Trifluridin / Tipiracil (1) – Lonsurf®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer submitted the results of the RECOURSE and J003-10040030 (J003) studies.
  • The RECOURSE trial is an international, randomised, double-blind Phase III trial in which trifluridine/tipiracil was directly compared with placebo, and best supportive care (BSC) formed part of the treatment in both treatment groups.

adult patients with metastatic colorectal cancer (CRC) who have already been treated with available therapies or who are unsuitable for these. These therapies include fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, as well as anti-VEGF and anti-EGFR agents

• For adult patients with metastatic colorectal cancer (CRC) who have already been treated with available therapies, including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF and anti-EGFR agents, or who are not suitable for these, there is a hint of a minor additional benefit.
• The G-BA classifies the extent of the additional benefit of trifluridine/tipiracil as minor, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the disease.
• For these reasons, the certainty of the finding (probability of additional benefit) for the overall conclusion on additional benefit is classified as a hint.
• mortality
  • overall survival
  • For the endpoint of overall survival, data cuts were provided on 24 January 2014 (primary analysis) and 8 October 2014, in which a statistically significant prolongation of overall survival was demonstrated for the overall population following treatment with trifluridine/tipiracil + BSC compared with placebo + BSC.
  • For the present benefit assessment, the second data cut-off (8 October 2014) for overall survival is considered decisive and is used: Here, treatment with trifluridine/tipiracil + BSC was associated with a statistically significant prolongation of overall survival in the overall population compared with the control arm (hazard ratio (HR): 0.69, 95% confidence interval (CI) [0.59; 0.81]; p < 0.001), with a median survival time of 7.2 months (trifluridine/tipiracil arm) compared with 5.2 months (control arm; absolute difference: +2.0 months).
• morbidity
  • Symptoms
  • Symptoms were not assessed in the RECOURSE study.
  • Progression-free survival
  • The endpoint ‘progression-free survival’ (PFS) is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • The median PFS differed (as at the data cut-off on 31 January 2014 and the update on 8 October 2014) between the treatment arms by an absolute difference of 0.3 months, which was statistically significant (2.0 months versus 1.7 months for the trifluridine/tipiracil arm and the control arm, respectively; Data cut-off (31 January 2014): HR 0.48, 95% CI [0.41; 0.57], p < 0.001; Update (8 October 2014): HR 0.49, 95% CI [0.42; 0.58], p < 0.001).
• quality of life
  • Health-related quality of life was not assessed in the RECOURSE study.
• Side effects
  • SAE (clinical progression and side effects)
  • The data presented for the SAE endpoint cannot be interpreted exclusively as side effects, as events for which the investigator indicated a link to clinical progression were also recorded.
  • In favour of treatment with trifluridine/tipiracil + BSC, the time to the occurrence of a SAE, including clinical progression, was statistically significantly prolonged for the overall population as at the data cut-off date of 31 January 2014 compared with the control arm (HR: 0.70, 95% CI [0.53; 0.91]; p = 0.008), although the median survival time in the intervention arm had not yet been reached (95% CI [8.7; n.a.]).
  • To the detriment of treatment with trifluridine/tipiracil + BSC, severe AEs of CTCAE grade ≥ 3, including clinical progression, occurred statistically significantly earlier in the overall population at the data cut-off date of 31 January 2014 than in the control arm (HR: 1.44, 95% CI [1.18; 1.77]; p < 0.001).
  • Withdrawal due to AEs
  • As of the data cut-off date of 31 January 2014, 19 (3.6%) patients in the active treatment arm and 4 (1.5%) patients in the control arm discontinued the trial solely due to AEs; however, this difference was not statistically significant (HR: 1.22, 95% CI [0.40; 3.75]; p = 0.723).
• Overall assessment
  • With regard to mortality outcomes, there is additional benefit for the endpoint of overall survival, as the results demonstrate a relevant prolongation of survival time.
  • In the side effects endpoint category, the results are mixed: a positive effect due to the prolonged time to the onset of a severe AE (SAE), and a negative effect associated with severe AEs (CTCAE grade ≥ 3), which occurred earlier in the trifluridine/tipiracil arm.
  • In the patient-relevant endpoint category of morbidity, no endpoints relating to symptoms were recorded, and no data were collected for the patient-relevant endpoint of health-related quality of life.
  • The overall assessment concludes that there is a moderate, rather than merely minor, improvement in treatment-related benefit and thus a minor additional benefit of trifluridine/tipiracil compared with best supportive care.

Courtesy translation only, please refer to the German original.