The two most advanced agents currently in clinical development are the selective BRAF inhibitors, vemurafenib (PLX4032, RG 7204) and GSK2118436 (GSK436).
Vemurafenib is an orally available, highly potent, ATP-competitive inhibitor of mutant BRAF. The phase I (dose extension phase), II and III trials for this agent included patients with BRAF V600E-mutant metastatic melanoma, confirmed by means of a polymerase chain reaction (PCR) assay (cobas 4800 BRAF V600 Mutation Test, Roche Molecular Systems Inc., Pleasanton, CA, USA). This assay involves hybridizing a probe, specific to the 1799T→A substitution that results in the V600E BRAF mutation, with DNA isolated from formalin-fixed, paraffin-embedded tumour tissue and determining the presence or absence of amplification after repeated chain-reaction cycles. Patients with other DNA alterations giving rise to V600E and non-V600E mutations were thus excluded.
The phase I study included a dose-escalation phase (from 160 mg twice daily to 1120 mg twice daily) and dose-extension phase (recommended phase II dose of 960 mg twice daily) and demonstrated a response rate (RR) of 69% (11 of 16 patients) in the dose-escalation phase and 81% (26 of 32 patients) in the dose-extension phase. At the time of publication, the estimated median PFS was more than 7 months with duration of response ranging from 2 months to over 18 months [Flaherty et al. 2010
The subsequent BRAF in Melanoma 2 (BRIM-2) phase II study included 132 patients and showed RR of 53%, stable disease (SD) in a further 29%, median PFS of 6.7 months and OS at 6 and 12 months of 77% and 58%, respectively. At the time of the report, the median OS had not been reached [Ribas et al. 2011]
The recent phase III BRAF Inhibitor in Melanoma 3 trial (BRIM-3) compared vemurafenib (960 mg twice daily) with dacarbazine (1000 mg/m2
) as first-line treatment in patients with BRAF V600E-mutant metastatic melanoma [Chapman et al. 2011
]. The RR was 48% for vemurafenib and 5% for dacarbazine with a significant prolonged median PFS of 5.3 months in the vemurafenib arm compared with 1.6 months on dacarbazine [hazard ratio (HR) 0.26; 95% confidence interval (CI) 0.20–0.33, p
< 0.0001]. Treatment with vemurafenib resulted in a 63% relative risk reduction for death and a 74% risk reduction for either death or disease progression. At 6 months, the OS was 84% for patients who received vemurafenib compared with 64% for patients who received dacarbazine. The adverse events (AEs) were consistent with those previously described in earlier trials and included grade 2 (G2) and G3 arthralgias (18% and 3%), rash (10% and 8%), photosensitivity (12% G2 or G3), fatigue (11% and 2%), cutaneous squamous-cell carcinoma (SCC, 12%), keratoacanthoma (2% and 6%), nausea (7% and 1%) and diarrhoea (5% and <1%). Dose interruption and modification were required in 38% of patients.
Interestingly, BRIM-3 also included 10 patients with a V600K mutation, 4 of whom demonstrated a good clinical response. Comparison of the PCR assay (cobas 4800 BRAF V600 Mutation Test) and Sanger sequencing has demonstrated higher sensitivity in the detection of V600E mutations with the PCR test; however, 6.8% of samples identified by the PCR assay were shown to have a V600K rather than V600E mutation, confirmed on Sanger sequencing [Bloom et al. 2011]
GSK436 is an ATP-competitive, reversible inhibitor of mutant BRAF V600E, as well as V600K and V600G kinases. A phase I–II trial enrolled 61 patients including 52 with BRAF-mutant melanoma [Kefford et al. 2010
]. There was a high RR with 18 of 30 patients (60%) demonstrating partial response (PR) at first restaging during weeks 8–9. The PFS at the expanded dose of 150 mg twice daily was 8.3 months.
In the dose expansion cohort of 20 patients, 77% had a BRAF V600E mutation and 19% had a V600K mutation [Kefford, 2010]
. Patients with a BRAF V600E mutation demonstrated RR of 77% and the subgroup of patients with a V600K mutation demonstrated a RR of 44% (four of nine).
Overall GSK436 was very well tolerated with side effects similar to those described with vemurafenib, including skin changes (37%, one G3), low-grade cutaneous SCC (two patients), headache (19%, one G3), nausea (18% G1), fatigue (15% G1) and vomiting (13%, four G2). Although the majority of side effects are similar between the two BRAF inhibitors, vemurafenib is associated with photosensitivity in up to 30% of patients (12% G2 or G3) while pyrexia is reported in 15% (2% G3) on GSK436.
Interestingly, in the dose-escalation phase with GSK436, a cohort of 10 patients with previously untreated brain metastases also demonstrated a significant RR to treatment. There was a reduction in size of the brain metastases in 9 of 10 patients, ranging from a 20% to a 100% reduction in brain metastases that were 3–15 mm in size prior to treatment. The reduction in brain metastases correlated with extra-cranial response [Long et al. 2010]
Further studies of GSK436 that have completed accrual and may be reported in 2012 include GSK436 versus dacarbazine in previously untreated patients with BRAF-mutant advanced or metastatic melanoma, as well as a study of GSK436 in BRAF-mutant metastatic melanoma to the brain [ClinicalTrials.gov Identifier NCT01227889].
Importantly, the response to BRAF inhibition with improvement in symptoms and performance status is usually rapid, occurring within the first 2 weeks, and has shown concordance with fluorodeoxyglucose positron emission tomography (FDG-PET) response [McArthur et al. 2010]
. Interestingly, heterogeneous FDG-PET response at day 15 of treatment has been demonstrated in up to 26% of patients in a substudy of 23 patients, with significantly shorter time to progression compared with those with a homogenous FDG-PET response [Carlino et al. 2011]
As evidenced with both selective BRAF inhibitors, though less commonly with GSK436 [Kefford et al. 2010
], the increased incidence of cutaneous SCC generally develops between weeks 2 and 14 and is hypothesized to be due to upstream RAS mutations in pre-existing SCC skin lesions, occurring in approximately 15% of patients. Selective inhibition of downstream BRAF can lead to CRAF signalling by mutant RAS with subsequent development of SCCs [Arkenau et al. 2010]
. The majority of these SCCs are keratoacanthoma type, well differentiated with no metastatic potential and can be treated with surgical excision [Flaherty et al. 2010