etic damage when tested in in vitro assays (bacterial mutation [AMES Assay], human lymphocyte chromosome aberration) or in the in vivo rat bone marrow micronucleus test.
No specific studies with vemurafenib have been conducted in animals to eva luate the effect on fertility; nevertheless, no histopathological findings were noted in reproductive organs in males and females in repeat-dose toxicology studies in rats at doses up to 450 mg/kg/day (approximately 0.6 and 1.6 times the human exposure based on AUC in males and females, respectively) and dogs at doses up to 450 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC in both males and females, respectively).
13.2 Animal Toxicology and/or Pharmacology
Consistent with the increased incidence of cutaneous squamous cell carcinomas in patients treated with vemurafenib, the treatment of mice implanted with human cuSCC cells with vemurafenib caused a dose dependent acceleration of the growth of the implanted tumors.
14 CLINICAL STUDIES
Treatment Naive Patients
The efficacy and safety of ZELBORAF in patients with treatment naive, BRAFV600E mutation-positive unresectable or metastatic melanoma as detected by the cobas® 4800 BRAF V600 Mutation Test were assessed in an international, randomized, open-label trial (Trial 1). The trial enrolled 675 patients; 337 were allocated to receive ZELBORAF 960 mg by mouth twice daily and 338 to receive dacarbazine 1000 mg/m2 intravenously on Day 1 every 3 weeks. Randomization was stratified according to disease stage, lactate dehydrogenase (LDH), ECOG performance status and geographic region. Treatment continued until disease progression, unacceptable toxicity, and/or consent withdrawal. The major efficacy outcome measures of the trial were overall survival (OS) and investigator-assessed progression-free survival (PFS). Other outcome measures included confirmed investigator-assessed best overall response rate.
Baseline characteristics were balanced between treatment groups. Most patients were male (56%) and Caucasian (99%), the median age was 54 years (24% were ≥ 65 years), all patients had ECOG performance status of 0 or 1, and the majority of patients had metastatic disease (95%).
Efficacy results are summarized in Table 4 and Figure 1.
Table 4 Efficacy of ZELBORAF in Treatment Naive Patients with BRAFV600E Mutation-Positive Melanoma* ZELBORAF
(N=337) Dacarbazine
(N=338) p-value†
Overall Survival
Number of Deaths 78 (23%) 121 (36%)
Hazard Ratio
(95% CI)‡ 0.44
(0.33, 0.59) <0.0001
Median Survival (months)
(95 % CI)§ Not Reached
(9.6, Not Reached) 7.9
(7.3, 9.6) -
Median Follow-up (months)
(range) 6.2
(0.4, 13.9) 4.5
(<0.1, 11.7)
Progression-free survival
Hazard Ratio
(95% CI)‡ 0.26
(0.20, 0.33) <0.0001
Median PFS (months)
(95% CI)§ 5.3
(4.9, 6.6) 1.6
(1.6, 1.7) -
*As detected by the cobas® 4800 BRAF V600 Mutation Test
† Unstratified log-rank test
‡Hazard ratio estimated using Cox model; a hazard ratio of < 1 favors ZELBORAF
§Kaplan-Meier estimate
Figure 1 Kaplan-Meier Curves of Overall Survival – Treatment Naive Patients
The confirmed, investigator-assessed best overall response |
