Tislelizumab (8) – Tevimbra®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer presented the results from the completed, double-blind, randomised, controlled Phase IIIRATIONALE 309 trial, which compared tislelizumab in combination with cisplatin and gemcitabine against cisplatin in combination with gemcitabine.

Adults with recurrent nasopharyngeal carcinoma (NPC) that is not suitable for curative surgery or radiotherapy, or with metastatic NPC; first-line treatment

• The conclusion is that there is no evidence of additional benefit for tislelizumab in combination with gemcitabine and cisplatin compared with gemcitabine in combination with cisplatin for adults with recurrent, Who are not eligible for curative surgery or radiotherapy, or who have metastatic nasopharyngeal carcinoma, have not been provided with proof.
• mortality
  • overall survival
  • In the RATIONALE 309 trial, overall survival was defined as the time from randomisation to death from any cause. No statistically significant difference was observed between the treatment arms for this endpoint.
• morbidity
  • Progression-free survival
  • Progression-free survival (PFS) was defined in the RATIONALE 309 study as the time from randomisation to the first objectively documented disease progression or to death, whichever occurred first, based on the date of the first radiological documentation of disease progression in accordance with the RECIST (Response Evaluation Criteria in Solid Tumours, Version 1.1) criteria.
  • PFS is statistically significantly prolonged with tislelizumab in combination with gemcitabine and cisplatin compared with gemcitabine in combination with cisplatin.
  • The PFS endpoint in question is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories. The ‘mortality’ component of the endpoint is already assessed as a standalone endpoint via the ‘overall survival’ endpoint. The ‘disease progression’ component of the morbidity endpoint is assessed according to RECIST criteria and thus predominantly by means of imaging procedures.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients.
  • The overall conclusion regarding additional benefit remains unaffected by this.
  • Symptoms (EORTC QLQ-C30 and EORTC QLQ-H&N35)
  • Symptoms were assessed using the EORTC QLQ-C30 questionnaire and its disease-specific supplementary module, the EORTC QLQ-H&N35. For the benefit assessment, the time to the first deterioration of ≥ 10 points is used.
  • There are no statistically significant differences between the treatment arms.
  • There is an effect modification, particularly due to the characteristic ‘presence of liver metastases’. For patients with liver metastases, there is a statistically significant difference in favour of tislelizumab on the ‘speech problems’ symptom scale and, in patients without liver metastases, a statistically significant difference to the detriment of tislelizumab on the ‘feeling unwell’ symptom scale.
  • Given that this effect modification is only evident for individual endpoints, the result for the overall population is used for the assessment.
  • Overall, there are no differences relevant to the benefit assessment in the morbidity endpoint category.
• Health-related quality of life
  • EORTC QLQ-C30 and EORTC QLQ-H&N35
  • Health-related quality of life was assessed using the EORTC QLQ-C30 questionnaire and its disease-specific supplementary module, the EORTC QLQ-H&N35. For the benefit assessment, the time to the first deterioration of ≥ 10 points is used.
  • There are no statistically significant differences between the treatment arms.
• Side effects
  • Total adverse events (AEs)
  • In the RATIONALE 309 trial, AEs occurred in almost all patients in both treatment arms. The results are presented here for supplementary information only.
  • Serious AEs (SAEs), severe AEs and discontinuation due to AEs
  • For the endpoints SAEs, severe AEs and discontinuation due to AEs, there were no statistically significant differences between the treatment arms in any case.
  • Specific AEs
  • In detail, a statistically significant disadvantage compared to tislelizumab in combination with gemcitabine and cisplatin was observed for the specific AEs ‘immune-mediated severe AEs’ and ‘fever (PT, AE)’. There is an effect modification by the characteristic ‘presence of liver metastases’. For patients with liver metastases, there is no statistically significant difference between the treatment arms for ‘fever (PT, AE)’.
  • In the overall assessment of the results regarding side effects, no overall advantage or disadvantage was identified for treatment with tislelizumab in combination with gemcitabine and cisplatin compared with gemcitabine in combination with cisplatin.
• Overall assessment
  • For the assessment of the additional benefit of tislelizumab in combination with gemcitabine and cisplatin in adults with recurrent nasopharyngeal carcinoma (NPC), results on mortality, morbidity, health-related quality of life and side effects are available from the randomised, controlled, double-blind Phase III RATIONALE 309 trial comparing the treatment with gemcitabine in combination with cisplatin. The analysis is based on the final data cut-off of 8 December 2023.
  • In the mortality endpoint category, there is no difference between the treatment arms.
  • For the endpoint categories of morbidity and health-related quality of life, there were no statistically significant differences in the endpoints of time to first worsening of symptoms or quality of life (assessed using the EORTC QLQ-C30 and EORTC QLQ-H&N35) respectively.
  • For the endpoint category ‘side effects’, there are also no differences relevant to the benefit assessment.
  • In the endpoint categories of morbidity and side effects, isolated instances of effect modification were observed, particularly in relation to the characteristic ‘presence of liver metastases’. According to statements made by clinical experts during the oral hearing, liver metastases are a relevant prognostic factor in the present therapeutic indication. Against this background, whilst the G-BA regards this as a relevant finding of the benefit assessment, the result for the overall population is used for the assessment due to the merely sporadic occurrence of this effect modification.
  • Overall, no differences relevant to the benefit assessment can be identified for treatment with tislelizumab in combination with gemcitabine and cisplatin across all endpoint categories. Additional benefit is not proven.

Courtesy translation only, please refer to the German original.