Tislelizumab (4) – Tevimbra®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer submitted the results from the completed, open-label, randomised, controlled Phase III trial RATIONALE 303, which compared tislelizumab with docetaxel.

a1) Patients with PD-L1 expression ≥ 1 %

• An additional benefit is not proven.
• No data are available to enable an assessment of additional benefit. In its dossier, the pharmaceutical manufacturer presents data only for patients with PD-L1 expression < 1 per cent. No data are available for patients with PD-L1 expression ≥ 1 per cent.

a2) Patients with PD-L1 expression < 1 %

• An additional benefit is not proven.
• Following a balanced assessment, the G-BA concludes that an additional benefit is not proven for tislelizumab.
• mortality
  • In the RATIONALE 303 study, overall survival is defined as the time from randomisation to death from any cause.
  • No statistically significant difference was observed between the treatment groups for the endpoint of overall survival.
• morbidity
  • Progression-free survival (PFS) was defined in the RATIONALE 303 trial as the time from randomisation to the first objective disease progression or to death from any cause.
  • No statistically significant difference was observed between the treatment groups for the PFS endpoint.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. The ‘mortality’ component of this endpoint was assessed in the present study via the ‘overall survival’ endpoint as a standalone endpoint. The morbidity component was not assessed on the basis of symptoms, but exclusively by means of imaging procedures (radiologically determined disease progression according to the RECIST Version 1.1 criteria).
  • 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.
• Morbidity – Alopecia (EORTC QLQ-LC13)
  • Symptoms (EORTC QLQ-C30 and EORTC QLQ-LC13)
  • An exception is formed by the results for the alopecia endpoint (EORTC QLQ-LC13), which are used for the benefit assessment, as the Kaplan-Meier curves diverge immediately after the start of the study and a clear difference in the course of the curves is discernible. This reveals a statistically significant advantage in favour of tislelizumab compared with docetaxel.
• Morbidity – Symptoms (EORTC QLQ-C30 and EORTC QLQ-LC13)
  • The analyses presented – both regarding the time to first confirmed deterioration and the time to first deterioration – cannot be meaningfully interpreted. The reasons for this are explained in the section‘On symptoms, health status and health-related qualityoflife’.
• Morbidity – Health status (EQ-5D VAS)
  • The analyses presented – both regarding the time to first confirmed deterioration and the time to first deterioration – cannot be meaningfully interpreted. The reasons for this are explained in the section‘On symptoms, health status and health-related qualityoflife’.
• Quality of life (EORTC QLQ-C30)
  • The analyses presented – both regarding the time to the first confirmed deterioration and the time to the first deterioration – cannot be meaningfully interpreted. The reasons for this are explained in the section‘On symptoms, health status and health-related quality of life’.
• On symptoms, health status and health-related quality of life
  • In the dossier, the pharmaceutical manufacturer presents, for the patient-reported endpoints of symptoms (assessed using the EORTC QLQ-C30 and EORTC QLQ-LC13), health status (assessed using the EQ-5D VAS) and health-related quality of life (assessed using the EORTC-QLQ C30), the pharmaceutical company presents both responder analyses and continuous evaluations using a mixed-effects model with repeated measurements (MMRM) to assess change from baseline.
  • However, the follow-up period for the patient-reported endpoints was, on the one hand, systematically and very significantly shorter than that for overall survival and, on the other hand, varied considerably between the treatment arms; consequently, the presented responder analyses could not be meaningfully interpreted given the available data.
  • The continuous analyses submitted in support of the case are not suitable for benefit assessment, as there were a high number of missing values in the analyses overall (> 50 %) and, in addition, large differences between the study arms.
  • The analyses regarding the time to first deterioration, which were submitted as part of the commenting procedure, show that by month 6 (or week 24), for the majority of endpoints in the comparator arm, only ≤ 10 patients remained under observation, and censoring occurred to a major extent as early as the first 2.5 months after the start of observation.
  • However, differences in the events occurring between the treatment arms only become apparent for most endpoints after month 3 and are therefore potentially influenced to a large extent by these censorings. Due to these considerable uncertainties, the subsequently submitted responder analyses up to the first deterioration in patient-reported endpoints cannot currently be meaningfully interpreted given the available data.
• Side effects – Total adverse events (AEs)
  • Total adverse events (AEs)
  • In the RATIONALE 303 study, AEs occurred in almost all patients in both treatment arms. The results are presented here for supplementary information only.
• Conclusion on side effects
  • Conclusion on side effects:
  • Overall, tislelizumab showed a statistically significant improvement in severe AEs (CTCAE grade ≥ 3) compared with docetaxel. In detail, advantages were predominantly observed for the specific AEs. No suitable data are available on immune-mediated AEs.
• Overall assessment
  • When the results are considered as a whole, tislelizumab shows a statistically significant improvement in the endpoint of alopecia, as assessed using the EORTC QLQ-LC13, and a clear advantage in terms of severe adverse events.
  • However, limitations relevant to the assessment arise from the fact that, apart from the endpoint of alopecia (assessed using the EORTC QLQ-LC13), no evaluable data are available for other morbidity endpoints. Similarly, no evaluable data are available on health-related quality of life. Data on health-related quality of life are considered particularly important in the context of advanced palliative care, as is the case here. No advantage in overall survival could be demonstrated.
  • Furthermore, it is taken into account that the study population under investigation is only of very limited relevance to real-world clinical practice, as treatment with an immune checkpoint inhibitor in addition to prior platinum-based therapy has since become the standard of care.

Courtesy translation only, please refer to the German original.