Trifluridin / Tipiracil (2) – Lonsurf®

• Clinical trials
  • The benefit assessment of the combination of active substances trifluridine and tipiracil is based on the pivotal, randomised, double-blind Phase III trial TAS-102-302 (TAGS).

Adult patients with metastatic gastric cancer, including adenocarcinoma of the gastro-oesophageal junction, who have already been treated with at least two systemic treatment regimens for advanced disease

• For trifluridine/tipiracil as monotherapy for the treatment of adult patients with metastatic gastric cancer, including adenocarcinoma of the gastro-oesophageal junction, who have already been treated with at least two systemic treatment regimens for advanced disease, there is an indication for a minor additional benefit.
• Consequently, the G-BA concludes that for trifluridine/tipiracil for the treatment of adult patients with metastatic gastric cancer, including adenocarcinoma of the gastro-oesophageal junction, who have already been treated with at least two systemic treatment regimens for advanced disease and who do not have a minor additional benefit.
• Consequently, the certainty of the evidence for the established additional benefit is classified as ‘indication’.
• Mortality – Overall survival
  • Treatment with trifluridine/tipiracil + best supportive care (BSC) results in a statistically significant prolongation of overall survival compared with placebo + BSC (hazard ratio (HR): 0.69; 95% confidence interval (CI) [0.56; 0.86]; p-value: < 0.001).
  • The median survival time is prolonged by 2.1 months with treatment with trifluridine/tipiracil + BSC (5.7 months) compared with the control arm (3.6 months).
  • The prolongation of overall survival achieved with trifluridine/tipiracil + BSC compared with placebo + BSC is considered a relevant improvement rather than a merely marginal one.
• Morbidity – Progression-free survival (PFS)
  • Trifluridine/tipiracil + BSC (2.0 months) statistically significantly extended the median PFS compared with the control arm (1.8 months) (HR: 0.57; 95% CI [0.47; 0.70]; p < 0.0001) by 0.2 months.
  • Disease progression occurred in 85.2% of patients (287) in the intervention arm and in 91.8% of patients (156) in the control arm.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • 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 criteria).
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint.
  • Overall, the sensitivity analyses for PFS are therefore not taken into account in the assessment.
• Morbidity – Symptoms
  • Symptoms were assessed using the symptom scales of the cancer-specific EORTC QLQ-C30 questionnaire and the gastric cancer-specific EORTC QLQ-STO22 questionnaire.
  • Analyses of symptoms are available only at baseline for ≥ 70 per cent of patients in both treatment arms.
  • Over the course of the study, response rates declined and, from the second assessment onwards, were minor at < 70 per cent of randomised patients; these rates also diverged increasingly and cannot be explained primarily by deaths.
  • Consequently, a significant proportion of patients is not included in the analysis, meaning that the corresponding results for symptoms are generally regarded as unusable.
• quality of life
  • Health-related quality of life was assessed using the functional scales and the global health status scale of the cancer-specific EORTC QLQ-C30 questionnaire.
  • The limitations of the data mentioned in connection with the assessment of disease symptoms—owing to minor and, over the course of the study, increasingly varying response rates among randomised patients—apply equally to the assessment of health-related quality of life.
  • For this reason, the results on health-related quality of life are considered unusable, in line with the explanations provided in the ‘Symptoms’ section.
• Side effects – Total adverse events (AEs)
  • Adverse events occurred in almost all study participants.
  • The results are presented only as supplementary information, as the operationalisation of side effects also includes events that are not relevant to patients.
• Overall assessment
  • For the assessment of the additional benefit of trifluridine/tipiracil for the treatment of adult patients with metastatic gastric cancer, including adenocarcinoma of the gastro-oesophageal junction, who have already been treated with at least two systemic therapy regimens for advanced disease. Results are available for the endpoint categories of mortality, morbidity, quality of life and side effects.
  • Trifluridine/tipiracil + BSC results in a statistically significant prolongation of median overall survival by 2.1 months compared with placebo + BSC (5.7 months vs. 3.6 months), thereby achieving a clinically relevant prolongation of overall survival.
  • For both the endpoint categories of morbidity and health-related quality of life, no usable data are available from the EORTC QLQ-C30 and EORTC QLQ-STO22 questionnaires, as the proportion of patients for whom no data are available is already very high at early analysis time points.
  • It is therefore not possible to assess how trifluridine/tipiracil affects patients’ disease-specific symptoms and health-related quality of life.
  • In the endpoint category of side effects, both positive and negative effects of trifluridine/tipiracil + BSC are evident when compared with placebo + BSC.
  • The advantage in terms of therapy discontinuations due to adverse events is offset by a disadvantage regarding the occurrence of severe adverse events (CTCAE grade ≥ 3).
  • With regard to specific adverse events, both advantages and disadvantages can be identified for trifluridine/tipiracil + BSC.
  • Taking an overall view of the available results for all patient-relevant endpoints, the G-BA concludes that, for trifluridine/tipiracil + BSC, compared with placebo + BSC, the advantages in terms of overall survival and therapy discontinuations due to adverse events are not entirely negated by the disadvantage relating to severe adverse events (CTCAE grade ≥ 3).
  • There is a moderate—and not merely minor—improvement in treatment-related benefit that has not been achieved previously.

Courtesy translation only, please refer to the German original.