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Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma
European Journal of Cancer, 7, 51, pages 833 - 840, Article in Press
To present the impact of treatments on health-related quality of life (HRQoL) from the double-blind, randomised phase III COMBI-d study that investigated the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients withBRAFV600E/K-mutant metastatic melanoma. COMBI-d showed significantly prolonged progression-free survival for the combination.
HRQoL was evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30, a generic cancer questionnaire (completed at baseline, during study treatment, at progression and post progression) assessing various dimensions (global health/QoL, functional status, and symptom impact). A mixed-model, repeated-measures analyses of covariance evaluated differences between arms.
Questionnaire completion rates were >95% at baseline, >85% to week 40 and >70% at disease progression. Baseline scores across both arms were comparable for all dimensions. Global health dimension scores were significantly better at weeks 8, 16 and 24 for patients receiving the combination during treatment and at progression. The majority of functional dimension scores (physical, social, role, emotional and cognitive functioning) trended in favour of the combination. Pain scores were significantly improved and clinically meaningful (6–13 point difference) for patients receiving the combination for all follow-up assessments versus those receiving dabrafenib monotherapy. For other symptom dimensions (nausea and vomiting, diarrhoea, dyspnoea, and constipation), scores trended in favour of dabrafenib monotherapy.
This analysis demonstrates that the combination of dabrafenib and trametinib provides better preservation of HRQoL and pain improvements versus dabrafenib monotherapy while also delaying progression. (Clinicaltrials.gov registration number: NCT01584648).
Keywords: Melanoma, Protein kinase inhibitors, Molecular targeted therapy, Proto-oncogene proteins B-raf, Dabrafenib, Trametinib.
The treatment landscape for metastatic melanoma has changed significantly since 2011 following the approval by the US Food and Drug Administration of three immunologic agents and three small molecules for the treatment of metastatic melanoma. The former include inhibitors of CTLA4 (ipilimumab) and PD-1 on T cells (pembrolizumab and nivolumab) and the latter include the BRAF inhibitors vemurafenib and dabrafenib and the MEK inhibitor trametinib for patients withBRAFV600-mutant melanoma.
Despite the improved response rates, progression-free survival (PFS) and overall survival (OS) in patients treated with these recently approved agents compared with dacarbazine chemotherapy, , , , , and , severe immune-mediated toxicities and the lack of a validated biomarker for patient selection may restrict the use of ipilimumab. The onset of resistance limits the efficacy of single-agent BRAF inhibitors  , with approximately 50% of patients developing resistance within 6–7 months of treatment initiation and .
The combination of BRAF and MEK inhibition delayed resistance and decreased the incidence of cutaneous hyperproliferative lesions compared with single-agent BRAF inhibition in preclinical models, and hence the combination was tested in phase I, II and III studies in patients withBRAFV600 mutation-positive metastatic melanoma, , , and . As a result, the combination of dabrafenib and trametinib received accelerated approval in the United States in 2014 based on the results of a randomised phase of an open-label phase I/II study comparing the combination with dabrafenib monotherapy in patients withBRAFV600-positive metastatic melanoma  . A double-blind, randomised, phase III study comparing the combination with dabrafenib monotherapy as first-line therapy in patients who had unresectable stage IIIC or stage IV melanoma withBRAFV600E or V600K mutations (COMBI-d)  demonstrated a statistically significant improvement in PFS (hazard ratio [HR] 0.75; 95% confidence interval (CI): 0.57–0.99;P = 0.035), and overall response rate (ORR) (67% versus 51%;P = 0.0015) for the combination versus dabrafenib monotherapy. Additionally, there was a 37% decrease in the risk of death that did not meet the pre-specified stopping criteria at a pre-specified interim analysis in favour of the combination (HR 0.63; 95% CI: 0.42–0.94;P = 0.023). The benefit of this combination over single-agent vemurafenib in terms of OS, PFS and response rates was observed in a second phase III trial (COMBI-v)  . Additionally, another combination of BRAF and MEK inhibitors (vemurafenib plus cobimetinib) demonstrated improved PFS compared with vemurafenib in the phase III coBRIM study  .
In the absence of a cure for patients with advanced or metastatic melanoma, the effects of a systemic drug treatment on health-related quality of life (HRQoL) and symptoms are important to consider in conjunction with efficacy and toxicities. Using the European Organisation for Research and Treatment of Cancer QOL Questionnaire-C30 (EORTC-QLQ-C30) and , we compared the effect of dabrafenib plus trametinib versus dabrafenib alone on HRQoL and symptoms (improvement or delay in worsening) in patients withBRAFV600E or V600K mutation-positive metastatic melanoma enrolled in the COMBI-d trial  .
2. Patients and methods
2.1. Study design and treatment regimen
COMBI-d (MEK115306; NCT01584648) is a randomised, double-blind, two-arm, international phase III study designed to evaluate the efficacy and safety of the combination of dabrafenib plus trametinib versus dabrafenib monotherapy  . Eligible patients with histologically confirmed, unresectable stage IIIC or stage IV melanoma withBRAFV600E or V600K mutations were randomly assigned in a 1:1 ratio to receive either a combination of oral dabrafenib (150 mg twice daily) and oral trametinib (2 mg once daily) or a combination of oral dabrafenib (150 mg twice daily) and placebo. Treatment continued until disease progression, death or withdrawal from the study, and no crossover was allowed. Patients who were receiving clinical benefit at the time of disease progression were allowed to continue study treatment with approval from the GlaxoSmithKline medical monitor. The primary end-point was investigator-assessed PFS. Secondary end-points included OS, response rate, response duration, safety, pharmacokinetics and HRQoL.
The study has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki). Informed consent was obtained for experimentation with human patients.
2.2. HRQoL assessments
HRQoL was evaluated in this study using the EORTC QLQ-C30. The EORTC QLQ-C30 is a self-reported, 30-item generic instrument for use in cancer patients across tumour types that includes overall health/global QoL, five functional scales and nine symptom scales or single-item questions. For global health status and the functional scales, a higher score reflects better global health or functioning. Conversely, for symptom scales or single items, higher scores indicate greater symptom severity.
The EORTC QLQ-C30 (the original English version as well as translations in various languages) has been shown to have good reliability, validity and responsiveness in different cancer populations, , , , and . Minimum clinically important differences (MCIDs) for the EORTC QLQ-C30 have been established previously and categorised as ‘small’ if mean changes in scores are 5–10 points, ‘moderate’ if 10–20 points and ‘large’ if >20 points  .
HRQoL assessments were carried out at baseline (before any study drug was administered), at week 8, every 8 weeks thereafter through week 56 and then every 12 weeks thereafter until disease progression. Assessments were also performed at the time of progressive disease and 5 weeks post-progression. Since the percentage of randomised patients available to complete the EORTC QLQ-C30 remained >40% in the combination arm and >30% in the dabrafenib monotherapy arm up until week 40 and then declined, only the data up to week 40 and at disease progression are reported.
2.3. Statistical analysis
HRQoL data from the intention-to-treat population collected until the data cutoff used for analyses of the primary end-point were included. Baseline scores (defined as HRQoL assessment before first dose) were reported with standard descriptive statistics. Changes in scores from baseline at each assessment were summarised for global health and for each functional and symptom scale or single item. Analysis of covariance—adjusted for baseline score using mixed-model repeated measures with time, treatment and treatment by time interaction as fixed effects—was carried out to assess differences between arms for global health and all functional and symptom dimension scores. Time was treated as the repeated variable. Unstructured covariance matrices were used for these analyses.
3.1. Baseline characteristics and questionnaire completion rates
From May 2012 to January 2013, a total of 423 patients were randomised to the two arms (211 to the combination arm and 212 to the dabrafenib monotherapy arm). Baseline demographic and disease characteristics have been previously reported  and were well balanced between arms. Completion rates for the EORTC-QLQ-C30 as a percentage of available patients were >90% at baseline and at weeks 8, 16, 24, 32 and 40 and >70% at disease progression in both treatment arms ( Table 1 ).
|Dabrafenib + Trametinib (Total N = 211)||Dabrafenib + Placebo (Total N = 212)|
|n/N a||Available patients,%||n/N a||Available patients,%|
|5 weeks post-disease progression||27/27||100||44/44||100|
a n/N = number of patients completing the questionnaire/number of patients who were available/eligible to complete the questionnaire.
Abbreviations:EORTC-QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; ITT, intention-to-treat.
At baseline, patients in both treatment arms reported comparable levels of global health status and functional and symptom-related HRQoL scores as measured by the EORTC-QLQ-C30, with differences of <5 points in the mean scores in all of the dimensions ( Fig. 1 ). Patients reported the highest levels of cognitive functioning among all the functional dimensions while they reported higher levels of pain and fatigue compared with other symptoms.
3.2. Impact on global health and functional HRQoL
Overall HRQoL as measured by the global health status score was consistently better (statistically significantly better at weeks 8, 16 and 24 and clinically meaningful at week 40) for patients receiving the combination therapy compared with those receiving dabrafenib monotherapy during treatment (3.7- to 5.8-point difference) and at disease progression (3-point difference; Fig. 2 ). For functional dimensions (physical, social, role, emotional and cognitive functioning) the majority of scores trended in favour of the combination therapy. Statistically significant improvements were observed in physical functioning at weeks 16 and 40, role functioning at weeks 24 and 32, social functioning at weeks 32 and 40, and cognitive functioning at week 40, and clinically meaningful improvements were observed in role functioning at weeks 24, 32, 40 and at disease progression, cognitive functioning at week 40, and social functioning at weeks 32 and 40 ( Fig. 3 ). Of these, role functioning consistently showed the most improvements (4–6 points) over the various follow-up visits for patients receiving combination therapy ( Fig. 3 ).
3.3. Impact on symptoms
In terms of symptom-related dimensions, pain scores significantly improved and were clinically meaningful (symptom improved by a 6–13 point difference) for patients receiving the combination therapy compared with those receiving dabrafenib monotherapy for all follow-up assessments ( Fig. 4 ). For other symptom dimensions, scores were comparable in patients receiving the combination therapy and those receiving dabrafenib monotherapy, although fatigue and insomnia trended in favour of the combination, and nausea/vomiting, diarrhoea, dyspnoea and constipation trended in favour of dabrafenib monotherapy ( Fig. 4 ).
In addition to clinical benefits, such as delayed progression, high tumour response rates and longer survival, HRQoL is an important consideration for patients with advanced melanoma, particularly as treatment is not curative in the majority of patients. In this study, the addition of trametinib to dabrafenib, which are both approved for the treatment ofBRAFV600-positive metastatic melanoma as monotherapies, did not result in a deterioration of the HRQoL of patients. In fact, based on the EORTC-QLQ-C30 questionnaire, the global health status score improved for patients receiving the combination therapy compared with those receiving dabrafenib monotherapy for all follow-up assessments. This finding, along with the improvement seen in other functional dimensions, supports the PFS benefit that the combination offers to patients.
Patients reported higher levels of pain at baseline compared with other symptoms, and improvement in pain scores were statistically significant and clinically meaningful in favour of the combination compared with dabrafenib monotherapy. These results support the value the combination may be offering to patients in reducing the level of distress associated with pain, a symptom commonly observed in patients with metastatic melanoma. In contrast, scores for nausea and vomiting, constipation and diarrhoea trended in favour (improved symptoms) of dabrafenib monotherapy, which is consistent with the gastrointestinal-related events (e.g. diarrhoea: 24% versus 14%; vomiting: 20% versus 14%) observed for the combination compared with dabrafenib monotherapy, respectively  . Pyrexia was reported as the most common adverse event for the combination (51% versus 28%). Although the EORTC QLQ C30 does not include any patient assessment of fever, one would expect that any impact from a functional HRQoL perspective is already captured within the patients’ responses.
Three phase III clinical trials have all demonstrated improved efficacy of combined BRAF and MEK inhibition over single-agent BRAF inhibition in terms of PFS and tumour control, , and , with a proven OS benefit of the combination of dabrafenib and trametinib compared with vemurafenib monotherapy  . These additional results not only show an absence of significant deterioration in the HRQoL of patients treated with the combination, but also provide evidence of better scores in most domains, except for a few symptoms, in patients treated with the combination compared with those receiving dabrafenib monotherapy. This supports the idea of a substantial supplementary benefit with the combination over monotherapy with a BRAF inhibitor, not only in survival but also quality of survival from the point of view of the patient. Combination should be preferred over single-agent BRAF inhibitors inBRAFV600-mutant metastatic melanoma, except in rare cases in which a MEK inhibitor is contraindicated.
Previous papers have presented the effect of interferon on the HRQoL of patients with melanoma, , and . However, to our knowledge this is the first paper reporting the effect of two targeted small molecules on HRQoL in patients with advanced or metastatic melanoma. HRQoL evidence in patients with treatment-naive advanced or metastatic melanoma has previously been reported (using the EORTC QLQ C30) for three of the newer treatments that are available as monotherapies—ipilimumab  , dabrafenib  and trametinib  , although each of them were compared with chemotherapy. The results of these studies suggested that patients who received the combination of ipilimumab plus dacarbazine or dacarbazine monotherapy showed small-to-moderate worsening in HRQoL scores  , whereas those who received trametinib monotherapy  or dabrafenib monotherapy  experienced greater functional and symptomatic benefits compared with chemotherapy (dacarbazine or paclitaxel). The combination of dabrafenib and trametinib has been shown to further preserve HRQoL than that shown by dabrafenib alone.
Patients in clinical trials may be more motivated and optimistic and therefore more likely to report benefit and endure more treatment-related toxicity. However, the results of this study are strengthened because it was double-blinded (thus reflective of how patients truly felt, with minimised bias), completion rates for the questionnaire were high, and patients’ baseline scores were comparable with EORTC QLQ-C30 reference values from an international sample of patients with stage III/IV malignant melanoma  , suggesting that the patient population in this study is representative of the general population of patients with metastatic melanoma. Additionally, the EORTC QLQ C30 is a widely used, reliable and valid questionnaire for evaluating HRQoL in patients with cancer, , and . Additional studies may be required to validate the results of this study as there were no a priori hypotheses, and the study was not powered for the HRQoL end-point.
In conclusion, the combination of trametinib and dabrafenib compared with dabrafenib monotherapy provides better preservation of HRQoL and improvement in pain in patients withBRAFV600-positive metastatic melanoma. These data further support the clinical benefit that the combination of dabrafenib and trametinib compared with dabrafenib alone has shown in terms of improved PFS.
This work was supported by GlaxoSmithKline. Medical writing support was provided by SciMentum and funded by GlaxoSmithKline.
Conflict of interest statement
DS received research funding from GlaxoSmithKline and participated in advisory boards and speaker bureaus for GlaxoSmithKline, Bristol-Myers Squibb, Amgen, MSD, Roche, Boehringer Ingelheim, and Novartis. HG declared advisory roles for Bristol-Myers Squibb, Roche, MSD, Amgen, GlaxoSmithKline, and Novartis. FB participated in advisory boards for GlaxoSmithKline. JJG participated in advisory boards and lectures for GlaxoSmithKline, Roche, and Bristol-Myers Squibb, participated in advisory boards for Merck, MSD, and Novartis, and received research funding from Roche. CG received research funding from GlaxoSmithKline, Bristol-Myers Squibb, and Roche, participated in advisory boards for GlaxoSmithKline, Amgen, Novartis, MSD, Bristol-Myers Squibb, and Roche, received honoraria from MSD, Bristol-Myers Squibb, and Roche, and received travel reimbursement from and provided consultancy to Roche. CL participated in advisory boards for GlaxoSmithKline, Roche, Bristol-Myers Squibb, MSD, Novartis, and Amgen. VC-S participated in advisory boards and congress activity for GlaxoSmithKline, Roche, Bristol-Myers Squibb, and MSD. MM participated in advisory boards for GlaxoSmithKline. AA received research funding from Roche and participated in advisory boards for GlaxoSmithKline, Roche, and Bristol-Myers Squibb. KTF provided consultancy to GlaxoSmithKline. PN participated in advisory boards for and received meeting attendance support from GlaxoSmithKline. AR participated in advisory boards for GlaxoSmithKline and Novartis (fees were paid to his institution). CR participated in advisory boards for Bristol-Myers Squibb, Roche, Merck, GlaxoSmithKline, Novartis, and Amgen. MMA and MC are employees of and own stock in GlaxoSmithKline. DJD is an employee of GlaxoSmithKline and holds an issued patent on a pharmaceutical composition containing trametinib and a pending patent on combinations of trametinib + gemcitabine. JI is an employee of GlaxoSmithKline. GA is a former employee of, holds stock options for, and has immediate family employed at GlaxoSmithKline. GVL provided consultancy to Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Novartis and Roche and received travel reimbursement from Roche. All remaining authors have declared no conflicts of interest.
Funding for this study was provided by GlaxoSmithKline (NCT01584648). All listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. The authors wish to acknowledge all the patients, families, investigators and staff at the sites involved in the COMBI-d (MEK115306) clinical trial. Editorial support in the form of collating author comments and copyediting was provided by SciMentum and was funded by GlaxoSmithKline.
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a Universitätsklinikum Essen, Hufelandstr. 55, Essen 45147, Germany
b GlaxoSmithKline, 1250 S Collegeville Rd, Collegeville, PA 19426, United States
c Moscow City Oncology Hospital #62, Moscow 143423, Russia
d Petrov Research Institute of Oncology, 68 Leningradskaya Street, Saint Petersburg 197758, Russia
e University of Athens, Aghiou Thoma 17, Athens 11527, Greece
f Fondazione IRCCS Istituto Nazionale Tumori, via Giacomo Venezian, 1, Milan, Italy
g Service de Dermatologie, Centre Hospitalo-Universitaire Sainte-Marguerite, 270 Boulevard de Sainte-Marguerite, Marseille 13009, France
h Dnepropetrovsk State Medical Academy, Dzerzhyns’koho Street 9, Dnepropetrovsk 49044, Ukraine
i Department of Dermatology, University Hospital Tuebingen, Liebermeisterstraße 25, Tuebingen 72076, Germany
j APHP Dermatology CIC Hôpital Saint Louis, University Paris Diderot, INSERM U976, Avenue Claude Vellefaux, Paris 75010, France
k Royal Marsden Hospital, Fulham Road, London SW3 6JJ, United Kingdom
l Melanoma and Esophageal Oncology Unit, Veneto Oncology Institute-IRCCS, via Gattamelata, 64, Padua 35128, Italy
m Sir Charles Gairdner Hospital, Hospital Avenue, Perth, WA 6009, Australia
n Hospital Clinic, Carrer Villarroel 170, Barcelona 08036, Spain
o Papa Giovanni XIII Hospital, Piazza OMS 1, Bergamo 24127, Italy
p Massachusetts General Hospital Cancer Center, 55 Fruit St, Boston 02114, MA, United States
q Mount Vernon Cancer Centre, Rickmansworth Road, Northwood HA6 2RN, United Kingdom
r David Geffen School of Medicine, UCLA, 10833 Le Conte Avenue, Los Angeles 90095, CA, United States
s Gustave Roussy and Paris 11 University, 114 Rue Edouard Vaillant, Villejuif-Paris-Sud 94805, France
t Melanoma Institute Australia & The University of Sydney, 40 Rocklands Road, Sydney 2060, Australia
1 Affiliation of M. Casey and G. Aktan at the time of the study.
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