Tebentafusp (2) – Kimmtrak®

• Clinical trials
  • The pivotal IMCgp100-202 trial is an ongoing, randomised, multicentre, controlled, open-label Phase II trial in which Tebentafusp is being compared with standard of care therapy (dacarbazine, ipilimumab and pembrolizumab).

Adults with inoperable or metastatic uveal melanoma who are HLA (human leukocyte antigen) A02:01-positive

• As a result, tebentafusp has been found to offer a considerable additional benefit over dacarbazine, ipilimumab and pembrolizumab.
• In summary, the G-BA derives a hint of the established additional benefit in terms of its significance.
• mortality
  • In the IMCgp100-202 study, overall survival is defined as the time from randomisation to death, regardless of the underlying cause of death.
  • A statistically significant advantage in favour of Tebentafusp compared with dacarbazine, ipilimumab and pembrolizumab was observed for overall survival.
  • The extent of the prolongation achieved in overall survival is regarded as a significant improvement.
  • Subgroup analyses for the overall survival endpoint revealed an interaction between treatment and the stratification variable LDH (≤ ULN vs. > ULN; p = 0.04). For the LDH ≤ ULN patient population, a statistically significant advantage was observed in favour of Tebentafusp. For the LDH > ULN patient population, no statistically significant advantage was observed.
• Morbidity – Symptoms (EORTC QLQ-C30)
  • Symptoms of the disease were assessed in the IMCgp100-202 study using the cancer-specific EORTC QLQ-C30 questionnaire.
  • In the study, the response rates in the comparator arm were already below 70% at baseline. Furthermore, the difference in response rates between the treatment arms was more than 15%. The results presented are therefore unsuitable for benefit assessment and will not be taken into account.
• Morbidity – Health status (EQ-5D, visual analogue scale)
  • Health status was assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • The results of the questionnaire were not taken into account due to the low response rates – which were already low at baseline – and the significant differences in response rates between the groups.
• Health-related quality of life (EORTC QLQ-C30)
  • Health-related quality of life was assessed in the IMCgp100-202 study using the functional scales and the global scale for general health status of the EORTC QLQ-C30.
  • The results on health-related quality of life from the EORTC QLQ-C30 are not used for the benefit assessment, as the response rates in the comparator arm were already below 70% at baseline and the difference in response rates between the treatment arms was more than 15%.
• Side effects – Total adverse events (AEs)
  • In the IMCgp100-202 study, an adverse event occurred in all patients in the control arm and in 95% of patients in the intervention arm.
• Side effects – serious adverse events (SAEs) and discontinuation due to AEs
  • For the endpoints of SADEs and discontinuation due to AEs, there was no statistically significant difference between the study arms in either case.
• Side effects – Severe AEs (CTCAE grade ≥ 3)
  • A statistically significant disadvantage of tebentafusp was observed with regard to severe adverse events of CTCAE grade 3 or 4.
• Side effects – Specific AEs
  • In detail, Tebentafusp showed a statistically significant advantage over dacarbazine, ipilimumab and pembrolizumab with regard to specific AEs involving disorders of the respiratory tract, thoracic cavity and mediastinum (SOC, SUEs).
  • In contrast, Tebentafusp showed a statistically significant disadvantage compared with dacarbazine, ipilimumab and pembrolizumab with regard to the specific AEs skin reactions, severe skin reactions, gastrointestinal disorders, eye diseases, headaches, paraesthesia, general disorders and administration site conditions, and vascular disorders.
  • In the category of side effects, therefore, an overall disadvantage of Tebentafusp compared with dacarbazine, ipilimumab and pembrolizumab can be observed.
• Overall assessment
  • For the benefit assessment of tebentafusp in the treatment of HLA (human leukocyte antigen) A02:01-positive adults with inoperable or metastatic uveal melanoma, results are available from the IMCgp100-202 study on mortality, morbidity (symptoms and health status), health-related quality of life and side effects.
  • The results for the endpoint of overall survival show that treatment with Tebentafusp, compared with dacarbazine, ipilimumab and pembrolizumab, results in a prolongation of overall survival, which is assessed as a significant improvement.
  • In the endpoint category of morbidity and health-related quality of life (assessed using the EORTC QLQ-C30 and EQ-5D VAS), no evaluable data are available for the benefit assessment due to minor response rates and major differences in response rates between the treatment arms. Conclusions regarding morbidity and quality of life are considered particularly important, especially in the context of palliative care as discussed here.
  • With regard to side effects, a statistically significant disadvantage for tebentafusp is observed for the endpoint of severe AEs (CTCAE ≥ 3). In detail, adverse effects predominate among the specific side effects. In the side effects category, therefore, an overall disadvantage for tebentafusp is observed.
  • On balance, the positive effect on overall survival is offset by negative side effects in the ‘adverse events’ endpoint category. Taking into account the extent of the positive effect on overall survival in an advanced palliative care setting, the G-BA concludes that the disadvantage regarding side effects does not, in the overall assessment, justify a downgrading of the extent of the additional benefit.

Courtesy translation only, please refer to the German original.