Trastuzumab deruxtecan (7) – Enhertu®

• Clinical trials
  • The open-label Phase III RCT DESTINY-Gastric04, which is currently still ongoing, began in May 2021.
  • Of the 494 patients, 246 were randomised to the intervention arm receiving trastuzumab deruxtecan and 248 to the control arm receiving ramucirumab in combination with paclitaxel.

a) Adults with advanced HER2-positive adenocarcinoma of the stomach or the gastro-oesophageal junction (GEJ); following prior trastuzumab-based first-line therapy

• Overall, the advantages in terms of overall survival and discontinuation due to AEs are not offset by any disadvantages.
• Overall, the G-BA concludes – particularly on the basis of the advantage in overall survival – that trastuzumab deruxtecan offers a modest additional advantage for the treatment of adults with advanced HER2-positive adenocarcinoma of the stomach or the gastro-oesophageal junction (GEJ) following prior trastuzumab-based first-line therapy.
• The certainty of the evidence for the established additional benefit is classified as ‘indication’ in this assessment.
• mortality
  • In the DESTINY-Gastric04 trial, overall survival is defined as the time from randomisation to death from any cause.
  • For the endpoint of overall survival, a statistically significant difference was observed in favour of trastuzumab deruxtecan compared with ramucirumab in combination with paclitaxel; the extent of this difference is assessed as a relevant improvement, though not exceeding a minor level.
• Morbidity – Progression-free survival
  • In the study, progression-free survival is defined as the time from randomisation to the first objective radiological progression of the disease or death (regardless of the underlying cause), whichever occurs first.
  • For the PFS endpoint, there is a statistically significant difference in favour of trastuzumab deruxtecan compared with ramucirumab in combination with paclitaxel.
  • The PFS endpoint in question is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint.
• Morbidity – Symptoms
  • Symptoms of the disease were assessed in the DESTINY-Gastric04 study using the PGIS questionnaire.
  • The data on symptoms and health status submitted by the pharmaceutical manufacturer cannot be assessed due to the sharply declining and varying response rates.
• Morbidity – Health status
  • Health status was assessed using the PGIC and the visual analogue scale (VAS) from the EQ-5D questionnaire.
  • The data on symptoms and health status provided by the pharmaceutical manufacturer cannot be assessed due to the sharply declining and varying response rates.
• Health-related quality of life
  • In the DESTINY-Gastric04 study, health-related quality of life was assessed using the FACT-Ga, which comprises both the FACT-General (FACT-G) and the gastric cancer-specific Gastric Cancer Subscale (GaCS).
  • The data on quality of life submitted by the pharmaceutical manufacturer cannot be assessed due to the sharply declining and varying response rates.
• Side effects – Total adverse events (AEs)
  • In the DESTINY-Gastric04 study, AEs occurred in almost all patients in both the control and intervention arms.
• Side effects – serious AEs (SAEs), severe AEs (CTCAE grade ≥ 3)
  • No statistically significant differences were observed between the treatment arms for the endpoints SAE and severe AEs.
• Side effects – Discontinuation due to AEs
  • For the endpoint ‘discontinuation due to AEs’, there was a statistically significant advantage in favour of trastuzumab deruxtecan compared with ramucirumab in combination with paclitaxel.
  • There is also evidence of an effect modification by the characteristic of age.
  • In the overall assessment of the available results from the DESTINY-Gastric04 study, this effect modification by the characteristic of age is not considered sufficient to derive separate conclusions regarding additional benefit in the overall evaluation.
• Side effects – Specific AEs – reduced platelet count (severe AEs) and ILD / pneumonitis (SUEs)
  • For the endpoints ‘reduced platelet count’ (severe AEs) and ‘interstitial lung disease’ (ILD) / pneumonitis (SUEs), there was no statistically significant difference between the treatment groups in either case.
• Overall assessment
  • Results on mortality, morbidity, health-related quality of life and adverse events are available from the randomised, multicentre, open-label, phase III study evaluating the additional benefit of trastuzumab deruxtecan in the treatment of adults with advanced HER2-positive adenocarcinoma of the stomach or the gastro-oesophageal junction (GEJ) following prior trastuzumab-based first-line therapy, results on mortality, morbidity, health-related quality of life and side effects are available from the randomised, multicentre, controlled DESTINY-Gastric04 trial.
  • For the endpoint of overall survival, a statistically significant advantage was observed in favour of trastuzumab deruxtecan compared with ramucirumab in combination with paclitaxel; the extent of this advantage is assessed as a relevant improvement, though not exceeding a minor level.
  • In the morbidity endpoint category, disease symptoms (PGIS) and health status (EQ-5D VAS and PGIC) were assessed. However, the data presented cannot be evaluated due to the sharply declining and varying response rates.
  • Health-related quality of life was assessed using the FACT-Ga. However, the data presented cannot be evaluated due to the sharply declining and varying response rates.
  • For the ‘side effects’ endpoint category, trastuzumab deruxtecan shows specific advantages and disadvantages for individual side effects; however, these are not reflected in the overall rates of SAEs and severe side effects. For the endpoint ‘discontinuation due to adverse events’, there is a statistically significant advantage in favour of trastuzumab deruxtecan. Overall, therefore, for the endpoint ‘discontinuation due to side effects’, an advantage of trastuzumab deruxtecan over ramucirumab in combination with paclitaxel can be identified, which is assessed as moderate.
  • On balance, the advantages in terms of overall survival and discontinuation due to AEs are not offset by any disadvantages. Overall, the G-BA concludes – particularly on the basis of the advantage in overall survival – that trastuzumab deruxtecan offers a modest added advantage for the treatment of adults with advanced HER2-positive adenocarcinoma of the stomach or the gastro-oesophageal junction (GEJ) following prior trastuzumab-based first-line therapy provides a minor additional benefit.

Courtesy translation only, please refer to the German original.