Durvalumab (4) – Imfinzi®

• Clinical trials
  • The POSEIDON trial is an open-label, randomised, controlled Phase III trial comparing durvalumab + tremelimumab + 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 durvalumab + tremelimumab + platinum-based chemotherapy and pembrolizumab.
  • This provides no hint of additional benefit from durvalumab + tremelimumab + 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 treatment cycles within the study arms, the PRO data from the POSEIDON study are deemed 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.
  • As the data for the overall population regarding the endpoints adverse events (AEs), serious adverse events (SAEs) and discontinuation due to AEs do not differ significantly between this predefined data cut-off and the data cut-offs (25 October 2021 and 22 March 2022 respectively), the data from the dossier will be used.
  • For the endpoint ‘severe AEs’ (CTCAE grade ≥ 3), however, the data for the overall population differ significantly between the predefined final data cut-off of 12 March 2021 and the data cut-off of 25 October 2021 submitted by the pharmaceutical manufacturer, meaning that no suitable data from the POSEIDON study are available for an indirect comparison for this endpoint.
  • No data are available for the relevant patient population in the KEYNOTE-042 trial.
  • Total adverse events (AEs): AEs occurred in almost all patients in the patient populations relevant for the indirect comparison from the POSEIDON and KEYNOTE-024 studies.
  • Serious adverse events (SAEs): For the SAE endpoint, the adjusted indirect comparison shows no statistically significant difference between durvalumab + tremelimumab + platinum-based chemotherapy and pembrolizumab.
  • Therapy discontinuations due to adverse events: 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.
  • PRO-CTCAE and immune-mediated adverse events: No data, or no suitable data, are available for the endpoints PRO-CTCAE and immune-mediated adverse events.
  • Overall, with regard to side effects, there is no hint that durvalumab + tremelimumab in combination with platinum-based chemotherapy causes greater or minor harm compared with pembrolizumab; greater or minor harm is therefore not proven.
• Overall assessment / Conclusion
  • 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 durvalumab in combination with tremelimumab 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

• An additional benefit is not proven.
• The dossier contains results from the adjusted indirect comparison of the POSEIDON study with the CA2 study for the assessment of the additional benefit of durvalumab in combination with tremelimumab and platinum-based chemotherapy compared with nivolumab in combination with ipilimumab and two cycles of platinum-based chemotherapy in adults with metastatic NSCLC with 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 assessment / Conclusion
  • Overall, there is no evidence of additional benefit for durvalumab in combination with tremelimumab 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 does not provide proof.

Courtesy translation only, please refer to the German original.