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Discontinuation trial of the MET/VEGF
receptor inhibitor cabozantinib in
metastatic melanoma
British Journal of Cancer
Take-home message
•
This was a phase II discontinuation
trial conducted to assess the effect
of cabozantinib, a TKI inhibitor, in
a cohort of patients with metastatic
melanoma. Cabozantinib 100 mg daily
was given to the 77 participants during a
12-week lead-in, after which those with
stable disease (39%) were randomised
to either cabozantinib or placebo. The
objective response rate at week 12
was 5%. Progression-free survival did
not differ significantly between groups
post randomization (4.1 months with
cabozantinib and 2.8 months with
placebo; HR, 0.59; P = 0.284).
•
Cabozantinib has clinical activity in
patients with metastatic melanoma,
meriting further clinical investigation.
Abstract
BACKGROUND
A phase II randomised discontin-
uation trial assessed cabozantinib (XL184), an
orally bioavailable inhibitor of tyrosine kinases
including VEGF receptors, MET, and AXL, in a
cohort of patients with metastatic melanoma.
METHODS
Patients received cabozantinib 100mg
daily during a 12-week lead-in. Patients with
stable disease (SD) per Response Evaluation
Criteria in Solid Tumours (RECIST) at week 12
were randomised to cabozantinib or placebo.
Primary endpoints were objective response rate
(ORR) at week 12 and postrandomisation pro-
gression-free survival (PFS).
RESULTS
Seventy-seven patients were enrolled
(62% cutaneous, 30% uveal, and 8%mucosal). At
week 12, the ORR was 5%; 39% of patients had
SD. During the lead-in phase, reduction in target
lesions from baseline was seen in 55% of eval-
uable patients overall and in 59% of evaluable
patients with uveal melanoma. Median PFS after
randomisation was 4.1 months with cabozantinib
and 2.8 months with placebo (hazard ratio of
0.59; P=0.284). Median PFS from study day 1 was
3.8 months, 6-month PFS was 33%, and median
overall survival was 9.4 months. The most com-
mon grade 3/4 adverse events were fatigue
(14%), hypertension (10%), and abdominal pain
(8%). One treatment-related death was reported
from peritonitis due to diverticular perforation.
CONCLUSIONS
Cabozantinib has clinical activity
in patients with metastatic melanoma, including
uveal melanoma. Further clinical investigation
is warranted.
Phase II randomised discontinuation trial of
the MET/VEGF receptor inhibitor cabozantinib
in metastatic melanoma.
Br J Cancer
2017 Jan
19;[EPub Ahead of Print], A Daud, HM Kluger, R
Kurzrock, et al.
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10–11
Vemurafenib inmetastatic melanoma patients
with brainmetastases
Annals of Oncology
Take-home message
•
This phase II study assessed the performance of vemurafenib in patients with and without
prior treatment for BRAF(V600)-mutated melanoma brain metastases (BM). The best
intracranial overall response rate in patients with previously untreated BM was 18%.
Extracranial best overall response rate was 33% among those with previously untreated
BM and 23% among those with previously treated BM.
•
The results showed that melanoma BM responded in a clinically meaningful way to
vemurafenib. This agent can be administered without causing significant CNS toxicity.
Abstract
BACKGROUND
Vemurafenib has shown activity in
patients with BRAF(V600) mutated melanoma
with brain metastases (BM). This phase 2 study
evaluated vemurafenib in patients with/without
prior treatment for BM.
METHODS
Patients with BRAF(V600) mutated
melanoma with BM were enrolled into cohort
1 (previously untreated BM) and cohort
2 (previously treated BM) and received
vemurafenib (960 mg BID) until disease
progression (PD) or intolerance. Primary
endpoint was best overall response rate (BORR)
in the brain in cohort 1 that was evaluated using
modified RECIST 1.1 criteria using lesions ≥0.5cm
to assess response.
RESULTS
146 patients were treated (cohort 1 n=90;
cohort 2 n=56), 62% of whomwere male. Median
(range) time since diagnosis of BM: 1.0 (0-9)
month in cohort 1 and 4.2 (1–68) months in cohort
2. Median duration of treatment was 4.1 months
(range 0.3-34.5) in cohort 1 and 4.1 months (range
0.2-27.6) in cohort 2. Intracranial BORR in cohort
1 by an independent review committee (IRC)
was 18% (2 CRs, 14 PRs). Extracranial BORR by
IRC was 33% in cohort 1 and 23% in cohort 2.
Median PFS (brain only, investigator-assessed)
was 3.7 months (range 0.03–33.4; IQR 1.9–5.6)
in cohort 1 and 4.0 months (range 0.3–27.4; IQR
2.2–7.4) in cohort 2. Median OS was 8.9 months
(range 0.6–34.5; IQR 4.9–17.0) in cohort 1 and 9.6
months (range 0.7–34.3; IQR 4.5–18.4) in cohort
2. Adverse events (AEs) were similar in type,
grade and frequency to other studies of single-
agent vemurafenib. Grade 3/4 AEs occurred in
59 (66%) patients in cohort 1 and 36 (64%) in
cohort 2. Overall, 84% of patients died during
the study (86% in cohort 1 and 80% in cohort 2),
mainly due to disease progression.
CONCLUSIONS
The study demonstrates clinically
meaningful response rates of melanoma BM to
vemurafenib that was well tolerated and without
significant CNS toxicity.
Vemurafenib in metastatic melanoma patients
with brain metastases: an open-label, single-
arm, phase 2, multicentre study.
Ann Oncol
2016 Dec 19;[EPub Ahead of Print], GA McArthur,
M Maio, A Arance, et al.
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