Clinicopathologic features associated with efficacy and long-term survival in metastatic melanoma patients treated with BRAF or combined BRAF and MEK inhibitors.

The degree of response and the duration of survival of patients treated with mitogen-activated protein kinase (MAPK) inhibitors are highly variable. Whether baseline clinicopathologic factors can predict the clinical course with treatment is largely unknown. For 142 consecutive immunotherapy- and MAPK inhibitor-naive patients with BRAF-mutant metastatic melanoma who were treated during clinical trials with BRAF inhibitors (n = 111) or a combination of dabrafenib and trametinib (n = 31), clinicopathologic factors were correlated with the response to MAPK inhibitors and survival. The median follow-up was 15.7 months (range, 0.6-60.5 months). The 2-, 3-, and 4-year overall survival (OS) rates were 43%, 24%, and 24%, respectively. A multivariate analysis demonstrated that the only clinicopathologic factors associated with longer progression-free survival (PFS) and OS were female sex and a normal pretreatment serum lactate dehydrogenase (LDH) level. The BRAF V600E genotype and an absence of primary melanoma ulceration were also independently associated with longer PFS but not OS. The median OS was 23.5 months for patients with normal LDH levels and 7.3 months for those with elevated LDH levels (hazard ratio, 0.31; P < .001). Complete responders had the best survival, but disease progression still occurred in 2 of 7 patients. Long-term survival occurs for a minority of patients receiving MAPK inhibitor treatment alone. Sex, serum LDH, BRAF genotype, and primary melanoma ulceration status are independent factors associated with treatment outcomes. Patients with a complete response to treatment have the best survival, but relapses still occur.

Menzies AM ，Wilmott JS ，Drummond M ，Lo S ，Lyle M ，Chan MM ，Thompson JF ，Guminski A ，Carlino MS ，Scolyer RA ，Kefford RF ，Long GV ... -  《-》

Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-l

In the COMBI-v trial, patients with previously untreated BRAF Val600Glu or Val600Lys mutant unresectable or metastatic melanoma who were treated with the combination of dabrafenib and trametinib had significantly longer overall and progression-free survival than those treated with vemurafenib alone. Here, we present the effects of treatments on health-related quality of life (HRQoL), an exploratory endpoint in the COMBI-v study. COMBI-v was an open-label, randomised phase 3 study in which 704 patients with metastatic melanoma with a BRAF Val600 mutation were randomly assigned (1:1) by an interactive voice response system to receive either a combination of dabrafenib (150 mg twice-daily) and trametinib (2 mg once-daily) or vemurafenib monotherapy (960 mg twice-daily) orally as first-line therapy. The primary endpoint was overall survival. In this pre-specified exploratory analysis, we prospectively assessed HRQoL in the intention-to-treat population with the European Organisation for Research and Treatment of Cancer quality of life (EORTC QLQ-C30), EuroQoL-5D (EQ-5D), and Melanoma Subscale of the Functional Assessment of Cancer Therapy-Melanoma (FACT-M), completed at baseline, during study treatment, at disease progression, and after progression. We used a mixed-model, repeated measures ANCOVA to assess differences in mean scores between groups with baseline score as covariate; all p-values are descriptive. The COMBI-v trial is registered with ClinicalTrials.gov, number NCT01597908, and is ongoing for the primary endpoint, but is not recruiting patients. From June 4, 2012, to Oct 7, 2013, 1645 patients at 193 centres worldwide were screened for eligibility, and 704 patients were randomly assigned to dabrafenib plus trametinib (n=352) or vemurafenib (n=352). Questionnaire completion rates for both groups were high (>95% at baseline, >80% at follow-up assessments, and >70% at disease progression) with similar HRQoL and symptom scores reported at baseline in both treatment groups for all questionnaires. Differences in mean scores between treatment groups were significant and clinically meaningful in favour of the combination compared with vemurafenib monotherapy for most domains across all three questionnaires during study treatment and at disease progression, including EORTC QLQ-C30 global health (7·92, 7·62, 6·86, 7·47, 5·16, 7·56, and 7·57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0·001 for all assessments except p=0·005 at week 40), EORTC QLQ-C30 pain (-13·20, -8·05, -8·82, -12·69, -12·46, -11·41, and -10·57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0·001), EQ-5D thermometer scores (7·96, 8·05, 6·83, 11·53, 7·41, 9·08, and 10·51 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0·001 for all assessments except p=0·006 at week 32), and FACT-M Melanoma Subscale score (3·62, 2·93, 2·45, 3·39, 2·85, 3·00, and 3·68 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0·001). From the patient's perspective, which integrates not only survival advantage but also disease-associated and adverse-event-associated symptoms, treatment with the combination of a BRAF inhibitor plus a MEK inhibitor (dabrafenib plus trametinib) adds a clear benefit over monotherapy with the BRAF inhibitor vemurafenib and supports the combination therapy as standard of care in this population.

Grob JJ ，Amonkar MM ，Karaszewska B ，Schachter J ，Dummer R ，Mackiewicz A ，Stroyakovskiy D ，Drucis K ，Grange F ，Chiarion-Sileni V ，Rutkowski P ，Lichinitser M ，Levchenko E ，Wolter P ，Hauschild A ，Long GV ，Nathan P ，Ribas A ，Flaherty K ，Sun P ，Legos JJ ，McDowell DO ，Mookerjee B ，Schadendorf D ，Robert C ... -  《-》

Dabrafenib and trametinib, alone and in combination for BRAF-mutant metastatic melanoma.

Dabrafenib and trametinib were approved for use as monotherapies in BRAF-mutant metastatic melanoma by the U.S. Food and Drug Administration (FDA) in 2013, and most recently, their use in combination has received accelerated FDA approval. Both drugs target the mitogen-activated protein kinase (MAPK) pathway: dabrafenib selectively inhibits mutant BRAF that constitutively activates the pathway, and trametinib selectively inhibits MEK1 and MEK2 proteins activated by RAF kinases. The phase III study of dabrafenib in BRAF(V600E) metastatic melanoma reported rapid tumor regression in most patients and a 59% objective RECIST response rate. The median progression-free survival (PFS) and overall survival (OS) were improved compared with dacarbazine. Toxicities were well tolerated and different from those reported for vemurafenib, the first FDA-approved BRAF inhibitor. Efficacy has been demonstrated in other BRAF-mutant genotypes. The phase III study of trametinib in BRAF inhibitor-naïve patients with BRAF(V600E) or BRAF(V600K) also showed benefit with a prolonged median PFS and OS compared with chemotherapy. Trametinib is ineffective in patients who have progressed on BRAF inhibitors. A phase II trial of combined dabrafenib and trametinib demonstrated higher response rates and longer median PFS than dabrafenib monotherapy, with less cutaneous toxicity. Here, we review the clinical development of both drugs as monotherapies and in combination, and discuss their role in the management of BRAF-mutant melanoma.

Menzies AM ，Long GV 《-》

Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma.

Patients who have unresectable or metastatic melanoma with a BRAF V600E or V600K mutation have prolonged progression-free survival and overall survival when receiving treatment with BRAF inhibitors plus MEK inhibitors. However, long-term clinical outcomes in these patients remain undefined. To determine 5-year survival rates and clinical characteristics of the patients with durable benefit, we sought to review long-term data from randomized trials of combination therapy with BRAF and MEK inhibitors. We analyzed pooled extended-survival data from two trials involving previously untreated patients who had received BRAF inhibitor dabrafenib (at a dose of 150 mg twice daily) plus MEK inhibitor trametinib (2 mg once daily) in the COMBI-d and COMBI-v trials. The median duration of follow-up was 22 months (range, 0 to 76). The primary end points in the COMBI-d and COMBI-v trials were progression-free survival and overall survival, respectively. A total of 563 patients were randomly assigned to receive dabrafenib plus trametinib (211 in the COMBI-d trial and 352 in the COMBI-v trial). The progression-free survival rates were 21% (95% confidence interval [CI], 17 to 24) at 4 years and 19% (95% CI, 15 to 22) at 5 years. The overall survival rates were 37% (95% CI, 33 to 42) at 4 years and 34% (95% CI, 30 to 38) at 5 years. In multivariate analysis, several baseline factors (e.g., performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both progression-free survival and overall survival. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an overall survival rate of 71% (95% CI, 62 to 79) at 5 years. First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline and Novartis; COMBI-d ClinicalTrials.gov number, NCT01584648; COMBI-v ClinicalTrials.gov number, NCT01597908.).

Robert C ，Grob JJ ，Stroyakovskiy D ，Karaszewska B ，Hauschild A ，Levchenko E ，Chiarion Sileni V ，Schachter J ，Garbe C ，Bondarenko I ，Gogas H ，Mandalá M ，Haanen JBAG ，Lebbé C ，Mackiewicz A ，Rutkowski P ，Nathan PD ，Ribas A ，Davies MA ，Flaherty KT ，Burgess P ，Tan M ，Gasal E ，Voi M ，Schadendorf D ，Long GV ... -  《-》

Improved overall survival in melanoma with combined dabrafenib and trametinib.

Robert C ，Karaszewska B ，Schachter J ，Rutkowski P ，Mackiewicz A ，Stroiakovski D ，Lichinitser M ，Dummer R ，Grange F ，Mortier L ，Chiarion-Sileni V ，Drucis K ，Krajsova I ，Hauschild A ，Lorigan P ，Wolter P ，Long GV ，Flaherty K ，Nathan P ，Ribas A ，Martin AM ，Sun P ，Crist W ，Legos J ，Rubin SD ，Little SM ，Schadendorf D ... -  《-》