Cobimetinib (1) – Cotellic®

• Clinical trials
  • In this randomised, actively controlled, double-blind Phase III trial, 495 patients with histologically confirmed unresectable (Stage IIIc) or metastatic (Stage IV) melanoma and a confirmed BRAF V600 mutation were randomised in a 1:1 ratio to either an intervention group, which received cobimetinib in combination with vemurafenib, or a control group, which received vemurafenib together with a placebo.

adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation

• As the results of only one study form the basis of the benefit assessment, this assessment can at most provide indications of additional benefit.
• mortality
  • overall survival
  • In the coBRIM study, overall survival was assessed as a secondary endpoint. At the third data cut-off (16 January 2015), treatment with the combination of cobimetinib and vemurafenib showed a statistically significant prolongation of overall survival compared with vemurafenib in combination with placebo (hazard ratio (HR): 0.65; 95% confidence interval (CI) [0.49; 0.87]; p = 0.003), although the median survival time in the intervention arm had not yet been reached.
  • A statistically significant prolongation of overall survival in the intervention arm (HR: 0.66; 95% CI [0.53; 0.81]; p < 0.001) was also observed in the intervention arm compared with the control arm at the fourth data cut-off (28 August 2015). The median survival time with cobimetinib and vemurafenib was 22.3 months, compared with 17.4 months with vemurafenib and placebo (absolute difference: +4.9 months).
  • These results are interpreted as a moderate prolongation of survival, indicating, at the endpoint level, a considerable additional benefit of the combination of cobimetinib and vemurafenib compared with vemurafenib monotherapy.
• Morbidity – Progression-free survival (IRF assessment)
  • Progression-free survival, defined as the time from randomisation to death or disease progression, was the primary endpoint of the study. An Independent Review Facility (IRF) was employed to independently assess both the occurrence and timing of progression using imaging procedures in accordance with RECIST criteria. The median progression-free survival (PFS) was 11.3 months for the cobimetinib-vemurafenib combination compared with 6.0 months in the control group (absolute difference: 5.3 months). The difference is statistically significant (HR 0.59; 95% CI [0.45; 0.79], p < 0.001).
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. The ‘mortality’ component of the endpoint was assessed in the study as a standalone endpoint via the ‘overall survival’ endpoint. The ‘disease progression’ component of the morbidity endpoint was not assessed on the basis of symptoms, but rather using imaging procedures. Taking the above aspects into account, there are differing views within the G-BA regarding the patient relevance of the PFS endpoint. This does not affect the overall conclusion regarding the extent of the additional benefit.
• Morbidity – Symptoms (EORTC QLQ-C30)
  • Data on tumour-related symptoms were collected using the symptom scales of the EORTC QLQ-C30 patient questionnaire. Analyses of the time to deterioration in symptom scales (an increase in score of ≥10 points) compared with baseline (responder analyses) are used for the benefit assessment.
  • For the endpoints of pain (HR 0.60; 95% CI [0.47; 0.77], p < 0.001), insomnia (HR 0.61; 95% CI [0.46; 0.82], p < 0.001) and fatigue (HR 0.74; 95% CI [0.59; 0.93], p < 0.011), a statistically significant difference was observed in favour of the combination of cobimetinib and vemurafenib.
  • For the endpoint of diarrhoea (HR 0.78; 95% CI [0.62; 0.99], p < 0.039), however, a statistically significant difference was observed to the detriment of the intervention arm.
  • No statistically significant difference was observed between the treatment groups for the endpoints of dyspnoea, loss of appetite, nausea and vomiting, or constipation.
• Health-related quality of life – EORTC-QLQ-C30
  • Health-related quality of life was assessed using the functional scales of the EORTC QLQ-C30 patient questionnaire. Analyses of time to deterioration in the functional scales (increase in score of ≥10 points) compared with baseline (responder analyses) are used for the benefit assessment.
  • For the endpoints of global health status (HR 0.78; 95% CI [0.61; 1.00], p = 0.047) and physical functioning (HR 0.70; 95% CI [0.54; 0.91], p = 0.009), a statistically significant difference was observed in favour of the combination of cobimetinib and vemurafenib.
  • For both endpoints, there was proof of an effect modification by the characteristic of age. Accordingly, patients aged over 65 may not benefit from treatment with cobimetinib and vemurafenib in terms of health-related quality of life. However, this does not affect the overall conclusion regarding the extent of the additional benefit.
  • For the endpoints of role functioning, emotional functioning, cognitive functioning and social functioning, no statistically significant difference was observed between the treatment groups.
• Side effects – severe adverse events (SAE)
  • For the endpoint ‘serious adverse events’ (SAE), no statistically significant difference was observed between the intervention and control groups.
• Overall assessment
  • The G-BA classifies the extent of the additional benefit of the combination of cobimetinib and vemurafenib as considerable, 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 the treatment of the disease.
  • Taking an overall view of the available results on mortality, morbidity, quality of life and side effects, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, cobimetinib in combination with vemurafenib results in a significant improvement in treatment-related benefit compared with the appropriate comparator therapy, which has not been achieved to date, which is based in particular on a moderate prolongation of survival, alongside positive effects on health-related quality of life and predominantly positive effects on disease-related symptoms.
  • When considering all endpoints in the ‘side effects’ category as a whole, both advantages and disadvantages of the combination therapy of cobimetinib and vemurafenib were observed compared with the appropriate comparator therapy. Overall, the side effects observed in the intervention arm are classified as significant for patients, but predominantly as manageable and treatable. However, taking into account the severity of the disease, the adverse effects that occur do not, in the G-BA’s assessment, lead to a downgrading of the extent of the additional benefit.

Courtesy translation only, please refer to the German original.