Tremelimumab (Tremelimumab AstraZeneca, 1) – Tremelimumab AstraZeneca®

• Clinical trials
  • The POSEIDON trial is an open-label, randomised, controlled Phase III trial comparing tremelimumab + durvalumab + platinum-based chemotherapy or durvalumab + platinum-based chemotherapy with platinum-based chemotherapy alone.
  • The KEYNOTE-024 trial is an open-label, randomised, controlled Phase III trial comparing pembrolizumab with platinum-based combination chemotherapy.
  • The KEYNOTE-042 trial is an open-label, randomised, controlled Phase III trial comparing pembrolizumab with a combination of carboplatin and either paclitaxel or pemetrexed.
  • The CA209-9LA trial is an ongoing, open-label, randomised, controlled Phase III trial comparing nivolumab in combination with ipilimumab and two cycles of platinum-based chemotherapy with platinum-based combination chemotherapy.

a) Adults with metastatic NSCLC with PD-L1 expression ≥ 50% and no genomic EGFR or ALK tumour mutations, first-line treatment

• An additional benefit is not proven.
• mortality
  • For the endpoint of overall survival, the adjusted indirect comparison shows no statistically significant difference between tremelimumab + durvalumab + platinum-based chemotherapy and pembrolizumab.
  • This provides no hint of additional benefit from tremelimumab + durvalumab + platinum-based chemotherapy compared with pembrolizumab; additional benefit is therefore not proven.
• Morbidity and health-related quality of life
  • No suitable data are available for the endpoints in the categories of morbidity and quality of life.
  • Given the uneven distribution of treatment burden across the course of the treatment cycle in the study arms, the PRO data from the POSEIDON study are considered unusable.
  • Consequently, no suitable data are available for the endpoints assessed using the EORTC QLQ-C30, EORTC QLQ-LC13, the EQ-5D VAS and the PGIC in an indirect comparison.
• Side effects
  • For the POSEIDON study, no data are available for the relevant patient population for the predefined final data cut-off date of 12 March 2021.
  • Adverse events occurred in almost all patients in the patient populations relevant for the indirect comparison in the POSEIDON and KEYNOTE-024 trials.
  • For the SAE endpoint, the adjusted indirect comparison shows no statistically significant difference between tremelimumab + durvalumab + platinum-based chemotherapy and pembrolizumab.
  • For the endpoint of therapy discontinuations due to AEs, the open-label design of both the POSEIDON and KEYNOTE-024 studies results in a high potential for bias in each case; consequently, the data are not suitable for indirect comparison due to insufficient certainty of the results.
  • No data, or no suitable data, are available for the PRO-CTCAE endpoints or for immune-mediated adverse events.
  • Overall, with regard to side effects, there is no hint that the combination of tremelimumab and durvalumab with platinum-based chemotherapy causes greater or minor harm compared with pembrolizumab; therefore, greater or minor harm is not proven.
• Overall assessment
  • For the assessment of the additional benefit of durvalumab in combination with tremelimumab and platinum-based chemotherapy compared with pembrolizumab in adults with metastatic NSCLC with a PD-L1 expression ≥ 50% and no genomic EGFR or ALK tumour mutations are available from the adjusted indirect comparison of the POSEIDON study with the KEYNOTE-024 and KEYNOTE-042 studies, using platinum-based chemotherapy as the bridge comparator.
  • The studies presented are sufficiently similar and, overall, suitable for conducting an adjusted indirect comparison.
  • For the endpoint of overall survival, no difference relevant to the assessment is evident.
  • No suitable data are available for the endpoint categories of morbidity and quality of life.
  • For the endpoint category ‘side effects’, no differences relevant to the assessment are evident in the SAE endpoint. No suitable data are available for severe side effects (CTCAE ≥ 3) or therapy discontinuations due to side effects.
  • Overall, there is no evidence of additional benefit for tremelimumab in combination with durvalumab and platinum-based chemotherapy compared with pembrolizumab in adults with metastatic NSCLC with a PD-L1 expression of ≥ 50% and no genomic EGFR or ALK tumour mutations does not provide proof.

b) Adults with metastatic NSCLC with PD-L1 expression < 50% and no genomic EGFR or ALK tumour mutations, first-line treatment

• The additional benefit is not proven.
• Mortality, morbidity, health-related quality of life and side effects
  • Due to relevant differences in the patient populations of the two studies with regard to the characteristic of ethnicity – which in the POSEIDON study represents a relevant, qualitative effect modifier for the endpoint of overall survival – and given that the pharmaceutical manufacturer has not provided any subgroup analyses to verify this point, the data presented are not suitable for an indirect comparison.
• Conclusion
  • For the assessment of the additional benefit of tremelimumab in combination with durvalumab and platinum-based chemotherapy compared with nivolumab in combination with ipilimumab and two cycles of platinum-based chemotherapy in adults with metastatic NSCLC with a PD-L1 expression < 50% and no genomic EGFR or ALK tumour mutations, the dossier contains results from the adjusted indirect comparison of the POSEIDON study with the CA209-9LA study, using platinum-based chemotherapy as the bridge comparator.
  • Due to relevant differences in the patient populations of the two studies with regard to the characteristic of ethnicity – which in the POSEIDON study represents a relevant, qualitative effect modifier for the endpoint of overall survival – and given that the pharmaceutical manufacturer has not provided any subgroup analyses to verify this point, the data submitted are not suitable for an indirect comparison.
  • Overall, there is no evidence of additional benefit for tremelimumab in combination with durvalumab and platinum-based chemotherapy compared with the appropriate comparator therapy for adults with metastatic NSCLC with a PD-L1 expression < 50% and no genomic EGFR or ALK tumour mutations do not provide proof.

Courtesy translation only, please refer to the German original.