Trifluridin / Tipiracil (4) – Lonsurf®

• Clinical trials
  • SUNLIGHT is a randomised, multicentre, open-label, controlled Phase III trial in which trifluridine/tipiracil in combination with bevacizumab was compared with trifluridine/tipiracil alone.

Adults with metastatic colorectal cancer (CRC) who had previously received two tumour therapies; these treatments include fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents and/or anti-EGFR agents

• Consequently, for trifluridine/tipiracil plus bevacizumab in the treatment of adults with metastatic colorectal cancer (CRC) who have previously received two cancer treatments, where these treatments include fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF and/or anti-EGFR agents, there is a hint of a considerable additional benefit compared with trifluridine/tipiracil.
• The certainty of evidence for the observed additional benefit is therefore classified as ‘hint ’.
• mortality
  • In the SUNLIGHT study, overall survival was defined as the period from randomisation to death, regardless of the underlying cause.
  • For the endpoint of overall survival, a statistically significant difference in favour of trifluridine/tipiracil + bevacizumab was observed, which, given the advanced stage of the disease and poor prognosis, is assessed as a marked improvement.
• Morbidity – Progression-free survival (PFS)
  • In the SUNLIGHT trial, PFS was defined as the time between randomisation and radiologically confirmed disease progression (assessed by the investigator according to RECIST version 1.1) or death, regardless of the underlying cause.
  • A statistically significant advantage in favour of trifluridine/tipiracil + bevacizumab was observed for PFS.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • 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.
• Morbidity – Symptoms
  • Symptoms were assessed in the SUNLIGHT study using the symptom scales of the cancer-specific EORTC QLQ-C30 questionnaire.
  • The pharmaceutical manufacturer has provided responder analyses for the proportion of patients for the time to first deterioration and for the time to confirmed deterioration.
  • Due to the significant differences in treatment duration between the two treatment arms, the time to first deterioration was used for this assessment.
  • No statistically significant difference was observed between the treatment arms. However, for the endpoints of nausea and vomiting, as well as pain, there is an effect modification by the characteristic of sex. Accordingly, for men, there is a statistically significant difference in favour of trifluridine/tipiracil + bevacizumab for both endpoints, whereas for women, no statistically significant difference is observed in either case.
  • In their statements on this benefit assessment, the scientific and medical societies noted that no generally valid conclusions regarding an advantage for men can be drawn from these findings.
  • Consequently, no separate assessment of additional benefit by gender is made for the endpoints of nausea and vomiting or pain, and no additional benefit is identified overall.
• quality of life
  • Health-related quality of life was assessed in the SUNLIGHT study using the functional scales of the EORTC QLQ-C30.
  • The pharmaceutical manufacturer has provided analyses for the time to first deterioration and for the time to multiple confirmed deteriorations.
  • For the ‘Physical Functioning’ endpoint, a statistically significant advantage in favour of trifluridine/tipiracil + bevacizumab is observed. However, this advantage is not reflected in any other subscale of the EORTC QLQ-C30.
  • In the overall assessment of the ‘quality of life’ endpoint category, against the background of the multimodal quality-of-life concept, no difference relevant to the benefit assessment is identified.
• Side effects – Serious adverse events (SAE)
  • For the SAE endpoint, a statistically significant difference in favour of trifluridine/tipiracil + bevacizumab is observed.
• Overall assessment
  • For the benefit assessment of trifluridine/tipiracil + bevacizumab for the treatment of adults with metastatic colorectal cancer (CRC) who have previously received two cancer therapies, where these therapies included fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF and/or anti-EGFR agents, results are available from the SUNLIGHT study on mortality, morbidity (symptoms and health status), health-related quality of life and side effects.
  • The results for the overall survival endpoint show that treatment with trifluridine/tipiracil + bevacizumab, compared with trifluridine/Tipiracil achieves an improvement in overall survival, which is regarded as a significant improvement given the advanced stage of the disease and poor prognosis.
  • In the morbidity endpoint category (assessed using the EORTC QLQ-C30 and EQ-5D VAS), there is an advantage for trifluridine/tipiracil + bevacizumab in terms of health status.
  • In the quality of life endpoint category, no difference relevant to the benefit assessment is identified overall.
  • With regard to the submitted analyses of side effects, the G-BA takes into account that, particularly in the present indication, distinguishing between drug-induced adverse events and disease-related events is particularly difficult. Based on the available analyses, trifluridine/tipiracil + bevacizumab shows an advantage over trifluridine/tipiracil in terms of serious adverse events.
  • On balance, the G-BA concludes that, particularly due to the advantages in overall survival, combined with the advantages in health status and the avoidance of serious adverse events, there is a significant overall improvement in treatment-related benefit.

Courtesy translation only, please refer to the German original.