First-Line Tislelizumab Plus Chemotherapy Shows OS Benefit in PD-L1+ ESCC Subgroups

The addition of tislelizumab (Tevimbra) to chemotherapy led to an improvement in overall survival (OS) vs placebo plus chemotherapy in patients with locally advanced unresectable or metastatic esophageal squamous cell carcinoma (ESCC) and a combined positive score (CPS) of at least 1 or a tumor area positivity (TAP) score of at least 1%, according to findings from an exploratory post-hoc analysis of the phase 3 RATIONALE-306 trial (NCT03783442) that were presented at the 2024 ESMO Gastrointestinal Cancers Congress.¹

Regarding TAP score, the HRs for patients with values of at least 10%, 5% to less than 10%, and 1% to less than 5% were 0.71 (95% CI, 0.53-0.95), 0.50 (95% CI, 0.33-0.75), and 0.86 (95% CI, 0.59-1.26), respectively. With regard to CPS, the respective HRs for patients with values of at least 10, 5 to less than 10, and 1 to less than 5 were 0.64 (95% CI, 0.48-0.86), 0.72 (95% CI, 0.47-1.09), and 0.71 (95% CI, 0.49-1.03). Raymond noted that the size of patient subgroups with less than 1% expression prevented accurate assessment of the data.

“These findings from the 3-year follow-up provide further support for the therapeutic advantages of tislelizumab plus chemotherapy over placebo plus chemotherapy as first-line treatment of ESCC, as well as the interchangeability of TAP score and CPS in measuring PD-L1 expression in ESCC,” lead study author Eric Raymond, MD, PhD, consultant and head of medical oncology at Saint-Joseph Hospital in Paris, France, said in a presentation of the data.

RATIONALE-306 is a randomized, double-blind, global phase 3 trial that enrolled patients with unresectable locally advanced or metastatic ESCC. Eligibility criteria required that patients have no prior systemic treatment for advanced disease, an ECOG performance status of 0 or 1, and measurable or evaluable disease per RECIST 1.1 criteria.

Previously reported findings from the trial demonstrated that the combination of tislelizumab and chemotherapy significantly increased OS vs chemotherapy alone in all randomly assigned patients (HR, 0.70; 95% CI, 0.59-0.83) and patients with a PD-L1 TAP score of at least 10% (HR, 0.70; 95% CI, 0.52-0.95).²

As part of the trial design, upon enrollment, patients were randomly assigned 1:1 to receive either 200 mg of intravenous tislelizumab every 3 weeks plus platinum and fluoropyrimidine or platinum plus paclitaxel; or placebo plus chemotherapy. Maintenance therapy was continued until unacceptable toxicity or disease progression.¹

The primary end points were OS in the intention-to-treat population. Secondary end points included OS in patients with a TAP score of at least 10%, progression-free survival (PFS), objective response rate, duration of response, health-related quality of life, and safety. Exploratory end points included OS and PFS using exploratory PD-L1 TAP and CPS cutoffs, as well as TAP score and CPS concordance.

“TAP score is a newly developed area scoring system evaluating both immune and tumor cells. The TAP score has been analytically developed and validated for advanced ESCC in the RATIONALE-306 study,” Raymond explained.

PD-L1 expression was stained using the VENTANA PD-L1 SP263 assay from Roche and determined by TAP. For the exploratory analysis pathologists in the central laboratory scored the same stained samples according to CPS.

Of the 649 patients who had been randomly assigned to treatment, 542 had evaluable TAP scores and 537 had evaluable post-hoc CPS. Raymond noted that the frequencies of TAP score and CPS were comparable across arms at different thresholds.

Additional OS data revealed similar trends in PD-L1–positive subgroups based on associated clinical cutoffs. For the population with a TAP score between 1% to less than 5%, the median OS was 13.0 months (95% CI, 10.8-18.3) with the combination vs 9.6 months (95% CI, 7.9-13.7) with chemotherapy alone. In the 5% to less than 10% population, the median OS was 23.1 months (95% CI, 16.4-28.3) with tislelizumab vs 9.8 months (95% CI, 8.0-13.0) with placebo. In patients with a TAP score of at least 10% , the median OS was 16.6 months (95% CI, 15.3-23.4) and 10.0 months (95% CI, 8.6-13.3) with the combination and chemotherapy alone, respectively.

When looking at CPS in the 1 to less than 5 subgroup, the median OS was 16.7 months (95% CI, 12.3-20.8) with the combination vs 9.5 months (95% CI, 7.7-13.7) with chemotherapy alone. In the 5 to less than 10 subgroup, the median OS was 16.8 months (95% CI, 11.2-23.9) and 10.8 months (95% CI, 8.0-16.7) with the combination and chemotherapy alone, respectively. In patients with a CPS of at least 10, the median OS was 17.2 months (95% CI, 15.3-24.1) with tislelizumab vs 9.4 months (95% CI, 8.5-12.3) with placebo.

Similar improvements in favor of the tislelizumab arm were also observed for PFS, although Raymond noted that the benefit extended to all PD-L1 subgroups. The HRs for patients with TAP scores of at least 10%, 5% to less than 10%, 1% to less than 5%, and less than 1% were 0.49 (95% CI, 0.36-0.67), 0.52 (95% CI, 0.34-0.79), 0.74 (95% CI, 0.49-1.11), and 0.83 (95% CI, 0.47-1.46), respectively. Regarding CPS, the respective HRs for patients with values of at least 10, 5 to less than 10, 1 to less than 5, and less than 1 were 0.45 (95% CI, 0.33-0.61), 0.74 (95% CI, 0.48-1.12), 0.66 (95% CI, 0.44-0.98), and 0.76 (95% CI, 0.51-1.23).

“Good correlation was observed between TAP score and CPS, as shown by the interclass correlation coefficient [ICC, 0.85; 95% CI, 0.80-0.88],” Raymond added. “TAP score and CPS showed substantial concordance at multiple cutoffs in terms of overall percent agreement [OPA] and Cohen’s Kappa at the 1% [OPA, 97%; 95% CI, 96%-98%], 5% [OPA, 85%; 95% CI, 82%-88%], and 10% [OPA, 89%; 95% CI, 87%-92%] thresholds of each score.”

Earlier in February 2024, the FDA accepted a biologics license application seeking the approval of tislelizumab plus fluoropyrimidine and platinum-containing chemotherapy as frontline therapy for patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma.³ In March 2024, the FDA green lit the use of tislelizumab monotherapy for the treatment of patients with unresectable or metastatic ESCC after systemic chemotherapy that did not include a PD-(L)1 inhibitor.⁴

References

1. Raymond E, Xu J, Kato K, et al. Tislelizumab (TIS) + chemotherapy (CT) vs placebo (PBO) + CT in advanced or metastatic esophageal squamous cell carcinoma (ESCC): PD-L1 biomarker analysis from RATIONALE-306. Ann Oncol. 2024; 35(supp 1): S162-S204. Doi: 10.1016/annonc/annonc1482
2. Yoon HH, Kato K, Raymond, et al. Global, randomized, phase III study of tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced/metastatic esophageal squamous cell carcinoma (RATIONALE-306 update): minimum 3-year survival follow-up. J Clin Oncol. 2024;42(suppl 16):4032. doi:10.1200/JCO.2024.42.16_suppl.4032
3. 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 July 1, 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/
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 July 1, 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/