials. Nivolumab has not progressed as much in this area. We expect that tislelizumab will be evaluated in combination with chemotherapy, immunotherapy, and targeted therapies for ESCC and other cancers, such as gastric cancer. Perioperative chemotherapy with or without tislelizumab may also be explored for further development.

What factors should oncologists consider when selecting tislelizumab over other options?

As I mentioned earlier, there are no obvious differences in efficacy or safety between tislelizumab, nivolumab, and pembrolizumab when combined with chemotherapy. However, tislelizumab may offer a slightly wider treatment window for patients with a PD-L1 CPS of 5% to 10%. Pembrolizumab is approved in the US for patients with a PD-L1 CPS of 10% or more, while tislelizumab is approved for patients with a PD-L1 CPS of 5% or more. This makes tislelizumab a viableoption for a broader patient population.

What are the next steps for research on tislelizumab in other cancers or in this space?

Tislelizumab is already being evaluated for gastric cancer in the RATIONALE 305 trial, which has shown a survival benefit when combined with chemotherapy for first-line treatment. Tislelizumab is also being studied in combination with other therapies, such as tyrosine kinase inhibitors, for gastric cancer. Additionally, perioperative chemotherapy with or without tislelizumab is being explored for further development. Tislelizumab is expected to expand into other cancer types, including gastric cancer, where pembrolizumab has already been approved. The combination strategies used for ESCC and gastric cancer will likely be applied to other indications as well.

[Overall], tislelizumab was developed in China, where many PD-1 and PD-L1 antibodies are being developed. However, most of these are only available in China. Tislelizumab is the first PD-1 antibody developed in China to gain global approval, which is a significant milestone. Its efficacy and safety profile make it a unique and important addition to the treatment options for ESCC and potentially other cancers.

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 11, 2025. https://tinyurl.com/bdzy9e59

2. 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