Zolbetuximab (1) – Vyloy®

• Clinical trials
  • The GLOW trial is a 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.
  • The SPOTLIGHT trial is a double-blind, randomised, placebo-controlled Phase III trial designed to investigate the efficacy of zolbetuximab in combination with oxaliplatin, 5-fluorouracil and folinic acid (modified FOLFOX-6 regimen; mFOLFOX6) compared with placebo in combination with mFOLFOX6.
  • The FAST study is an open-label, randomised, placebo-controlled Phase II study designed to investigate the efficacy and safety of zolbetuximab in combination with epirubicin, oxaliplatin and capecitabine (EOX) compared with placebo in combination with EOX.

Adults with locally advanced, inoperable or metastatic HER2-negative adenocarcinoma of the stomach or the gastro-oesophageal junction, whose tumours are CLDN 18.2-positive

• On balance, the positive effect on overall survival is offset by disadvantages in terms of side effects. These disadvantages do not call into question the extent of the improvement in overall survival. No assessable data are available regarding morbidity and health-related quality of life. Overall, therefore, a minor additional benefit is identified.
• The strength of the evidence for the identified additional benefit is classified overall as an indication.
• mortality
  • In the GLOW and SPOTLIGHT studies, overall survival is defined as the time from randomisation to death from any cause or the end of the study.
  • For the endpoint of overall survival, the GLOW and SPOTLIGHT studies, as well as the meta-analysis of these two studies, show a statistically significant difference between the treatment arms. The extent of the prolongation in overall survival achieved is assessed as a relevant improvement, though not exceeding a minor level.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival (PFS) was defined in the GLOW and SPOTLIGHT trials as the time from randomisation to the occurrence of radiological disease progression or to death from any cause.
  • For the PFS endpoint, both the GLOW and SPOTLIGHT studies demonstrated a statistically significant advantage of zolbetuximab in combination with CAPOX (GLOW study) and mFOLFOX6 (SPOTLIGHT study), respectively.
  • 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 – Symptoms
  • Symptoms were assessed using the EORTC QLQ-C30, EORTC QLQ-OG25 and EQ-5D-5L-VAS instruments. In addition, pain intensity was assessed using a numerical rating scale (NRS).
  • The results are not presented due to minor response rates at the end of treatment (< 70 %) and during the follow-up phase (30- and 90-day follow-up). Particularly as the probability of a deterioration in health status increases at the end of treatment, or a deterioration in health status may lead to the end of treatment, these data at the end of treatment are necessary in order to fully assess the effects/effects of the intervention and control group on symptoms and to be able to interpret and compare the results adequately. Furthermore, no information is available on the reasons for censoring.
• Health-related quality of life – EORTC QLQ-C30
  • Health-related quality of life was assessed using the EORTC QLQ-C30 instrument.
  • The results are not presented due to minor response rates at the end of treatment (< 70 %) and during the follow-up phase (30- and 90-day follow-up). Furthermore, no information is available on the reasons for censoring (detailed description in the section on symptoms).
• Side effects – Total adverse events (AEs)
  • In the GLOW and SPOTLIGHT studies, AEs occurred in almost all patients in both study arms. The results are presented here only as supplementary information.
• Side effects – Serious adverse events (SAEs)
  • No statistically significant difference was observed between the treatment groups for any of the endpoints.
• Side effects – Severe adverse events (CTCAE Grade 3 or 4)
  • For the endpoint of severe AEs, a statistically significant difference was observed in the SPOTLIGHT study and in the meta-analysis of the GLOW and SPOTLIGHT studies, to the disadvantage of zolbetuximab in combination with mFOLFOX6 or chemotherapy.
• Side effects – Therapy discontinuations due to adverse events
  • For the endpoint of discontinuation due to adverse events, the meta-analysis of the GLOW and SPOTLIGHT studies shows a statistically significant difference in favor of zolbetuximab in combination with chemotherapy compared to its disadvantage.
• Conclusion on side effects
  • Overall, with regard to the endpoint category of side effects, zolbetuximab in combination with fluoropyrimidine- and platinum-based chemotherapy showed disadvantages compared with placebo in combination with fluoropyrimidineand platinum-based chemotherapy in the SPOTLIGHT study; in the meta-analysis, there were disadvantages in terms of severe adverse events as well as discontinuation due to adverse events. In detail, there are disadvantages as well as individual advantages for specific adverse events.
• Overall assessment / Conclusion
  • For the endpoint of overall survival, there is a statistically significant advantage in favour of zolbetuximab in combination with CAPOX or mFOLFOX6. The extent of the prolongation in overall survival achieved is assessed as a relevant improvement, though not exceeding a minor extent.
  • No evaluable data are available regarding morbidity and health-related quality of life.
  • On balance, the positive effect on overall survival is offset by disadvantages in terms of side effects. These disadvantages do not call into question the extent of the improvement in overall survival. No evaluable data are available regarding morbidity and health-related quality of life. Overall, therefore, a minor additional benefit is identified.

Courtesy translation only, please refer to the German original.