Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study.

Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients. This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics. Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and <3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use. These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.

Long GV ，Flaherty KT ，Stroyakovskiy D ，Gogas H ，Levchenko E ，de Braud F ，Larkin J ，Garbe C ，Jouary T ，Hauschild A ，Chiarion-Sileni V ，Lebbe C ，Mandalà M ，Millward M ，Arance A ，Bondarenko I ，Haanen JBAG ，Hansson J ，Utikal J ，Ferraresi V ，Mohr P ，Probachai V ，Schadendorf D ，Nathan P ，Robert C ，Ribas A ，Davies MA ，Lane SR ，Legos JJ ，Mookerjee B ，Grob JJ ... -  《-》

Open-label, phase IIa study of dabrafenib plus trametinib in East Asian patients with advanced BRAF V600-mutant cutaneous melanoma.

This study (NCT02083354) assessed the efficacy and safety of dabrafenib plus trametinib in East Asian patients with advanced BRAF V600-mutant cutaneous melanoma. Overall, 77 patients of East Asian origin (including 61 from Mainland China) with unresectable or metastatic BRAF V600-mutant cutaneous melanoma were enrolled. Prior treatment was allowed except with BRAF/MEK inhibitors. Patients received dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The primary end-point was objective response rate (ORR) using Response Evaluation Criteria in Solid Tumours 1.1. Secondary end-points were duration of response (DOR), progression-free survival (PFS), overall survival (OS), pharmacokinetics and safety. At data cutoff (February 23, 2018; median follow-up, 8.3 months), treatment was ongoing in 36 patients (47%). The median age was 52 years; 32% of patients had elevated lactate dehydrogenase, and 84% had received prior systemic therapy. ORR was 61% (95% confidence interval: 49.2-72.0), with four patients (5%) achieving complete response. Median DOR and PFS were 11.3 and 7.9 months, respectively. Median OS was not reached. The most common adverse event (AE) of any grade was pyrexia (56%). Grade ≥III AEs occurred in 29 patients (38%). The most common grade ≥III AEs were pyrexia (8%) and anaemia (6%). AEs led to permanent discontinuation in five patients (6.5%). Mean Cmax for dabrafenib and trametinib was 3560 and 11.5 ng/mL (day 1) and 2680 and 27.1 ng/mL (day 15), respectively. These results support the efficacy and tolerability of dabrafenib in combination with trametinib in East Asian patients with unresectable or metastatic BRAF V600-mutant cutaneous melanoma.

Si L ，Zhang X ，Shin SJ ，Fan Y ，Lin CC ，Kim TM ，Dechaphunkul A ，Maneechavakajorn J ，Wong CS ，Ilankumaran P ，Lee DY ，Gasal E ，Li H ，Guo J ... -  《-》

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 ... -  《-》

Patient-reported outcomes in patients with resected, high-risk melanoma with BRAF(V600E) or BRAF(V600K) mutations treated with adjuvant dabrafenib plus trametinib (COMBI-AD): a randomised, placebo-controlled, phase 3 trial.

In the phase 3 COMBI-AD study, patients with resected, stage III melanoma with BRAFV600E or BRAFV600K mutations received adjuvant dabrafenib plus trametinib or placebo. The primary analysis showed that dabrafenib plus trametinib significantly improved relapse-free survival at 3 years. These results led to US Food and Drug Administration approval of dabrafenib plus trametinib as adjuvant treatment for patients with resected stage III melanoma with BRAFV600E or BRAFV600K mutations. Here, we report the patient-reported outcomes from COMBI-AD. COMBI-AD was a randomised, double-blind, placebo-controlled, phase 3 study done at 169 sites in 25 countries. Study participants were aged 18 years or older and had complete resection of stage IIIA (lymph node metastases >1 mm), IIIB, or IIIC cutaneous melanoma as per American Joint Committee on Cancer 7th edition criteria, with BRAFV600E or BRAFV600K mutations, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) via an interactive voice response system, stratified by mutation type and disease stage, to receive oral dabrafenib (150 mg twice daily) plus oral trametinib (2 mg once daily) or matching placebos for 12 months. Patients, physicians, and the investigators who analysed the data were masked to treatment allocation. The primary endpoint was relapse-free survival, reported elsewhere. Health-related quality of life, reported here, was a prespecified exploratory endpoint, and was assessed with the European Quality of Life 5-Dimensions 3-Levels (EQ-5D-3L) questionnaire in the intention-to-treat population. We used a mixed-model repeated-measures analysis to assess differences in health-related quality of life between groups. This study is registered with ClinicalTrials.gov, number NCT01682083. The trial is ongoing, but is no longer recruiting participants. Between Jan 31, 2013, and Dec 11, 2014, 870 patients were enrolled and randomly assigned to receive dabrafenib plus trametinib (n=438) or matching placebos (n=432). Data were collected until the data cutoff for analyses of the primary endpoint (June 30, 2017). The median follow-up was 34 months (IQR 28-39) in the dabrafenib plus trametinib group and 33 months (20·5-39) in the placebo group. During the 12-month treatment phase, there were no significant or clinically meaningful changes from baseline between groups in EQ-5D-3L visual analogue scale (EQ-VAS) or utility scores. During treatment, there were no clinically meaningful differences in VAS scores or utility scores in the dabrafenib plus trametinib group between patients who did and did not experience the most common adverse events. During long-term follow-up (range 15-48 months), VAS and utility scores were similar between groups and did not differ from baseline scores. At recurrence, there were significant decreases in VAS scores in both the dabrafenib plus trametinib group (mean change -6·02, SD 20·57; p=0·0032) and the placebo group (-6·84, 20·86; p<0·0001); the mean change in utility score also differed significantly at recurrence for both groups (dabrafenib plus trametinib -0·0626, 0·1911, p<0·0001; placebo -0·0748, 0·2182, p<0·0001). These findings show that dabrafenib plus trametinib did not affect patient-reported outcome scores during or after adjuvant treatment, and suggest that preventing or delaying relapse with adjuvant therapy could be beneficial in this setting. Novartis.

Schadendorf D ，Hauschild A ，Santinami M ，Atkinson V ，Mandalà M ，Chiarion-Sileni V ，Larkin J ，Nyakas M ，Dutriaux C ，Haydon A ，Robert C ，Mortier L ，Lesimple T ，Plummer R ，Schachter J ，Dasgupta K ，Manson S ，Koruth R ，Mookerjee B ，Kefford R ，Dummer R ，Kirkwood JM ，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 ... -  《-》