Sorafenib and dacarbazine as first-line therapy for advanced melanoma: phase I and open-label phase II studies

Article (PDF Available)inBritish Journal of Cancer 105(3):353-9 · July 2011with20 Reads
DOI: 10.1038/bjc.2011.257 · Source: PubMed
Abstract
The safety of oral sorafenib up to a maximum protocol-specified dose combined with dacarbazine in patients with metastatic, histologically confirmed melanoma was investigated in a phase I dose-escalation study and the activity of the combination was explored in an open-label phase II study. In the phase I study, three patients were treated with sorafenib 200 mg twice daily (b.i.d.) plus 1000 mg m(-2) dacarbazine on day 1 of a 21-day cycle and 15 patients had the sorafenib dose escalated to 400 mg b.i.d. without reaching the maximum tolerated dose of the combination. In the phase II study (n=83), the overall response rate was 12% (95% CI: 6, 21): one complete and nine partial, with median response duration of 46.7 weeks. Stable disease was the best response in 37%; median duration was 13.3 weeks. Median overall survival (OS) was 37.0 weeks (95% CI: 33.9, 46.0). Oral sorafenib combined with dacarbazine had acceptable toxicity and some antineoplastic activity against metastatic melanoma.
Sorafenib and dacarbazine as first-line therapy for advanced
melanoma: phase I and open-label phase II studies
T Eisen
*
,1
, R Marais
2
, A Affolter
2
, P Lorigan
3
, C Robert
4
, P Corrie
1
, C Ottensmeier
5
, C Chevreau
6
, D Chao
7
,
PD Nathan
8
, T Jouary
9
, M Harries
10
, S Negrier
11
, E Montegriffo
12
, T Ahmad
13
, I Gibbens
13
, MG James
13
,
UP Strauss
14
, S Prendergast
12
and ME Gore
13
1
Department of Oncology (R4), Cambridge Biomedical Research Centre, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0QQ, UK;
2
Division of
Cancer Biology, Institute of Cancer Research, London SW3 6JB, UK;
3
Department of Medical Oncology, Christie Hospital, Withington, Manchester
M20 4BX, UK;
4
Department of Medicine, Institut Gustave-Roussy, Villejuif 94805, France;
5
Cancer Sciences Division, Southampton University Hospitals,
Southampton SO16 6YD, UK;
6
Department of Medical Oncology, Institut Claudius Regaud, Toulouse Cedex 31052, France;
7
Cancer Services Division,
The Royal Free Hospital, London NW3 2QG, UK;
8
Cancer Services Division, Mt Vernon Cancer Centre, Northwood, Middlesex HA6 2RN, UK;
9
Department of Dermatology, Hop
ˆ
ital Saint Andre
´
, Bordeaux Cedex 33075, France;
10
Cancer Services Division Guy’s and St Thomas’ Hospital, London
SE1 7EH, UK;
11
Cance
´
rologie Me
´
dicale, Centre Le
´
on Be
´
rard, Lyon Cedex 39373, France;
12
Bayer plc, Strawberry Hill, Newbury, Berkshire RG14 1JA, UK;
13
Department of Medicine, Royal Marsden Hospital, London SW3 6JJ, UK;
14
Bayer Schering Pharma, Leverkusen 51368, Germany
METHOD: The safety of oral sorafenib up to a maximum protocol-specified dose combined with dacarbazine in patients with
metastatic, histologically confirmed melanoma was investigated in a phase I dose-escalation study and the activity of the combination
was explored in an open-label phase II study.
RESULTS: In the phase I study, three patients were treated with sorafenib 200 mg twice daily (b.i.d.) plus 1000 mg m
2
dacarbazine on
day 1 of a 21-day cycle and 15 patients had the sorafenib dose escalated to 400 mg b.i.d. without reaching the maximum tolerated
dose of the combination. In the phase II study (n ¼ 83), the overall response rate was 12% (95% CI: 6, 21): one complete and nine
partial, with median response duration of 46.7 weeks. Stable disease was the best response in 37%; median duration was 13.3 weeks.
Median overall survival (OS) was 37.0 weeks (95% CI: 33.9, 46.0).
CONCLUSION: Oral sorafenib combined with dacarbazine had acceptable toxicity and some antineoplastic activity against metastatic
melanoma.
British Journal of Cancer (2011) 105, 353 359. doi:10.1038/bjc.2011.257 www.bjcancer.com
Published online 12 July 2011
& 2011 Cancer Research UK
Keywords: melanoma; sorafenib; dacarbazine; combination therapy; biomarker
The incidence of melanoma worldwide has been on the rise for at
least 30 years, with rates as high as 35% per year in high-risk
populations (Danson and Lorigan, 2005; MacKie et al, 2009;
American Cancer Society, 2010). Mortality rates associated with
melanoma have been decreasing in the younger patient population
by 2% to 3% per year since 1990, but increasing in the older
population by o1% per year (American Cancer Society, 2010). The
prognosis for patients with metastatic disease is poor; the highest
quoted 5-year survival rate for patients with stage IV melanoma is
18% with a median survival of 8 months (Balch et al, 2001; Gimotty
et al, 2005; Thompson et al, 2005). Although dacarbazine is the
standard of care for advanced disease and has an acceptable
toxicity profile, it has a low objective response rate of o20% with a
median progression-free survival (PFS) of o 2 months and no
proven survival benefit (Middleton et al, 2000; Eggermont and
Kirkwood, 2004; Bedikian et al, 2006; Flaherty, 2006). In recent
clinical studies, more promising outcomes have been observed
with new systemic therapies that target immunoregulatory
molecules or have highly selective inhibition of mutant pathway-
signalling molecules (Hodi et al, 2010; Flaherty et al, 2010a).
The Raf/MEK/ERK pathway regulates cell proliferation, differ-
entiation, and survival (Roberts and Der, 2007). Activating
mutations in the components of this pathway are implicated in
60 90% of melanomas. Mutations in NRAS and BRAF are present
in B20% and 450% of melanomas, respectively (Davies et al,
2002; Akslen et al, 2005). In vitro studies have demonstrated that
sorafenib is a selective multikinase inhibitor targeting Raf kinases
and receptor tyrosine kinases, including platelet-derived growth
factor and vascular endothelial growth factor (VEGF) receptors,
and had antitumour activity in preclinical models of melanoma
(Karasarides et al, 2004; Sharma et al, 2005; Wilhelm et al, 2008).
Although sorafenib was not effective as a single agent in advanced
melanoma (Eisen et al, 2006), it was thought worthwhile to explore
the utility of sorafenib in combination with chemotherapeutic
agents in the treatment of patients with advanced disease,
especially given the absence of efficacious treatment options.
The present paper reports the results from two studies
investigating sorafenib dacarbazine combination therapy in
patients with advanced melanoma. The phase I study was designed
to explore the safety of sorafenib up to a maximum protocol-
specified dose in combination with dacarbazine, as well as to
Received 19 January 2011; revised 7 June 2011; accepted 16 June 2011;
published online 12 July 2011
*Correspondence: Dr T Eisen; E-mail: tgqe2@cam.ac.uk
British Journal of Cancer (2011) 105, 353 359
&
2011 Cancer Research UK All rights reserved 0007 0920/11
www.bjcancer.com
Clinical Studies
provide insight into the efficacy of the combination. Promising
results in the phase I study led to the initiation of the open-label
single treatment group phase II study, which was designed to
further explore the efficacy and safety of this regimen.
PATIENTS AND METHODS
Patient selection
In both studies, patients with metastatic, histologically confirmed
melanoma were eligible for inclusion. The main inclusion criteria
were: age X18 years; Eastern Cooperative Oncology Group
(ECOG) performance status p1; life expectancy X12 weeks; and
adequate bone marrow, liver, and renal function. The main
exclusion criteria were: primary ocular or mucosal melanoma;
previous or concurrent cancer distinct from the cancer evaluated
in this trial; clinically evident congestive heart failure; cardiac
arrhythmia; coronary artery disease; ischaemia; active, clinically
serious infections; chronic hepatitis B or C; and active metastatic
brain or leptomeningeal tumours. Previous chemotherapy, radio-
therapy p3 weeks, surgery p4 weeks before the first dose of study
drug (major surgery in phase II study), or treatment with
inhibitors of the RAS pathway (including trastuzumab, EGFR
inhibitors, farnesyl transferase inhibitors, or MEK inhibitors), or
with a VEGF-targeting drug was prohibited. Previous immuno-
therapy or cytokine, biologic, or vaccine therapy was permitted.
Before participation in the phase II study, a 4-week recovery was
required after previous immunotherapy, cytokine, and biologic
administration, and 3 months after previous vaccine therapy.
Study design
The phase I single-centre, open-label study was conducted in the
United Kingdom between April 2004 and May 2005. The study had
two phases: the dose-escalation phase (cohorts 1 and 2) and the
expansion phase (expansion cohort 2). Patients in all cohorts
received a 1-h intravenous (i.v.) infusion of 1000 mg m
2
dacarbazine on day 1 of a 21-day cycle, with this dose maintained
throughout the study. Cohort 1 (three patients) received 200 mg
oral sorafenib twice daily (b.i.d.) from days 1 to 21. If safe and
tolerated, the dosage of sorafenib was to be increased to 400 mg
b.i.d. in cohort 2 (three patients). If safety data warranted, cohort 1
could be expanded to six patients and cohort 2 expanded to nine
patients. When the MTD of sorafenib was established, or the
maximum allowed full dose (400 mg b.i.d.) was reached, a maximum
of up to 18 patients receiving combination therapy at this dose could
be enroled into an expansion cohort (expansion cohort 2).
The phase II two-stage, open-label, uncontrolled study was
conducted at eight sites in the United Kingdom and four sites in
France between April 2005 and June 2008. Based on tumour
activity observed in stage I, patients could enrol in stage II.
During each stage, patients received a 1-h i.v. infusion of
1000 mg m
2
dacarbazine on day 1 of a 21-day cycle and 400 mg
b.i.d. sorafenib continuously.
Sorafenib tablets were supplied by Bayer plc (Newbury,
Berkshire, UK). Dacarbazine was supplied by the study-site
pharmacy. The studies were conducted in accordance with the
Declaration of Helsinki. Local institutional review boards or
independent ethics committees approved the protocols. Written
informed consent was obtained from all patients.
Study outcomes
The MTD of sorafenib in combination with 1000 mg m
2
dacarbazine was investigated in the phase I study. The MTD was
defined as the maximum dose that could be given to six patients,
with not more than two patients experiencing a dose-limiting
toxicity (DLT). The DLT was defined as treatment-related
occurrence of grade 4 neutropenia, decrease in platelet count to
o25 000 ml
1
, or grade 3 or 4 nonhaematological toxicity as
described by the National Cancer Institute Common Terminology
Criteria for Adverse Events, version 3.0 (NCI CTCAE v3). The DLT
assessments were made in the first cycle of chemotherapy.
Safety For both phase I and II studies, patients who received at
least one dose of treatment and who were assessed for safety at
least once after treatment were included in safety analyses. The
safety profile was based on reported adverse events (AEs), physical
examinations, clinical laboratory tests, vital sign measurements,
and electrocardiograms. Safety assessments occurred on days 1, 8,
and 15 (cycles 1 and 2), day 1 (subsequent cycles), at end of
treatment, and at follow-up (28 days post treatment in phase I and
active follow-up visits in phase II). The AEs were classified and
graded using the NCI CTCAE v3.
Efficacy In both studies, efficacy results were calculated for
patients who completed at least one cycle of treatment and had
their disease re-evaluated. Where applicable, patients without a
disease re-evaluation were included in the denominator of the
efficacy analysis. In phase I, evaluation of tumour response was a
secondary objective, with variables including tumour response,
overall response duration, and overall survival (OS). For the phase
II study, the primary end point was overall tumour response rate
(ORR; complete response (CR) plus partial response (PR) rates).
Secondary end points included: response duration (first determi-
nation of CR or PR to progression), disease control rate (DCR; the
sum of CR and PR and stable disease (SD), OS (treatment start to
death), TTP (treatment start to progression), and PFS.
In both studies, tumour measurements were made at baseline
and every two cycles (6 weeks) up to cycle 8 and every four cycles
thereafter (phase II only) using Response Evaluation Criteria in
Solid Tumours (RECIST) (Therasse et al, 2000). Per RECIST
guidelines, CR and PR required confirmation by a scan at X6
weeks; SD required a measurement at X6 weeks.
Biomarkers Tumour and normal (punch) skin biopsy samples
collected at baseline were frozen in liquid nitrogen for genomic
DNA isolation and analysis of genetic mutations BRAF, NRAS,
KRAS, and/or PI3K by DNA polymerase chain reaction (PCR)
techniques performed at the laboratory of Dr Richard Marais at the
Institute of Cancer Research (London, UK). PCR products were
purified by gel electrophoresis and sequenced with primers used in
the amplification step. Automated dideoxy sequencing was
performed using Big-Dye Terminator RR mix (Applied Biosys-
tems, Foster City, CA, USA) and analysed using the Sequencer 4.2.1
program (Gene Codes Corporation, Ann Arbor, MI, USA). DNA
genotype analysis included exons 11 and 15 of BRAF (phase I and
II studies), exons 2 and 3 of NRAS and KRAS (phase I study), and
also exons 9 and 20 of PI3K (phase II study).
Statistical analysis
As the phase I study was primarily a descriptive analysis of safety
and tolerability, no formal sample size estimation was performed,
with a rule-based design being used (Simon, 2008). A maximum of
30 patients could be enroled, with a maximum of 15 in the dose-
escalation cohort, as safety data warranted, and a maximum of 18
patients in the expansion cohort.
Using a Simon two-stage optimal design for the phase II study,
the sample size was estimated to be 82 (30 patients in the first stage
and 52 in the second) (Simon, 1989). If the number of responses
(complete and partial) was less than six (20%) in stage I, it would
be concluded that the treatment had insufficient efficacy and the
trial would be stopped. Although the results at the end of stage 1
showed only five responses in the first 30 treated subjects, the
study was amended to allow enrolment of subjects for stage 2 for
Sorafenib with dacarbazine in advanced melanoma
T Eisen et al
354
British Journal of Cancer (2011) 105(3), 353 359 & 2011 Cancer Researc h UK
Clinical Studies
the following reasons: (1) studies in renal cell carcinoma have
shown sorafenib to be efficacious (PFS) in spite of low response
rates (Ratain et al, 2006; Escudier et al, 2007), and similar results
were reported in hepatocellular carcinoma (Llovet et al, 2008);
(2) the median PFS at the end of stage I of the study was 129 days
(4.3 months) compared with historical data of 1.5 to 1.6 months in
phase III studies with dacarbazine monotherapy (Middleton et al,
2000; Eggermont and Kirkwood, 2004; Bedikian et al, 2006); (3) at
the end of stage I, 15 (50%) patients had a best response of SD with
median duration of 104 days; and (4) the combination treatment
had not resulted in unacceptable toxicity by the end of stage I.
If the total number of responses in stages I and II were o18
(22%), it would be concluded that the combination treatment did
not provide a greater response than dacarbazine alone. If there
were X6 responses (X20%) in stage I and at least 18 responses in
all (22%), the conclusion would be that the treatment had
sufficient efficacy to warrant further evaluation.
RESULTS
In all, 20 patients enroled in the phase I study; 18 patients were
treated; all were eligible for inclusion in safety and efficacy
analyses. Two patients were excluded during the screening period
because of violation of eligibility criteria (presence of brain
metastases and previous chemotherapy). Of the 18 patients who
received treatment, 4 (22%) discontinued treatment because of
AEs and 14 (70%) owing to disease progression. In the phase II
study, 96 patients were enroled; 13 were excluded during screening
because of violation of eligibility criteria (brain metastasis, n ¼ 5;
abnormal lab values, n ¼ 5; no lesion, n ¼ 1; cardiac arrhythmia,
n ¼ 1; AE, n ¼ 1). In all, 32 patients were treated in stage I and 51 in
stage II; all 83 patients were eligible for inclusion in safety and
efficacy analyses. Of these 83 patients, 16 (19%) discontinued
treatment because of AEs, 60 patients (72%) owing to disease
progression, 2 patients (2%) because of death (1 due to treatment-
related haemorrhage and 1 due to thrombosis that was considered to
be disease-related), 2 patients (2%)becauseofwithdrawalofconsent
and 3 patients (4%) because of study termination. The baseline
characteristics of patients in both studies are presented in Table 1.
Maximum tolerated dose of sorafenib
Three patients in cohort 1 received 200 mg sorafenib b.i.d. and did
not experience DLTs. One of three patients in cohort 2 (400 mg
b.i.d.) experienced dose-limiting grade 3 handfoot skin reaction.
Three additional patients were enroled in cohort 2 and did not
experience DLTs. As the maximum allowed dose of sorafenib for
this study was 400 mg b.i.d., no further dose escalation was carried
out. Nine patients were enroled in expansion cohort 2 and treated
with 400 mg b.i.d. sorafenib. No DLTs were experienced by these
patients (Supplementary Figure 1). Thus, the sorafenib dose
selected for use in combination with dacarbazine in the phase II
study was 400 mg b.i.d.
Safety In the phase I study, all patients received X90% of the
planned doses of both sorafenib and dacarbazine. In the phase II
study, 71 patients (86%) received X 90% of the planned dose of
dacarbazine and 12 patients (14%) received 70% to o90%; the
mean dacarbazine dose per cycle was 973 mg m
2
. Nine patients
(11%) received 50% to o70% of the planned dose of sorafenib,
57 patients (69%) received 30% to o50%, and 17 patients (20%)
received 10% to o30%; the mean sorafenib dose per cycle was
623 mg. Sorafenib dose reductions occurred in 25 patients and
interruptions in 61 patients; 495% were because of AEs alone or
in combination with other reasons. Further dosing and drug
exposure data are presented in Supplementary Tables 1A and B.
Common treatment-related AEs in both studies were predomi-
nantly grade 1/2 and included events in blood/bone marrow,
gastrointestinal, dermatology/skin, constitutional symptoms,
neurological symptoms, and pain. The most frequently occurring
treatment-emergent grade 3/4 AEs are listed in Table 2.
In the phase I study, serious treatment-emergent AEs occurred
in 11 (61%) patients; events occurring in 41 patient were
abnormal haemoglobin and lipase levels, seizures, and tumour
pain (2 patients each). Most AEs occurred after the first treatment
cycle, and were not considered DLTs.
In the phase II study, serious treatment-emergent AEs occurred
in 40 patients (48%) and included abnormal haemoglobin and
platelet levels, fatigue, fever, thrombosis/embolism, and abdominal
pain. In both studies, 22% of patients (4 in phase I and 18 in
phase II) reported serious treatment-emergent AEs that were drug
related. One patient in the phase II study experienced a grade 1
radiation recall skin reaction in response to treatment. Thyroid
function tests were not routinely performed in these studies. A
total of 15 deaths were reported in the phase I study; 5 occurred
Table 1 Baseline characteristics of patients
Characteristic
Phase I
(N ¼ 18)
Phase II
(N ¼ 83)
Sex, n (%)
Male 12 (67) 50 (60)
Female 6 (33) 33 (40)
Race, n (%)
White 18 (100) 82 (99)
Asian 0 1 (1)
Age, years, median (range) 55 (36 72) 56 (25 78)
ECOG performance status, n (%)
0 4 (22) 52 (63)
1 14 (78) 28 (34)
Missing 0 3 (4)
Previous therapy, n (%)
Radiotherapy 4 (22) 11 (13)
Anticancer surgery 18 (100) 46 (55)
Adjuvant systemic anticancer treatment 5 (28) 18 (22)
Metastatic sites (X20% of patients), n (%)
Lung 16 (89) 53 (64)
Liver 9 (50) 40 (48)
Abdomen 7 (39) 12 (14)
Pelvis 5 (28) 4 (5)
Lymph node 4 (22) 34 (41)
Spleen 4 (22) 5 (6)
Number of tumour sites, n (%)
a
1 1 (6) 8 (10)
2 3 (17) 20 (24)
3 4 (22) 16 (19)
X4 10 (56) 38 (46)
Missing 0 1 (1)
AJCC stage, n (%)
a,b
IV M1a 0 4 (5)
IV M1b 1 (6) 12 (14)
IV M1c 16 (89) 66 (80)
Missing 1 (6) 1 (1)
Lactate dehydrogenase levels, n (%)
o10% over ULN 4 (22) 54 (65)
X10% over ULN 12 (67) 26 (31)
Missing 2 (11) 3 (4)
Abbreviations: AJCC ¼ American Joint Committee on Cancer; ECOG ¼ Eastern
Cooperative Oncology Group; ULN ¼ upper limit of normal.
a
Percentages do not
add up to 100% due to rounding up of numbers.
b
For the phase II study, AJCC stage
was supplied separately by the medical expert.
Sorafenib with dacarbazine in advanced melanoma
T Eisen et al
355
British Journal of Cancer (2011) 105(3), 353 359& 2011 Cancer Research UK
Clinical Studies
within 30 days after sorafenib treatment ended (progression of
metastatic melanoma, n ¼ 4; renal failure-metastatic melanoma,
n ¼ 1). In the phase II study, 66 deaths were reported; none
occurred during study treatment and 9 occurred within 30 days of
the end of study treatment (disease progression, n ¼ 6; metastatic
melanoma, n ¼ 1; haemorrhage, n ¼ 1; and thrombosis, n ¼ 1). One
of the deaths (cerebrovascular haemorrhage) was considered by
the investigator to be related to study treatment.
Efficacy The efficacy data for both studies are presented in
Table 3. The change in tumour burden over time for all patients in
the phase II study is illustrated in Figure 1 and the largest change
per patient is provided in Supplementary Figure 2; KaplanMeier
plots for OS and TTP are presented in Figures 2A and B,
respectively.
In the phase II study, sorafenib combined with dacarbazine was
associated with a confirmed, independently assessed ORR of 12%
(95% CI: 6, 21), comprising one CR and nine PRs (Table 3). The
median duration of response for the CR and PRs was 46.7 weeks
(30% censorship) and the median time to response was 48 days.
An additional 31 (37%) patients had SD as best response, with a
median duration of 13.3 weeks (7% censorship). The median OS
was 37.0 weeks (95% CI: 33.9, 46.0). Three patients from the study
entered the Sorafenib Long-Term Extension Programme (STEP).
Biomarkers
Mutation status of BRAF, RAS, and PI3K: In the phase I study,
tumour biopsies from nine patients were analysed for mutation
status of BRAF and RAS; normal skin samples were available from
seven of the nine patients. Of the nine tumour samples, 5 had
activating mutations in exon 15 of BRAF; four were V600E BRAF
mutations and one was a V600K BRAF mutation. None of the
tumour samples had mutations in exon 11 of BRAF or in exons 2
and 3 of NRAS and KRAS.NoBRAF or RAS mutations were detected
in control skin biopsies. There was no apparent correlation between
BRAF mutation status and response to treatment.
In phase II, 20 tumour samples were obtained to investigate
mutation status of BRAF and the PI3K subunit, P13KCA. Three of
the samples had V600E mutations in exon 15 of BRAF;no
Table 2 Treatment-emergent grade 3 or 4 adverse events in X10% of
patients
Phase I Phase II
Event
Cohort 1
(n ¼ 3)
n (%)
Cohort 2
a
(n ¼ 15)
n (%)
Total
(N ¼ 18)
n (%)
Total
(N ¼ 83)
n (%)
Blood/bone marrow
Neutrophils 0 2 (13) 2 (11) 30 (36)
Leukocytes 0 2 (13) 2 (11) 6 (7)
Platelets 0 0 0 18 (22)
Cardiac
Hypertension 2 (67) 1 (7) 3 (17) 2 (2)
Fatigue 0 4 (27) 4 (22) 7 (8)
Infection
Febrile neutropenia 0 3 (20) 3 (17) 1 (1)
Metabolic/laboratory any event
Lipase 1 (33) 2 (13) 3 (17) 2 (2)
Neurology
Seizure 1 (33) 0 1 (6) NR
Pain
Tumour pain 0 2 (13) 2 (11) 0
Other 0 2 (13) 2 (11) NR
Renal failure 0 2 (13) 2 (11) NR
Abbreviation: NR ¼ not reported.
a
Includes cohort 2 and expansion cohort 2.
Table 3 Best response, overall survival, and time to progression
Phase I Phase II
Efficacy variables
Cohort 1
(n ¼ 3)
Cohort 2
a
(n ¼ 15)
Total
b
(N ¼ 18)
Total
(N ¼ 83)
Best response
Patients not evaluable, n (%) 0 1 (7) 1 (6) 8 (10)
CR
n (%) 0 0 0 1 (1)
95% CI 0, 7
PR
n (%) 1 (33) 2 (13) 3 (17) 9 (11)
95% CI 1, 91 2, 41 4, 41 5, 20
SD
n (%) 2 (67) 9 (60) 11 (61) 31 (37)
95% CI 9, 99 32, 84 36, 83 27, 49
Progressive disease
n (%) 0 3 (20) 3 (17) 34 (41)
95% CI 4, 48 4, 41 30, 52
Overall best response rate (CR+PR)
n (%) 1 (33) 2 (13) 3 (17) 10 (12)
95% CI 1, 91 2, 41 4, 41 6, 21
Overall survival
Patients not evaluable, n (%) 0 0 0 0
Censorship rate, % 0 20 17 20
Median, weeks 30.1 23.1 26.1 37.0
95% CI 26.1, 35.6 17.0, 32.6 17.3, 31.7 33.9, 46.0
Time to progression
Patients not evaluable, n (%) 0 1 (7) 1 (6) 5 (6)
Censorship rate, % 0 29 24 8
Median, weeks 22.7 13.0 13.0 14.6
95% CI 11.3, 33.6 11.3, 19.6 11.3, 19.6 12.6, 19.9
Abbreviations: CI ¼ confidence interval; CR ¼ complete response; PR ¼ partial
response; SD ¼ stable disease.
a
Includes cohort 2 and expansion cohort 2.
b
Response
rate (%) and 95% CI based on intent-to-treat patients.
100
80
60
40
20
0
Relative change from baseline by RECIST
–20
–40
–60
–80
–100
0 2 4 6 8 101214161820
Cycle
22 24 26 28 30 32 34 36 38 40
Figure 1 Phase II study: percentage change in tumour burden with time.
Sorafenib with dacarbazine in advanced melanoma
T Eisen et al
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British Journal of Cancer (2011) 105(3), 353 359 & 2011 Cancer Researc h UK
Clinical Studies
mutations in exon 11 of BRAF or exons 9 and 20 of PI3K were
found.Thelowincidenceislikelybecauseofthesmallsamplesize.
Given that samples from only a minority of patients had mutational
analysis, we cannot exclude the possibility that we inadvertently
introduced a bias that reduced the chance of sampling patients with a
V600E mutation in their tumour. Two of the three patients with
V600E mutations had progressive disease as best response; the third
was not assessable. All three had shorter OS and two had TTP shorter
than the study median (OS: 95 days, 122 days, 26 days; TTP: 50 days,
71 days, not available for one patient).
DISCUSSION
The current studies were designed to determine the safety and
efficacy of the sorafenib/dacarbazine combination in patients with
advanced melanoma. The dose-escalation period of the phase I
study demonstrated that the regimen was well tolerated. Given our
experience with single-agent sorafenib in melanoma (Eisen et al,
2006), we wanted to obtain preliminary efficacy data; therefore, the
phase I study design included an option for enrolment into the
expansion cohort. Based on the activity noted in the phase I study,
the phase II clinical trial was initiated.
In the phase II study, the ORR was 12%; thus, the study did not
meet its predefined primary end point. However, end points such
as PFS or TTP that measure disease stabilisation are better suited
to measure the activity of sorafenib (Stone et al, 2007). Results
from a randomised double-blind phase II study published
previously also reported the efficacy and safety of the sorafenib/
dacarbazine combination in patients with advanced melanoma
(McDermott et al, 2008). This study did not meet its primary end
point of PFS; however, an improvement in PFS with sorafenib plus
dacarbazine compared with placebo plus dacarbazine was reported
at 6 and 9 months (secondary and tertiary end points in the study).
A significant improvement in TTP was observed. In this context, it
is interesting to note that the median duration of response in this
study was a surprisingly long 46.7 weeks. This might substantiate
the findings of the randomised trial by McDermott et al (2008).
A comparison of results in different phase II studies is fraught
with risk. Nevertheless, some hypotheses can be considered. Given
this proviso, lower efficacy was observed in all end points of the
present study than in the randomised phase II study. The ORR in
the sorafenib plus dacarbazine group of the randomised study was
24% compared with 12% in the current study; median TTP was
21.1 weeks vs 15.0 weeks, and median OS values were 45.6 weeks vs
37.0 weeks, respectively (McDermott et al, 2008). The percentage
of patients with AJCC stage IV M1c disease was greater in the
present study (80%) compared with that in the randomised study
(55%). On the other hand, the percentage of patients with elevated
lactate dehydrogenase was notably low in the study reported here,
which would be expected to select a relatively lower-risk
population. Thus, the differences between the studies cannot be
explained by differences in patient characteristics.
In studies of sorafenib in combination with carboplatin (C)/
paclitaxel (P), the phase I/II data were promising (Flaherty et al,
2008); however, two randomised phase III trials (one of first-line
and one of second-line therapy) demonstrated no improvement in
the primary end point of PFS for sorafenib plus C/P vs C/P alone
(Hauschild et al, 2009; Flaherty et al, 2010b). In the current phase
II study as well as in the randomised phase II study (McDermott
et al, 2008), both conducted in a first-line setting and at similar
mean daily sorafenib doses (623.1 mg and 640.5 mg, respectively),
the sorafenib/dacarbazine combination demonstrated some evi-
dence of activity regardless of failure of both to meet the
predefined objectives. No further studies investigating this
combination are currently planned.
The present phase I and II studies demonstrated a clinically
acceptable toxicity profile for the sorafenib/dacarbazine combina-
tion regimen with dose reductions as per protocol. It should be
noted that all patients who continued on treatment required dose
reductions to below 70% of the dose planned at study entry,
particularly in later cycles. For the most part, the safety profile was
comparable with that observed in the phase II randomised study at
a similar mean daily sorafenib dose, with the exception that
although grade 3/4 CNS haemorrhages were observed in the
randomised study, no CNS haemorrhages were reported in the
current studies (McDermott et al, 2008).
A recent preclinical study demonstrated that, in vitro, low
concentration of sorafenib promoted MAPK signalling through
stabilisation of activating mutant BRAF complexes (Karreth et al,
2009). In contrast to sorafenib, recent studies of vemurafenib
(PLX4032), a kinase inhibitor that specifically targets mutated
BRAF, produced single-agent responses in BRAF-mutant melano-
ma but did not demonstrate antitumour activity in patients
without an activated BRAF mutation (Flaherty et al, 2010a). This is
consistent with the hypotheses that either sorafenib does not
effectively inhibit BRAF in melanoma or that one of the other
effects of sorafenib, such as CRAF inhibition, counters any RAF
inhibitory effect that is achieved (Karreth et al, 2009).
In the current phase II study, mutations in PI3K were also
investigated, as the PTEN/PI3K/Akt pathway exhibits elevated
activity in a large fraction of melanoma tumours. However, no
PI3K mutations were detected in the samples analysed. The loss of
PTEN, which is a more frequent occurrence, was not assessed. No
conclusions can be drawn regarding the utility of BRAF mutations
as biomarkers to predict response because of the small sample size
for biomarker analyses in both studies. However, when viewed
with similar data from other studies, it seems reasonable to
conclude that there is no evidence that BRAF status predicts
response to sorafenib either as a single agent or in combination
with chemotherapy (Eisen et al, 2006; Amaravadi et al, 2007;
Flaherty et al, 2008).
0 20 40 60
Duration (weeks)
* Censored observation
80 100 120 140 160
1.0
0.9
0.8
0.7
0.6
0.5
Survival probability
0.4
0.3
0.2
0.1
0.0
*
*
*
**
*
*
*
*
**
**
**
*
*
0 20 40 60
Duration (weeks)
* Censored observation
80 100
1.0
0.9
0.8
0.7
0.6
0.5
Survival probability
0.4
0.3
0.2
0.1
0.0
*
*
*
*
**
A
B
Figure 2 Phase II study Kaplan Meier plots: (A) overall survival and (B)
time to progression. Data available from 78 subjects for time to
progression.
Sorafenib with dacarbazine in advanced melanoma
T Eisen et al
357
British Journal of Cancer (2011) 105(3), 353 359& 2011 Cancer Research UK
Clinical Studies
Given this lack of correlation, the antitumour activity detected
in this trial may have been because of the antiangiogenic
properties of sorafenib as an inhibitor of VEGF. In recent trials,
other molecules that target angiogenesis receptors have shown
potential benefit in melanoma (Fruehauf et al, 2008; O’Day et al,
2009; Hong et al 2010). Furthermore, in an in vitro study
investigating the potential for continuous low-dose antiangiogenic
chemotherapy, sorafenib inhibited the growth of both normal
endothelial and melanoma cells (Murray et al, 2010).
The results of the two present studies show that the combination
of sorafenib and dacarbazine has a manageable toxicity profile
and exhibits some evidence of activity. Given the substantial
antitumour activity of BRAF inhibitors such as vemurafenib in
BRAF-mutant disease, there seems little rationale for pursuing the
combination of sorafenib and dacarbazine in that setting; the
antitumour activity of sorafenib detected in this study could be
further explored in patients without activating BRAF mutations.
ACKNOWLEDGEMENTS
We acknowledge Sarah Guadagno, Onyx Pharmaceuticals, Inc.,
for editorial review and the medical writing assistance of
Meenakshi Subramanian and Ann Garvey, UBC-Envision Group,
on behalf of Onyx Pharmaceuticals, Inc., in the preparation of this
manuscript.
Conflict of interest
E Montegriffo, UP Strauss, and S Prendergast are employees of
Bayer Pharmaceuticals. T Eisen receives research support from
Bayer and has received honoraria for advisory boards and
speaking engagements. R Marais has received honoraria and
research support from Bayer Healthcare Pharmaceuticals. PD
Nathan has received honoraria for advisory boards and speaking
engagements for Bayer Healthcare. T Jouary has received
honoraria for consulting from Bristol Myer Squibb. I Coombes
received financial support from Bayer Healthcare to attend
meetings (2004). ME Gore is funded by the National Institute
for Health Research, UK. A Affolter, P Lorigan, C Robert, P Corrie,
C Ottensmeier, M Harries, MG James, C Chevreau, D Chao,
S Negrier, and T Ahmad declare no conflict of interest.
Supplementary Information accompanies the paper on British
Journal of Cancer website (http://www.nature.com/bjc)
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    • "The sorafenib dose (400 mg b.i.d) is administered in combination with standard chemotherapy, such as dacarbazine, in patients with advanced melanoma because it has few side effects as a single agent, indeed the response rate was 21% with a median time from treatment initiation of 2.3 months (26). Although this combination does not cause toxic effects and shows antitumor activity, it is not applied in clinical practice because selective inhibitors of B-RAF are more effective in the treatment of malignant melanoma (27). "
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