Vemurafenib (1) – Zelboraf®

• Clinical trials
  • The BRIM3 trial was a comparative, two-arm, open-label Phase III trial.
  • In the treatment arm, patients were treated with 960 mg of vemurafenib twice daily; in the control arm, they received 1000 mg/m² of dacarbazine every 3 weeks.

Patients with BRAF V600 mutation-positive unresectable or metastatic melanoma

• The certainty of the evidence (probability of additional benefit) is classified as ‘indication’.
• In summary, the additional benefit of vemurafenib is assessed as follows: For adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, there is an indication of considerable additional benefit compared with the appropriate comparator therapy.
• The G-BA classifies the extent of the additional benefit of 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.
• On the basis of these considerations, the information in the dossier, the results of the benefit assessment and the expert opinions, the G-BA concludes that there is evidence of considerable additional benefit from vemurafenib compared with dacarbazine.
• Mortality – Overall survival
  • With regard to the endpoint ‘overall survival’, the G-BA assesses the extent of the additional benefit of vemurafenib compared with the appropriate comparator therapy, dacarbazine, as considerable.
  • This represents a significant improvement in treatment-related benefit that has not been achieved previously, as a moderate prolongation of survival is achieved.
• Morbidity – Visual Analogue Scale (VAS) pain
  • Data are available for vemurafenib on the patient-relevant endpoint ‘Visual Analogue Scale (VAS) pain’ to assess the additional benefit in terms of morbidity.
  • The result is not statistically significant.
  • Consequently, additional benefit or less benefit from vemurafenib for this endpoint is not proven.
  • Pain frequently occurs as an adverse event during treatment with vemurafenib (according to the SmPC for Zelboraf®: very common: headache, joint pain, muscle pain, back pain, pain in the extremities and/or the musculoskeletal system).
  • With regard to the assessment of the ‘pain’ endpoint, there is no evidence to indicate whether the pain observed in the studies was caused by the treatment or by the tumour disease.
  • With regard to morbidity, apart from the ‘pain’ endpoint, no data were collected on other patient-relevant symptoms – such as shortness of breath, dizziness, coagulation disorders, loss of appetite and fatigue – as separate endpoints.
• Health-related quality of life – Functional Assessment of Cancer Therapy – Melanoma (FACT-M)
  • For the‘health-related quality of life’ dimension (Functional Assessment of Cancer Therapy – Melanoma, FACT-M), the data presented do not indicate any additional benefit or less benefit of vemurafenib compared with the appropriate comparator therapy.
  • The FACT-M questionnaire consists of six subscales (physical, social, emotional and functional well-being, as well as a subscale relating to surgical treatment of melanoma and a subscale for ‘additional concerns’).
  • The pharmaceutical manufacturer did not include the surgical subscale in the questionnaire and therefore used an abridged version.
  • Consequently, the total score for the questionnaire could not be calculated, which is why the analyses of the total score are considered invalid.
  • The results for two of the five subscales showed statistically significant findings with differing directions of effect. Thus, the result for the ‘Physical Well-being’ subscale favoured vemurafenib (group difference 2.32 points, p = 0.004), whilst the result for the ‘Emotional Well-being’ subscale was statistically significant in favour of dacarbazine (group difference 1.38 points, p = 0.004).
• Side effects
  • The additional benefit of vemurafenib is offset by side effects.
  • In the BRIM3 trial, the overall rate of adverse events in the vemurafenib arm was statistically significantly higher (an average of 10.3 vs. 4.5 events per patient) and a statistically significantly higher number of patients were affected by adverse events with a CTCAE (Common Terminology Criteria for Adverse Events) grade 3 or higher, as well as by serious adverse events.
  • The discontinuation rates due to adverse events were comparable in both study arms.
  • When considering the most common side effects at the MedDRA System Organ Class (SOC) level, side effects in the SOCs ‘Skin and subcutaneous tissue disorders’ (in particular rash, alopecia, photosensitivity, pruritus and hyperkeratosis), “Musculoskeletal and connective tissue disorders” (in particular arthralgia), ‘Neurological disorders’ (in particular headache), ‘Benign, malignant and unspecified neoplasms’ (in particular skin papillomas, squamous cell carcinomas, keratoacanthomas and seborrhoeic keratosis) and “metabolic and nutritional disorders” occurred statistically significantly more frequently in the vemurafenib arm than in the dacarbazine arm.
  • By contrast, adverse events classified under the SOC ‘Disorders of the blood and lymphatic system’ (in particular cytopenia) occurred statistically significantly less frequently in the vemurafenib arm than in the dacarbazine arm.
  • A notable feature among the side effects is malignant neoplasms of the skin and mucous membranes, in particular squamous cell carcinomas (12% versus 0.3%) and keratoacanthomas (8% versus 0%).
  • Due to these potential side effects, the summary of product characteristics (SmPC) recommends that vemurafenib patients undergo comprehensive examinations of the skin (dermatological examination), the head and neck – in particular the oral mucosa and lymph nodes – chest CT scans, and examinations of the anal and vaginal mucous membranes.
  • Overall, the side effects are classified as significant for patients but manageable.
• Overall assessment
  • When the results on mortality, quality of life and side effects are considered as a whole, there is no sustained, previously unattained major improvement in treatment-related benefit compared with the appropriate comparator therapy, in particular, no cure, no major prolongation of survival, and no long-term freedom from serious symptoms.
  • Therefore, a classification as a major additional benefit is not justified.
  • Taking into account the data on quality of life and side effects, the results regarding survival duration are assessed as a clear improvement in benefit not previously achieved compared with the appropriate comparator therapy, and in particular as a moderate prolongation of survival duration.

Courtesy translation only, please refer to the German original.