Regorafenib (1) – Stivarga®

• Clinical trials
  • The CORRECT trial was a randomised, controlled, double-blind Phase III trial in which regorafenib was compared with placebo.

Patients with metastatic colorectal cancer who had previously received fluoropyrimidine-based chemotherapy, anti-VEGF-based therapy, and, where KRAS wild-type, anti-EGFR-based therapy, or who are not eligible for such therapy

• For patients with metastatic colorectal cancer who have previously been treated with available therapies or who are unsuitable for such therapies, there is a hint of a minor additional benefit.
• The G-BA classifies the extent of the additional benefit of regorafenib as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of 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
  • Treatment with regorafenib was associated with a statistically significant prolongation of overall survival compared with best supportive care.
  • As of the data cut-off date of 21 July 2011, the median survival in the regorafenib group was 196 days compared with 151 days in the best supportive caregroup, representing a median survival benefit of 45 days (HR: 0.77, CI: 0.64–0.94, p-value = 0.011).
  • This result is consistent with the subsequent data cut-off on 13 November 2011 (median survival 194 days vs. 152 days; absolute difference: 42 days).
  • Given the advanced stage of the disease in this context, where currently available standard treatments have been exhausted and no further treatment options with proven survival benefit are available, this is considered a significant prolongation of survival.
• morbidity
  • There are no evaluable endpoints available for assessing the additional benefit with regard to morbidity.
  • Progression-free survival
  • The endpoint ‘progression-free survival (PFS)’ shows a statistically significant median prolongation of progression-free survival of 7 days for the regorafenib group compared with the best supportive care group.
  • For these reasons, whilst the ‘progression-free survival’ endpoint is presented, it is not taken into account in this assessment, as the overall conclusion regarding additional benefit remains unaffected by it.
  • Objective tumour response rate (ORR) and associated endpoints
  • The endpoints ‘objective tumour response rate (ORR)’ and the associated endpoints ‘disease control rate (DCR)’ and “Duration of Tumour Stabilisation” are not included in this assessment, as no patient-relevant operationalisation was applied and this endpoint was assessed exclusively by means of imaging procedures.
• quality of life
  • The data provided are insufficient to assess the additional benefit in terms of quality of life.
  • Health-related quality of life was assessed in the CORRECT study using the EORTC QLQ-C30 and EQ-5D questionnaires.
  • Among the data presented in the dossier, relevant data were available at the end of treatment for only a subset of patients. The low response rate for the questionnaires could not be explained predominantly by patient deaths.
  • Due to the limited validity of the data submitted on quality of life, this endpoint is not taken into account in this assessment.
• Side effects
  • In the CORRECT trial, almost every patient experienced at least one adverse event, both in the regorafenib group (100 per cent) and in the best supportive care group (97.0 per cent).
  • Serious adverse events (SAEs) occurred in the study without any statistically significant difference between the treatment groups (43.8% and 39.5%, respectively).
  • With regard to the severe adverse events (CTCAE grade ≥ 3) observed in the study, patients treated with regorafenib were statistically significantly more likely to experience severe adverse events with a CTCAE grade ≥ 3: 78.0% in the regorafenib group versus 49.0% in the best supportive care group.
  • The observed difference is largely attributable to individual, severe adverse events of CTCAE grade 3, which occurred significantly more frequently with regorafenib (group difference ≥ 5%) – these included hand-foot syndrome (16.6% vs. 0.4%), diarrhoea (8.2% vs. 2.0%), rash (5.8% vs. 0.4%), fatigue (15.0% vs. 8.3%) and hypertension (7.6% vs. 0.8%).
  • The proportion of patients experiencing severe adverse events (CTCAE grades 4 and 5) did not differ statistically significantly.
  • The proportion of patients who discontinued treatment due to adverse events was 17.6% in the regorafenib group and 12.6% in the best supportive care group. The difference was not statistically significant.
  • When considering the adverse event endpoints as a whole, severe adverse events (CTCAE grade 3) occurred significantly more frequently with regorafenib.
• Overall assessment
  • In view of the mortality results, there is additional benefit for the endpoint of overall survival, demonstrating a relevant prolongation of survival. At the same time, severe adverse events (CTCAE grade 3) occurred.
  • For other patient-relevant endpoints in this indication, such as health-related quality of life or disease-related symptoms, there are no suitable data available that can be taken into account.
  • The overall assessment concludes that there is a moderate, rather than merely minor, improvement in treatment-related benefit and, consequently, a minor additional benefit of regorafenib compared with best supportive care.

Courtesy translation only, please refer to the German original.