Vemurafenib (2) – 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

• 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.
• Compared with the appropriate comparator therapy, dacarbazine, this represents a significant improvement in treatment-related benefit that has not previously been achieved, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, as a moderate prolongation of survival (endpoint ‘overall survival’) is achieved.
• The certainty of the finding (probability of additional benefit) is classified in the ‘indication’ category.
• 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 an indication of considerable additional benefit of vemurafenib compared with dacarbazine.
• mortality
  • With regard to the ‘overall survival’ endpoint, 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.
  • Due to the early crossover following the first data cut-off, an increased potential for bias at the endpoint level is assumed for the ‘overall survival’ endpoint.
  • At the first data cut-off, the potential for bias in the results due to patients switching treatments is minor.
  • However, due to the short follow-up period and the associated high censoring rates, the certainty of the results regarding sustained treatment effects is limited.
• Morbidity – Visual Analogue Scale (VAS) pain
  • To assess the additional benefit for the morbidity dimension, data are available for vemurafenib on the patient-relevant endpoint ‘Visual Analogue Scale (VAS) pain’.
  • 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: headaches, 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 allow any additional benefit or less benefit of vemurafenib compared with the appropriate comparator therapy to be inferred.
  • 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, as of the 4th data cut-off point, a statistically significant higher number of patients in the vemurafenib arm were affected by adverse events with a CTCAE (Common Terminology Criteria for Adverse Events) severity grade of ≥ 3, as well as by serious adverse events, compared with the dacarbazine arm.
  • Therapy discontinuations due to adverse events were also observed significantly more frequently with vemurafenib.
  • When considering the most common side effects at the MedDRA System Organ Class (SOC) level, side effects were observed in the SOCs ‘Skin and subcutaneous tissue disorders (in particular rash, alopecia, photosensitivity, pruritus and hyperkeratosis)’, ‘Musculoskeletal and connective tissue disorders (in particular arthralgia and pain in the extremities)’, ‘Nervous system disorders (in particular headache)’, ‘Benign, malignant and unspecified neoplasms (in particular skin papillomas, cutaneous squamous cell carcinomas, keratoacanthomas, seborrhoeic keratosis and melanocytic naevi)’, “Metabolic and nutritional disorders”, “General disorders and administration site conditions (in particular pyrexia and peripheral oedema)”, “Liver function disorders” and “QT prolongation” occurred with statistically significant greater frequency 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 (19% versus 0.7%) and keratoacanthomas (11% versus 0.7%).
  • 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.

Courtesy translation only, please refer to the German original.