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Original article
A single-centre experience of patients with metastatic melanoma enrolled in a dabrafenib named patient programme David K. Laua, Miles C. Andrewsa, Natalie Turnera, Arun A. Azada, Ian D. Davisa,b and Jonathan S. Cebona We studied the efficacy, tolerability and clinical courses of dabrafenib in patients with metastatic melanoma who were ineligible for enrolment into a clinical trial. Between July 2011 and May 2013, patients with unresectable stage III or stage IV, V600-mutated metastatic melanoma who were not eligible for inclusion into clinical trials were offered treatment with dabrafenib through a named patient programme. Routine efficacy and toxicity data were collected throughout treatment and studied retrospectively. The endpoints were progression-free survival (PFS), overall survival and best overall response. Thirty-one patients commenced dabrafenib therapy including six individuals who had progressed on a prior BRAF-inhibitor treatment. The majority of patients had cerebral metastases (n = 17) and/or a poor performance status [Eastern Cooperative Oncology Group (ECOG) Z 2, n = 11]. Median overall survival was 5.6 months (range 0.1–22 months). Median PFS was 3.3 months (range 0.1–21) and was similar despite performance status. One patient had a complete response and eight showed partial responses
to treatment. Patients with cerebral metastases (n = 17) had a median PFS of 4.6 months. Five patients (16%) had dose-limiting toxicities. Despite several poor prognostic features, dabrafenib is a safe and effective treatment in the community setting, with occasional impressive c 2014 Wolters outcomes. Melanoma Res 24:144–149 Kluwer Health | Lippincott Williams & Wilkins.
Introduction
such as poor performance status and presence of brain metastases [5,6] are often excluded from trials. For this reason, our goal was to examine and publish our experience of using dabrafenib in the non-clinical-trial population, focusing on differences in disease characteristics, toxicities and outcomes.
Until recently, few effective systemic treatment options were available for metastatic melanoma. Molecular treatment approaches identified the mitogen activated protein kinase (MAPK) pathway as an effective target in melanoma, such that mutation-selective BRAF inhibitors have become the mainstay of treatment in 40–50% of metastatic melanoma patients harbouring activating V600 mutations of BRAF [1]. Dabrafenib (GSK2118436) is a potent and selective inhibitor of mutant BRAF kinase with proven activity in BRAF V600E/K melanoma [2]. A phase III study of dabrafenib demonstrated a significant improvement in progression-free survival (PFS) in comparison with dacarbazine (5.1 vs. 2.7 months) [3]. Phase III studies of another BRAF inhibitor, vemurafenib, have demonstrated similar efficacy, although to date there are no head-to-head comparative data [4]. A common criticism of clinical trials is that the patient population being studied is not representative of patients seen in community practice. Whereas these studies clearly show a benefit in individuals who are ideal clinical trial candidates, patients with adverse prognostic factors c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0960-8931
Melanoma Research 2014, 24:144–149 Keywords: BRAF inhibitor, cerebral metastasis, dabrafenib, metastatic melanoma, named patient programme a Ludwig Institute for Cancer Research – Austin Branch, Joint Ludwig-Austin Medical Oncology Unit, Olivia Newton John Cancer and Wellness Centre, Austin Health and bEastern Health Clinical School, Monash University, Victoria, Australia
Correspondence to Jonathan S. Cebon, Ludwig Institute for Cancer Research – Austin Branch, Level 5, Joint Ludwig-Austin Medical Oncology Unit, Olivia Newton John Cancer and Wellness Centre, 145-163 Studley Road, Heidelberg, Victoria 3084, Australia Tel: + 61 3 9496 5763; fax: + 61 3 9457 6698; e-mail: [email protected] Received 29 August 2013 Accepted 18 October 2013
Eligibility
During the period of enrolment, the Therapeutic Goods Administration had yet to approve dabrafenib for the treatment of V600 mutant melanoma. At the Austin Hospital, Melbourne, Australia, patients who were not eligible for enrolment in BRAF-inhibitor trials, for reasons such as poor performance status or cerebral metastases, were potentially eligible to receive dabrafenib through a named patient programme (NPP) sponsored by GlaxoSmithKline (GSK, BRF115252). The main inclusion criteria were unresectable stage III or stage IV melanoma harbouring a BRAF V600 mutation, Eastern Cooperative Oncology Group performance status of 0–3, adequate haematologic, hepatic and renal function, and absence of comorbid conditions deemed likely to be competitively limiting on prognosis. Patients who DOI: 10.1097/CMR.0000000000000036
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Dabrafenib named patient program Lau et al. 145
were eligible for enrolment in a BRAF-inhibitor clinical trial or who were receiving concurrent systemic therapy for melanoma were not permitted for inclusion in this programme. Prior BRAF-inhibitor therapy was not permitted; however, applications were made for BRAFinhibitor rechallenge if prior discontinuation was due to an adverse event not expected to recur with dabrafenib, or if a sufficiently long period had elapsed since last exposure to a BRAF inhibitor such that a reasonable expectation of clinical benefit remained. Applications were made on behalf of the patients with their express written informed consent, and applications were considered by both local and global medical review boards at GSK.
and died of rapidly progressive disease within 2 weeks after application submission. One patient was deemed not eligible because of recent progression in a BRAFinhibitor clinical trial. One patient was approved for dabrafenib treatment but subsequently did not actually commence therapy.
Treatment
Baseline clinical characteristics of the patients are shown in Table 1. Out of the 31 patients who commenced dabrafenib therapy, 36% had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or 3. The majority of the patients (74%) had stage IVc disease with an elevated lactate dehydrogenase level. Seventeen patients (55%) had brain metastases, among whom 10 had undergone either surgery or radiotherapy before commencement of dabrafenib (Table 2).
Dabrafenib was administered at a dose of 150 mg twice daily orally, ongoing until progression or unacceptable toxicity. There was an option to continue treatment post progression if it was believed that the patient was still benefitting from the treatment, typically in the context of oligometastatic progression with availability of suitable alternative treatments for the progressing sites. Patients with symptomatic cerebral metastases generally underwent surgery and/or radiotherapy before commencement of dabrafenib therapy.
All patients were commenced on a dabrafenib dose of 150 mg twice daily orally, except in two instances: one in which a patient had previously experienced hepatic toxicity on vemurafenib and another in which a patient experienced pyrexia on dabrafenib, as observed from clinical trials. These two patients were commenced on 75 mg dabrafenib twice daily. The median time from diagnosis of stage IV disease to commencement of dabrafenib treatment was 2.5 months (range 1–46).
Grade 2 or worse adverse events believed to be related to dabrafenib were generally managed by withholding dabrafenib and administering best supportive care. If the adverse event improved to grade 1 or lower, dabrafenib could be resumed at a lower dose. In the case of dermatological toxicity, such as development of possible squamous cell carcinomas, patients were referred to a dermatologist for review. Reporting and assessments
Patients underwent baseline tumour assessments by computed tomography or MRI and were restaged at the discretion of the treating physician, typically every 8–12 weeks. Responses were defined by RECIST 1.1 criteria. Frequently, 18F-fluorodeoxyglucose PET assessments were also made in cases in which there was uncertainty and the treating clinicians felt that this would provide additional clinically-relevant information. Reporting of non-serious and serious adverse events was mandated by GSK. Physician assessments were carried out and progress updates were delivered monthly for at least the first 6 months of treatment. Patient updates were subsequently required to be submitted every second month.
Results Between July 2011 and May 2013, 36 applications were submitted for consideration for inclusion in the dabrafenib NPP. Out of the four patients who did not receive dabrafenib, three patients had poor performance status
Efficacy
At the time of analysis (14 May 2013), nine patients were continuing on dabrafenib through the NPP. The median Table 1 Baseline characteristics of patients treated with dabrafenib in the named patient programme Characteristics Sex Male Female Total Age (years) Median (range) < 65 Prior systemic therapies BRAF inhibitor Chemotherapy Immunotherapy ECOG performance status 0 1 2 3 Metastatic stage at diagnosis Stage IVa Stage IVb Stage IVc LDH Elevated BRAF mutation V600E V600K V600R Brain metastases
Number (%) 19 (61) 12 (39) 31 55.3 (26.4–78.3) 23 (74) 6 (19)a,b 3 (10) 5 (16) 8 12 7 4
(26) (39) (23) (13)
4 (13) 4 (13) 23 (74) 22 (71) 22 7 2 17
(71) (23) (6) (55)
ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase. One patient had also received prior chemotherapy and BRAF-inhibitor therapy. Three patients also received trametinib in a clinical trial.
a
b
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duration of treatment was 5.1 months (range 0.1–21.7). Median survival after 19 deaths was 5.6 months (range 0.1–22). Twenty-seven patients met the criteria for PFS, defined as time to progression or death from commencement of dabrafenib. The median PFS was 3.3 months
Table 2
Baseline characteristics of patients with brain metastases
(n = 17) Age [median (range)] (years) Male [N (%)] Female [N (%)] BRAF mutation [N (%)] V600E V600K Brain therapies before dabrafenib [N (%)]a Radiotherapy Surgery After commencement of dabrafenib [N (%)] Radiotherapy Surgery
54.5 (26–78) 10 (59) 7 (41) 13 (76) 4 (24) 8 (41) 3 (18) 4 (24) 0 (0)
a
One patient underwent both surgery and radiotherapy before dabrafenib therapy.
(range 0.1–21). One patient ceased treatment after 10 months because of progression of dementia, which was considered to be due to whole-brain radiotherapy rather than disease progression or dabrafenib. Patients with ECOG status of 0 or 1 receiving dabrafenib as first-line therapy had a median overall survival of 9.3 months (range 1.9–22). For patients with ECOG status of 2 or 3, the median overall survival was 5.2 months (range 1.4–12). Best response was not evaluable in seven patients either because of death before imaging or lack of measureable disease. Stable disease and partial responses were observed in 26 and 19% of patients, respectively. One complete response was observed in a patient with skeletal muscle, subcutaneous and lung metastases with resected solitary brain and small bowel disease before commencing treatment. Figure 1 details the best response in relation to the duration of treatment.
Fig. 1
Complete response Partial response Stable disease Individual patients
Progressive disease Non-evaluable Ongoing therapy Disease progressed
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Duration of treatment (months)
Duration of treatment for metastatic melanoma treated with dabrafenib. A total of 31 patients were treated. Colours of each bar represent the best response achieved by each individual. Crosses denote the time of disease progression. Arrows indicate that treatment is ongoing as of 14 May 2013.
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Dabrafenib named patient program Lau et al. 147
alternative modality locoregional therapy to a site of oligometastatic progression (Table 4).
Of the 17 patients with brain metastases, seven patients (41%) had a partial response and five patients (30%) had stable disease. The median PFS and overall survival in the subgroup of patients with cerebral metastases were 4.6 and 5.6 months, respectively.
Despite the poor performance status, five individuals achieved an overall survival of more than 5 months. This is an important subset of patients with widespread disease, including cerebral metastases, who nevertheless stand to benefit from BRAF-inhibitor therapy despite poor baseline clinical characteristics. Table 5 shows the characteristics of these patients in greater detail.
Six patients in this series were permitted to commence dabrafenib therapy after previous treatment with a BRAF inhibitor (Table 3). Three of these patients had previously received dabrafenib and trametinib (a MEK1/2inhibitor) in a clinical trial (BRF113220, clinicaltrials.gov number, NCT01072175) but had ceased therapy because of progressive disease. Although the median PFS for firstline BRAF-inhibitor therapy was 6.1 months (range 1.2–11 months), the median PFS with dabrafenib as second-line therapy in the NPP was 1.4 months. The median interval between previous BRAF-inhibitor therapy and commencement of dabrafenib was 3 months (range 2.4–12 months). The overall survival from the time of first exposure to a BRAF inhibitor was 11 months (range 5.8–25).
Toxicity
Overall, dabrafenib at a dose of 150 mg twice daily was well tolerated. Patients commonly experienced grade 1–2 toxicities such as arthralgia, fatigue and pyrexia as reported previously. Five patients required dose reductions because of plantopalmar erythema, neutropenia, fatigue and fever (n = 2). Three patients developed significant hyperkeratotic lesions such as keratoacanthoma; however, no new primary melanomas or squamous cell carcinomas were detected.
Discussion
In our cohort, 12 patients underwent therapy for more than 2 weeks after progression. The median duration of dabrafenib therapy for these patients was 2 months longer than the median PFS of the entire group. Three patients achieved significant prolongation of their dabrafenib therapy, and thus overall disease control, by undergoing Table 3
This study on a cohort of patients with metastatic melanoma treated with dabrafenib in an NPP demonstrates clinical utility in a ‘real-world’ setting. Toxicity was comparable, and PFS in this cohort was consistent with the 5.1-month PFS reported recently in the
Overall and subgroup outcomes Best response Median PFS (months)
Median OS (months)
Overall (n = 31) 3.3 (0.1–21.2) 5.6 According to prior BRAF inhibitor exposure BRAF inhibitor as first line (n = 25) 3.5 (0.1–21.20) 5.4 Prior BRAF inhibitor (n = 6) 1.18 (0.1–3.50) 1.61 According to performance status (patients receiving dabrafenib as first-line therapy) ECOG 0/1 (n = 15) 3.5 (0.8–21.2) 9.3 ECOG 2/3 (n = 10) 3.5 (0.1–10.6) 5.2 According to presence of brain metastases Brain metastases (n = 17) 4.6 (0.8–13.0) 5.6
CR
PR
SD
PD
NE
(0.1–22.0)
1
8
9
6
7
(0.1–22.0) (0.1–6.1)
1
8
8 1
4 2
4 3
(1.9–22.0) (1.38–12.4)
0 1
7 1
4 4
2 2
2 2
(1.9–12.4)
1
7
7
2
CR, complete response; ECOG, Eastern Cooperative Oncology Group; NE, not evaluable; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.
Table 4
Characteristics of poor performance status patients with better-than-median progression-free survival
Age/ sex
Performance status (ECOG)
Sites of disease
BRAF Stage mutation
57F 66F
3 2
Brain, mediastinum Brain, lung, liver, small bowel
IVc IVc
V600E V600E
Raised Raised
SD SD
6.2 4.6
68M
2
Brain, spleen, mesentery
IVc
V600E
Normal
SD
9.7
45M
2
IVc
V600E
–
CR
10.0a
53M
2
Brain, lung, subcutaneous tissue, small bowel Brain, lung, mediastinum, adrenal gland, bone
IVc
V600E
Raised
PR
3.4
LDH
Best response PFS
OS
Prior treatment
7.0 WBRT 12.3 Excision of cerebral metastasis, stereotactic brain radiotherapy, multiple liver/lung resections Splenectomy/mesenteric excision, excision of solitary brain metastasis, WBRT Excision of solitary brain metastasis, WBRT 5.3 Nil
CR, complete response; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease; WBRT, whole-brain radiotherapy. a Ongoing therapy as of 14 May 2013.
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Melanoma Research 2014, Vol 24 No 2
Table 5
Characteristics of patients who reachieved disease control while continuing dabrafenib therapy beyond radiological progression
Age/ sex
Performance status (ECOG)
54M
0
Brain, lung, myocardium, liver, subcutaneous tissue
IVc
43M
0
26M
0
Lung/pleura, epi/pericardium, lymph nodes Brain, lymph nodes, bone, skeletal muscle, stomach, subcutaneous tissue
Sites of disease
BRAF Stage mutation
Time on Progression-free survival dabrafenib (months) therapy (months)
LDH
Best response
V600K
Raised
PR
7.9
17.6
IVb
V600E
Raised
SD
1.8
5.7
IVc
V600E
Normal
PR
1.4
7.4
Treatment received while on dabrafenib WBRT, excision of solitary recurrent subcutaneous metastasis Excision of right lung metastases Stereotactic radiotherapy to cerebral metastases
All patients were still receiving therapy as of 14 May 2013. ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; PR, partial response; SD, stable disease; WBRT, whole-brain radiotherapy.
randomized phase III clinical trial that compared dabrafenib with dacarbazine [3]. Nevertheless, lower response rates were noted, with much of this variability being explained by the inclusion of patients with poor prognostic factors such as poor performance status, cerebral metastases and prior treatment with a BRAF inhibitor. In this series, 55% of patients had cerebral metastases at commencement of BRAF-inhibitor therapy, and evaluation of progression was compromised because follow-up imaging did not follow a rigid protocol. Nonetheless, our objective response rate (complete response + partial response) of 47% compares favourably with previously published data reporting rates of 31–38% for V600E [7]. Despite reports to the contrary [8], our own experience with rechallenging patients with BRAF inhibitors after failure of prior therapy was dismal, with median PFS and overall survival of only 1.2 and 1.6 months, respectively, in the six patients treated. As the numbers are small, identifying a subgroup that may have benefited was not possible. As far as we could tell, there was no advantage for patients with a greater interval between BRAFinhibitor exposures, prior exposure to a different BRAF inhibitor or prior exposure to an MEK inhibitor. It has been proposed that intermittent dosing may improve durability of response; however, this was not addressed here [9]. We have observed that some patients with a good performance status benefit by using locoregional therapies upon progression while continuing with BRAF-inhibitor therapy, with three patients being able to continue therapy for at least 4 months after deemed progression. In light of this, it is clear that further studies are required to define the role of this strategy in optimizing disease control. Despite concern that concurrent dabrafenib administration and radiotherapy cause serious skin toxicity [10], this was not observed in the four patients we treated using this strategy. The median time from diagnosis to treatment was 2.5 months. Several factors contribute to this such as referral to a tertiary care centre, molecular testing, delay in
approval of applications and receipt of drugs in the pharmacy. Although it would be ideal to have earlier commencement of therapy if possible, the effect on responses and outcomes is not known. Time to initiation of therapy will improve as access to this molecular testing protocol and medication becomes widespread. Overall, the observations from this access programme are that dabrafenib is a feasible treatment in daily clinical practice. Dabrafenib is safe and effective in a non-trial setting. Further, the judicious use of BRAF inhibitors beyond progression may offer some patients enhanced periods of disease control, particularly once more data exist to guide the rational combination of systemic and locoregional therapies. The duration of clinical efficacy still remains short, and a better understanding of how to prevent treatment resistance is required. MEK inhibitors have been shown to have clinical activity in BRAF mutant melanoma, and the median PFS has been prolonged with a combination of dabrafenib and trametinib (MEK inhibitor) [11–13]. Phase III studies of this combination are underway (clinicaltrials.gov NCT01689519, NCT 01584648). The combination of molecular therapies with immunotherapies is also an area of current research interest [14]. For patients to whom the clinical trials may not directly apply, we also anticipate that, in time, larger datasets will enable better identification of those patients who stand to gain the most from BRAF-inhibitor therapy, thus optimizing clinical decision making in the first-line and subsequent-line settings.
Acknowledgements The authors thank participating patients and families; Anna Lucas and Jim Siderov for their expert assistance in managing and dispensing patient supplies of dabrafenib; Joanne Hawking for her expertise in the melanoma clinic; Dr Katrina Vanin and the staff at GSK Australia. JC is supported in part by grants from the Melanoma Research Agency (MRA), the Australian National Health and Medical Research Council (NHMRC, Project #1007381) and Victorian State Government Operational Infrastructure Support Program. MA is supported by an NHMRC Medical Postgraduate Research Scholarship (NHMRC #1055456).
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Dabrafenib named patient program Lau et al.
Conflicts of interest
Professor Cebon reports receiving consulting fees, lecture fees and research grants from GSK. GSK provided dabrafenib at no expense to the patient nor Austin Hospital. Further, GSK did not contribute to the authorship of this manuscript.
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Original article
A single-centre experience of patients with metastatic melanoma enrolled in a dabrafenib named patient programme David K. Laua, Miles C. Andrewsa, Natalie Turnera, Arun A. Azada, Ian D. Davisa,b and Jonathan S. Cebona We studied the efficacy, tolerability and clinical courses of dabrafenib in patients with metastatic melanoma who were ineligible for enrolment into a clinical trial. Between July 2011 and May 2013, patients with unresectable stage III or stage IV, V600-mutated metastatic melanoma who were not eligible for inclusion into clinical trials were offered treatment with dabrafenib through a named patient programme. Routine efficacy and toxicity data were collected throughout treatment and studied retrospectively. The endpoints were progression-free survival (PFS), overall survival and best overall response. Thirty-one patients commenced dabrafenib therapy including six individuals who had progressed on a prior BRAF-inhibitor treatment. The majority of patients had cerebral metastases (n = 17) and/or a poor performance status [Eastern Cooperative Oncology Group (ECOG) Z 2, n = 11]. Median overall survival was 5.6 months (range 0.1–22 months). Median PFS was 3.3 months (range 0.1–21) and was similar despite performance status. One patient had a complete response and eight showed partial responses
to treatment. Patients with cerebral metastases (n = 17) had a median PFS of 4.6 months. Five patients (16%) had dose-limiting toxicities. Despite several poor prognostic features, dabrafenib is a safe and effective treatment in the community setting, with occasional impressive c 2014 Wolters outcomes. Melanoma Res 24:144–149 Kluwer Health | Lippincott Williams & Wilkins.
Introduction
such as poor performance status and presence of brain metastases [5,6] are often excluded from trials. For this reason, our goal was to examine and publish our experience of using dabrafenib in the non-clinical-trial population, focusing on differences in disease characteristics, toxicities and outcomes.
Until recently, few effective systemic treatment options were available for metastatic melanoma. Molecular treatment approaches identified the mitogen activated protein kinase (MAPK) pathway as an effective target in melanoma, such that mutation-selective BRAF inhibitors have become the mainstay of treatment in 40–50% of metastatic melanoma patients harbouring activating V600 mutations of BRAF [1]. Dabrafenib (GSK2118436) is a potent and selective inhibitor of mutant BRAF kinase with proven activity in BRAF V600E/K melanoma [2]. A phase III study of dabrafenib demonstrated a significant improvement in progression-free survival (PFS) in comparison with dacarbazine (5.1 vs. 2.7 months) [3]. Phase III studies of another BRAF inhibitor, vemurafenib, have demonstrated similar efficacy, although to date there are no head-to-head comparative data [4]. A common criticism of clinical trials is that the patient population being studied is not representative of patients seen in community practice. Whereas these studies clearly show a benefit in individuals who are ideal clinical trial candidates, patients with adverse prognostic factors c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0960-8931
Melanoma Research 2014, 24:144–149 Keywords: BRAF inhibitor, cerebral metastasis, dabrafenib, metastatic melanoma, named patient programme a Ludwig Institute for Cancer Research – Austin Branch, Joint Ludwig-Austin Medical Oncology Unit, Olivia Newton John Cancer and Wellness Centre, Austin Health and bEastern Health Clinical School, Monash University, Victoria, Australia
Correspondence to Jonathan S. Cebon, Ludwig Institute for Cancer Research – Austin Branch, Level 5, Joint Ludwig-Austin Medical Oncology Unit, Olivia Newton John Cancer and Wellness Centre, 145-163 Studley Road, Heidelberg, Victoria 3084, Australia Tel: + 61 3 9496 5763; fax: + 61 3 9457 6698; e-mail: [email protected] Received 29 August 2013 Accepted 18 October 2013
Eligibility
During the period of enrolment, the Therapeutic Goods Administration had yet to approve dabrafenib for the treatment of V600 mutant melanoma. At the Austin Hospital, Melbourne, Australia, patients who were not eligible for enrolment in BRAF-inhibitor trials, for reasons such as poor performance status or cerebral metastases, were potentially eligible to receive dabrafenib through a named patient programme (NPP) sponsored by GlaxoSmithKline (GSK, BRF115252). The main inclusion criteria were unresectable stage III or stage IV melanoma harbouring a BRAF V600 mutation, Eastern Cooperative Oncology Group performance status of 0–3, adequate haematologic, hepatic and renal function, and absence of comorbid conditions deemed likely to be competitively limiting on prognosis. Patients who DOI: 10.1097/CMR.0000000000000036
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Dabrafenib named patient program Lau et al. 145
were eligible for enrolment in a BRAF-inhibitor clinical trial or who were receiving concurrent systemic therapy for melanoma were not permitted for inclusion in this programme. Prior BRAF-inhibitor therapy was not permitted; however, applications were made for BRAFinhibitor rechallenge if prior discontinuation was due to an adverse event not expected to recur with dabrafenib, or if a sufficiently long period had elapsed since last exposure to a BRAF inhibitor such that a reasonable expectation of clinical benefit remained. Applications were made on behalf of the patients with their express written informed consent, and applications were considered by both local and global medical review boards at GSK.
and died of rapidly progressive disease within 2 weeks after application submission. One patient was deemed not eligible because of recent progression in a BRAFinhibitor clinical trial. One patient was approved for dabrafenib treatment but subsequently did not actually commence therapy.
Treatment
Baseline clinical characteristics of the patients are shown in Table 1. Out of the 31 patients who commenced dabrafenib therapy, 36% had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or 3. The majority of the patients (74%) had stage IVc disease with an elevated lactate dehydrogenase level. Seventeen patients (55%) had brain metastases, among whom 10 had undergone either surgery or radiotherapy before commencement of dabrafenib (Table 2).
Dabrafenib was administered at a dose of 150 mg twice daily orally, ongoing until progression or unacceptable toxicity. There was an option to continue treatment post progression if it was believed that the patient was still benefitting from the treatment, typically in the context of oligometastatic progression with availability of suitable alternative treatments for the progressing sites. Patients with symptomatic cerebral metastases generally underwent surgery and/or radiotherapy before commencement of dabrafenib therapy.
All patients were commenced on a dabrafenib dose of 150 mg twice daily orally, except in two instances: one in which a patient had previously experienced hepatic toxicity on vemurafenib and another in which a patient experienced pyrexia on dabrafenib, as observed from clinical trials. These two patients were commenced on 75 mg dabrafenib twice daily. The median time from diagnosis of stage IV disease to commencement of dabrafenib treatment was 2.5 months (range 1–46).
Grade 2 or worse adverse events believed to be related to dabrafenib were generally managed by withholding dabrafenib and administering best supportive care. If the adverse event improved to grade 1 or lower, dabrafenib could be resumed at a lower dose. In the case of dermatological toxicity, such as development of possible squamous cell carcinomas, patients were referred to a dermatologist for review. Reporting and assessments
Patients underwent baseline tumour assessments by computed tomography or MRI and were restaged at the discretion of the treating physician, typically every 8–12 weeks. Responses were defined by RECIST 1.1 criteria. Frequently, 18F-fluorodeoxyglucose PET assessments were also made in cases in which there was uncertainty and the treating clinicians felt that this would provide additional clinically-relevant information. Reporting of non-serious and serious adverse events was mandated by GSK. Physician assessments were carried out and progress updates were delivered monthly for at least the first 6 months of treatment. Patient updates were subsequently required to be submitted every second month.
Results Between July 2011 and May 2013, 36 applications were submitted for consideration for inclusion in the dabrafenib NPP. Out of the four patients who did not receive dabrafenib, three patients had poor performance status
Efficacy
At the time of analysis (14 May 2013), nine patients were continuing on dabrafenib through the NPP. The median Table 1 Baseline characteristics of patients treated with dabrafenib in the named patient programme Characteristics Sex Male Female Total Age (years) Median (range) < 65 Prior systemic therapies BRAF inhibitor Chemotherapy Immunotherapy ECOG performance status 0 1 2 3 Metastatic stage at diagnosis Stage IVa Stage IVb Stage IVc LDH Elevated BRAF mutation V600E V600K V600R Brain metastases
Number (%) 19 (61) 12 (39) 31 55.3 (26.4–78.3) 23 (74) 6 (19)a,b 3 (10) 5 (16) 8 12 7 4
(26) (39) (23) (13)
4 (13) 4 (13) 23 (74) 22 (71) 22 7 2 17
(71) (23) (6) (55)
ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase. One patient had also received prior chemotherapy and BRAF-inhibitor therapy. Three patients also received trametinib in a clinical trial.
a
b
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duration of treatment was 5.1 months (range 0.1–21.7). Median survival after 19 deaths was 5.6 months (range 0.1–22). Twenty-seven patients met the criteria for PFS, defined as time to progression or death from commencement of dabrafenib. The median PFS was 3.3 months
Table 2
Baseline characteristics of patients with brain metastases
(n = 17) Age [median (range)] (years) Male [N (%)] Female [N (%)] BRAF mutation [N (%)] V600E V600K Brain therapies before dabrafenib [N (%)]a Radiotherapy Surgery After commencement of dabrafenib [N (%)] Radiotherapy Surgery
54.5 (26–78) 10 (59) 7 (41) 13 (76) 4 (24) 8 (41) 3 (18) 4 (24) 0 (0)
a
One patient underwent both surgery and radiotherapy before dabrafenib therapy.
(range 0.1–21). One patient ceased treatment after 10 months because of progression of dementia, which was considered to be due to whole-brain radiotherapy rather than disease progression or dabrafenib. Patients with ECOG status of 0 or 1 receiving dabrafenib as first-line therapy had a median overall survival of 9.3 months (range 1.9–22). For patients with ECOG status of 2 or 3, the median overall survival was 5.2 months (range 1.4–12). Best response was not evaluable in seven patients either because of death before imaging or lack of measureable disease. Stable disease and partial responses were observed in 26 and 19% of patients, respectively. One complete response was observed in a patient with skeletal muscle, subcutaneous and lung metastases with resected solitary brain and small bowel disease before commencing treatment. Figure 1 details the best response in relation to the duration of treatment.
Fig. 1
Complete response Partial response Stable disease Individual patients
Progressive disease Non-evaluable Ongoing therapy Disease progressed
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Duration of treatment (months)
Duration of treatment for metastatic melanoma treated with dabrafenib. A total of 31 patients were treated. Colours of each bar represent the best response achieved by each individual. Crosses denote the time of disease progression. Arrows indicate that treatment is ongoing as of 14 May 2013.
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Dabrafenib named patient program Lau et al. 147
alternative modality locoregional therapy to a site of oligometastatic progression (Table 4).
Of the 17 patients with brain metastases, seven patients (41%) had a partial response and five patients (30%) had stable disease. The median PFS and overall survival in the subgroup of patients with cerebral metastases were 4.6 and 5.6 months, respectively.
Despite the poor performance status, five individuals achieved an overall survival of more than 5 months. This is an important subset of patients with widespread disease, including cerebral metastases, who nevertheless stand to benefit from BRAF-inhibitor therapy despite poor baseline clinical characteristics. Table 5 shows the characteristics of these patients in greater detail.
Six patients in this series were permitted to commence dabrafenib therapy after previous treatment with a BRAF inhibitor (Table 3). Three of these patients had previously received dabrafenib and trametinib (a MEK1/2inhibitor) in a clinical trial (BRF113220, clinicaltrials.gov number, NCT01072175) but had ceased therapy because of progressive disease. Although the median PFS for firstline BRAF-inhibitor therapy was 6.1 months (range 1.2–11 months), the median PFS with dabrafenib as second-line therapy in the NPP was 1.4 months. The median interval between previous BRAF-inhibitor therapy and commencement of dabrafenib was 3 months (range 2.4–12 months). The overall survival from the time of first exposure to a BRAF inhibitor was 11 months (range 5.8–25).
Toxicity
Overall, dabrafenib at a dose of 150 mg twice daily was well tolerated. Patients commonly experienced grade 1–2 toxicities such as arthralgia, fatigue and pyrexia as reported previously. Five patients required dose reductions because of plantopalmar erythema, neutropenia, fatigue and fever (n = 2). Three patients developed significant hyperkeratotic lesions such as keratoacanthoma; however, no new primary melanomas or squamous cell carcinomas were detected.
Discussion
In our cohort, 12 patients underwent therapy for more than 2 weeks after progression. The median duration of dabrafenib therapy for these patients was 2 months longer than the median PFS of the entire group. Three patients achieved significant prolongation of their dabrafenib therapy, and thus overall disease control, by undergoing Table 3
This study on a cohort of patients with metastatic melanoma treated with dabrafenib in an NPP demonstrates clinical utility in a ‘real-world’ setting. Toxicity was comparable, and PFS in this cohort was consistent with the 5.1-month PFS reported recently in the
Overall and subgroup outcomes Best response Median PFS (months)
Median OS (months)
Overall (n = 31) 3.3 (0.1–21.2) 5.6 According to prior BRAF inhibitor exposure BRAF inhibitor as first line (n = 25) 3.5 (0.1–21.20) 5.4 Prior BRAF inhibitor (n = 6) 1.18 (0.1–3.50) 1.61 According to performance status (patients receiving dabrafenib as first-line therapy) ECOG 0/1 (n = 15) 3.5 (0.8–21.2) 9.3 ECOG 2/3 (n = 10) 3.5 (0.1–10.6) 5.2 According to presence of brain metastases Brain metastases (n = 17) 4.6 (0.8–13.0) 5.6
CR
PR
SD
PD
NE
(0.1–22.0)
1
8
9
6
7
(0.1–22.0) (0.1–6.1)
1
8
8 1
4 2
4 3
(1.9–22.0) (1.38–12.4)
0 1
7 1
4 4
2 2
2 2
(1.9–12.4)
1
7
7
2
CR, complete response; ECOG, Eastern Cooperative Oncology Group; NE, not evaluable; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.
Table 4
Characteristics of poor performance status patients with better-than-median progression-free survival
Age/ sex
Performance status (ECOG)
Sites of disease
BRAF Stage mutation
57F 66F
3 2
Brain, mediastinum Brain, lung, liver, small bowel
IVc IVc
V600E V600E
Raised Raised
SD SD
6.2 4.6
68M
2
Brain, spleen, mesentery
IVc
V600E
Normal
SD
9.7
45M
2
IVc
V600E
–
CR
10.0a
53M
2
Brain, lung, subcutaneous tissue, small bowel Brain, lung, mediastinum, adrenal gland, bone
IVc
V600E
Raised
PR
3.4
LDH
Best response PFS
OS
Prior treatment
7.0 WBRT 12.3 Excision of cerebral metastasis, stereotactic brain radiotherapy, multiple liver/lung resections Splenectomy/mesenteric excision, excision of solitary brain metastasis, WBRT Excision of solitary brain metastasis, WBRT 5.3 Nil
CR, complete response; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease; WBRT, whole-brain radiotherapy. a Ongoing therapy as of 14 May 2013.
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Table 5
Characteristics of patients who reachieved disease control while continuing dabrafenib therapy beyond radiological progression
Age/ sex
Performance status (ECOG)
54M
0
Brain, lung, myocardium, liver, subcutaneous tissue
IVc
43M
0
26M
0
Lung/pleura, epi/pericardium, lymph nodes Brain, lymph nodes, bone, skeletal muscle, stomach, subcutaneous tissue
Sites of disease
BRAF Stage mutation
Time on Progression-free survival dabrafenib (months) therapy (months)
LDH
Best response
V600K
Raised
PR
7.9
17.6
IVb
V600E
Raised
SD
1.8
5.7
IVc
V600E
Normal
PR
1.4
7.4
Treatment received while on dabrafenib WBRT, excision of solitary recurrent subcutaneous metastasis Excision of right lung metastases Stereotactic radiotherapy to cerebral metastases
All patients were still receiving therapy as of 14 May 2013. ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; PR, partial response; SD, stable disease; WBRT, whole-brain radiotherapy.
randomized phase III clinical trial that compared dabrafenib with dacarbazine [3]. Nevertheless, lower response rates were noted, with much of this variability being explained by the inclusion of patients with poor prognostic factors such as poor performance status, cerebral metastases and prior treatment with a BRAF inhibitor. In this series, 55% of patients had cerebral metastases at commencement of BRAF-inhibitor therapy, and evaluation of progression was compromised because follow-up imaging did not follow a rigid protocol. Nonetheless, our objective response rate (complete response + partial response) of 47% compares favourably with previously published data reporting rates of 31–38% for V600E [7]. Despite reports to the contrary [8], our own experience with rechallenging patients with BRAF inhibitors after failure of prior therapy was dismal, with median PFS and overall survival of only 1.2 and 1.6 months, respectively, in the six patients treated. As the numbers are small, identifying a subgroup that may have benefited was not possible. As far as we could tell, there was no advantage for patients with a greater interval between BRAFinhibitor exposures, prior exposure to a different BRAF inhibitor or prior exposure to an MEK inhibitor. It has been proposed that intermittent dosing may improve durability of response; however, this was not addressed here [9]. We have observed that some patients with a good performance status benefit by using locoregional therapies upon progression while continuing with BRAF-inhibitor therapy, with three patients being able to continue therapy for at least 4 months after deemed progression. In light of this, it is clear that further studies are required to define the role of this strategy in optimizing disease control. Despite concern that concurrent dabrafenib administration and radiotherapy cause serious skin toxicity [10], this was not observed in the four patients we treated using this strategy. The median time from diagnosis to treatment was 2.5 months. Several factors contribute to this such as referral to a tertiary care centre, molecular testing, delay in
approval of applications and receipt of drugs in the pharmacy. Although it would be ideal to have earlier commencement of therapy if possible, the effect on responses and outcomes is not known. Time to initiation of therapy will improve as access to this molecular testing protocol and medication becomes widespread. Overall, the observations from this access programme are that dabrafenib is a feasible treatment in daily clinical practice. Dabrafenib is safe and effective in a non-trial setting. Further, the judicious use of BRAF inhibitors beyond progression may offer some patients enhanced periods of disease control, particularly once more data exist to guide the rational combination of systemic and locoregional therapies. The duration of clinical efficacy still remains short, and a better understanding of how to prevent treatment resistance is required. MEK inhibitors have been shown to have clinical activity in BRAF mutant melanoma, and the median PFS has been prolonged with a combination of dabrafenib and trametinib (MEK inhibitor) [11–13]. Phase III studies of this combination are underway (clinicaltrials.gov NCT01689519, NCT 01584648). The combination of molecular therapies with immunotherapies is also an area of current research interest [14]. For patients to whom the clinical trials may not directly apply, we also anticipate that, in time, larger datasets will enable better identification of those patients who stand to gain the most from BRAF-inhibitor therapy, thus optimizing clinical decision making in the first-line and subsequent-line settings.
Acknowledgements The authors thank participating patients and families; Anna Lucas and Jim Siderov for their expert assistance in managing and dispensing patient supplies of dabrafenib; Joanne Hawking for her expertise in the melanoma clinic; Dr Katrina Vanin and the staff at GSK Australia. JC is supported in part by grants from the Melanoma Research Agency (MRA), the Australian National Health and Medical Research Council (NHMRC, Project #1007381) and Victorian State Government Operational Infrastructure Support Program. MA is supported by an NHMRC Medical Postgraduate Research Scholarship (NHMRC #1055456).
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Dabrafenib named patient program Lau et al.
Conflicts of interest
Professor Cebon reports receiving consulting fees, lecture fees and research grants from GSK. GSK provided dabrafenib at no expense to the patient nor Austin Hospital. Further, GSK did not contribute to the authorship of this manuscript.
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