Fruquintinib (1) – Fruzaqla®

• Clinical trials
  • FRESCO-2 is a double-blind, randomised, multicentre Phase III trial comparing fruquintinib + best supportive care (hereinafter: fruquintinib) with best supportive care.

Adults with metastatic colorectal cancer (mCRC) who have previously been treated with available standard therapies, including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, anti-VEGF agents and anti-EGFR agents, and who have experienced disease progression on, or are intolerant of, treatment with trifluridine/tipiracil or regorafenib

• The overall assessment concludes that fruquintinib offers a minor additional benefit compared with best supportive care.
• Due to relevant uncertainties regarding the conduct of the studies and the generalisability of the study results to real-world clinical practice, the certainty of the evidence for the identified additional benefit is classified overall as a ‘hint’.
• mortality
  • Overall survival was defined in the FRESCO-2 trial as the time from randomisation to death from any cause.
  • For the endpoint of overall survival, a statistically significant prolongation of survival time was observed in favour of fruquintinib compared with BSC.
  • Taking into account the advanced stage of the disease and treatment, the prolongation in survival time achieved is assessed as a relevant improvement, albeit one that does not go beyond a minor extent.
• Morbidity – Progression-free survival (PFS)
  • In the FRESCO-2 study, PFS is defined as the period from randomisation to the first documented instance of disease progression or death from any cause, whichever occurs first.
  • A statistically significant advantage in PFS was observed between the treatment groups, in favour of fruquintinib.
  • 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.
• Morbidity – symptoms (assessed using the EORTC QLQ-C30) and health status (assessed using the EQ-5D VAS)
  • Patients’ symptoms were assessed in the FRESCO-2 study using the EORTC QLQ-C30. Health status was assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • A sharp decline in questionnaire response rates was observed at an early stage of the study. Furthermore, there were marked differences in response rates between the treatment arms. Due to the minor proportion of patients for whom data were collected, it is therefore not possible to draw any valid conclusions. Consequently, the data presented cannot be used for benefit assessment.
• quality of life
  • Quality of life among patients was assessed in the FRESCO-2 study using the EORTC QLQ-C30.
  • A sharp decline in questionnaire response rates was observed early on in the course of the study. Furthermore, there are marked differences in response rates between the treatment arms. Due to the minor proportion of patients for whom data were collected, it is therefore not possible to draw any valid conclusions. Consequently, the data presented cannot be used for benefit assessment.
• Side effects – Total adverse events
  • Adverse events occurred in 98.7% of patients in the fruquintinib arm and in 91.7% of patients in the BSC arm.
• Side effects – serious AEs (SAEs), severe AEs (CTCAE grade ≥ 3), therapy discontinuation due to AEs
  • No statistically significant differences were observed between the treatment arms for the endpoints SAE, severe AEs (CTCAE grade ≥ 3) and therapy discontinuation due to AEs.
• Side effects – Abnormal liver function (SMQ, SAE)
  • For the endpoint ‘abnormal liver function’ (SMQ, SAE), there was an advantage for fruquintinib compared with the control arm.
• Side effects – Gastrointestinal perforation (SMQ, AE) and bleeding (SMQ, AE, severe AE)
  • For the endpoints gastrointestinal perforation (SMQ, AE) and bleeding (SMQ, AE, severe AE), no statistically significant differences were observed between the treatment groups in either case.
• Side effects – diarrhoea (TT, AE), hand-foot syndrome (PT, severe AE), hypertension (SMQ, severe AE), mucosal inflammation (PT, AE), stomatitis (PT, AE) and dysphonia (PT, AE)
  • For the endpoints diarrhoea (TT, AE), hand-foot syndrome (PT, severe AE), high blood pressure (SMQ, severe AE), mucosal inflammation (PT, AE), stomatitis (PT, AE) and dysphonia (PT, AE), fruquintinib had a disadvantage compared to best standard care in each case.
• Overall assessment
  • For the endpoint of overall survival, there is a statistically significant prolongation of survival in favour of fruquintinib, which is assessed as a relevant improvement, albeit one that does not go beyond a minor extent.
  • No evaluable data are available for the endpoints relating to symptoms (assessed using the EORTC QLQ-C30) and health status (assessed using the EQ-5D VAS). Similarly, no evaluable data are available for health-related quality of life. This is due to a sharp decline in questionnaire response rates at an early stage of the trial, with significant differences also observed between the treatment arms. Consequently, data were collected for only a minor proportion of patients, which is why no valid conclusions can be drawn for the respective endpoints. Conclusions regarding symptoms and quality of life are considered particularly important in the present context of advanced, palliative care.
  • With regard to side effects, there is no relevant difference when considered as a whole. In detail, specific AEs show both disadvantages and one advantage.
  • The overall assessment concludes that fruquintinib offers a minor additional benefit compared with best supportive care.

Courtesy translation only, please refer to the German original.