Zolbetuximab (2) – Vyloy®

• Clinical trials
  • The GLOW trial is an ongoing, double-blind, randomised, placebo-controlled Phase III trial designed to investigate the efficacy of zolbetuximab in combination with capecitabine and oxaliplatin (CAPOX) compared with placebo in combination with CAPOX.

a) Adults with locally advanced, inoperable or metastatic HER2-negative adenocarcinoma of the stomach or the gastro-oesophageal junction (GEJ) with Claudin (CLDN) 18.2-positive tumours with PD-L1 expression of ≥ 1 (Combined Positive Score; CPS); first-line treatment

• The pharmaceutical manufacturer has not identified any suitable study for patients with a PD-L1 expression of ≥ 1 (CPS). This is appropriate. Consequently, no data are available for the benefit assessment for this patient population.
• There is no evidence of additional benefit from zolbetuximab in first-line treatment of patients with locally advanced, inoperable or metastatic HER2-negative adenocarcinoma of the stomach or the gastro-oesophageal junction (GEJ) with Claudin (CLDN) 18.2-positive tumours with PD-L1 expression of ≥ 1 (CPS) is not proven.

b) Adults with locally advanced, inoperable or metastatic HER2-negative adenocarcinoma of the stomach or the gastro-oesophageal junction (GEJ) with Claudin (CLDN) 18.2-positive tumours with a PD-L1 expression of < 1 (Combined Positive Score; CPS); first-line treatment

• On balance, the GBA concludes that, given the minor improvement in overall survival and the fact that neither benefits nor disadvantages are evident in the endpoint categories of morbidity, health-related quality of life and side effects, a minor additional benefit of zolbetuximab in first-line treatment for patients with locally advanced, inoperable or metastatic HER2-negative adenocarcinoma of the stomach or the gastro-oesophageal junction (GEJ) with Claudin (CLDN) 18.2-positive tumours with a PD-L1 expression of < 1 (CPS).
• The certainty of evidence for the established additional benefit is classified as ‘hint’.
• mortality
  • In the GLOW trial, overall survival was defined as the time from randomisation to death from any cause.
  • For the endpoint of overall survival, a statistically significant difference was observed between the treatment groups in favour of zolbetuximab in combination with CAPOX.
  • The extent of the prolongation in overall survival achieved is assessed as a minor improvement.
• Morbidity – Progression-free survival
  • In the GLOW study, progression-free survival was defined as the time from randomisation to the occurrence of radiological disease progression (according to RECIST version 1.1), assessed by a blinded independent review committee (IRC), or until death from any cause, whichever occurred first.
  • No statistically significant difference was observed between the study arms for the PFS endpoint.
  • 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 ‘radiological progression of the disease’ component of morbidity is assessed according to RECIST criteria and is therefore not symptom-based, but determined exclusively by imaging procedures.
  • Taking the above aspects into account, there are differing views within the GBA regarding the clinical relevance of the PFS endpoint to patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
• Morbidity – Symptoms (assessed using the EORTC QLQ-C30 and EORTC QLQ-OG25)
  • Symptoms of the disease were assessed in the GLOW study using the EORTC QLQ-C30 questionnaire and the EORTC QLQ-OG25 supplementary module. Responder analyses were presented for the time to the first deterioration of ≥ 10 points, which are used for the present benefit assessment.
  • For nausea and vomiting, which occur particularly in connection with the first loading dose of zolbetuximab, the relevant items of the EORTC QLQ-C30 could not be meaningfully interpreted in either study arm due to limitations relating to antiemetic treatment.
• Health-related quality of life
  • Health-related quality of life was assessed in the GLOW study using the EORTC QLQ-C30 questionnaire. Responder analyses were presented for the time to the first deterioration of ≥ 10 points, which are used for the present benefit assessment.
  • With regard to health-related quality of life, no statistically significant difference was observed between the treatment arms for any of the endpoints: ‘global health status’, ‘physical functioning’, ‘role functioning’, ‘cognitive functioning’, ‘emotional functioning’ and ‘social functioning’.
  • In the subgroup analyses, the ‘social functioning’ scale showed an effect modification by the characteristic ‘age’, as assessed using the EORTC QLQ-C30. Specifically, a statistically significant disadvantage compared to zolbetuximab + CAPOX was observed for patients aged > 65 years, whilst no statistically significant difference between the treatment arms was observed for patients aged ≤ 65 years. The results for the overall population are used for the assessment.
  • Overall, therefore, neither an advantage nor a disadvantage is identified for the endpoint category of health-related quality of life.
• Side effects – Total adverse events (AEs)
  • In the GLOW trial, an AE occurred in almost all patients in both the control and intervention arms. The results are presented here for supplementary information only.
• Overall view
  • For the benefit assessment, results are available on mortality, morbidity, quality of life and side effects from the ongoing, double-blind, randomised, placebo-controlled Phase III GLOW study comparing zolbetuximab in combination with capecitabine and oxaliplatin (CAPOX) with placebo in combination with CAPOX.
  • For the endpoint of overall survival, the GLOW study shows a statistically significant advantage in favour of zolbetuximab. The extent of the prolongation in overall survival achieved is assessed as a minor improvement.
  • For the morbidity endpoint category, no statistically significant differences were observed between the treatment groups for the endpoints of symptoms (assessed using the EORTC QLQ-C30 and the disease-specific supplementary module EORTC QLQ-OG25), pain intensity (assessed using the NRS) and health status (via the EQ-5D VAS), no statistically significant differences were observed between the treatment groups.
  • For the health-related quality of life endpoint category, which was assessed using the EORTC QLQ-C30, there was no statistically significant difference between the treatment groups.
  • The results regarding side effects show no statistically significant differences between the treatment arms in terms of SAE, severe AEs and discontinuations due to AEs. In detail, a disadvantage was observed for the specific AE ‘reduced appetite’. When the results on side effects are considered as a whole, neither an advantage nor a disadvantage can be identified.
  • On balance, the GBA concludes that, given the minor improvement in overall survival and the fact that neither advantages nor disadvantages are evident in the endpoint categories of morbidity, health-related quality of life and side effects, a minor additional benefit of zolbetuximab in first-line treatment for patients with locally advanced, inoperable or metastatic HER2-negative adenocarcinoma of the stomach or the gastro-oesophageal junction (GEJ) with Claudin (CLDN) 18.2-positive tumours with a PD-L1 expression of < 1 (CPS).

Courtesy translation only, please refer to the German original.