Annual Meeting Proceedings Part 1 - American Society of Clinical ...

544s Melanoma/Skin Cancers
8516 Poster Discussion Session (Board #5), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Predicting early relapse in patients with BRAFV600E melanoma with a highly
sensitive blood BRAF assay. Presenting Author: Ryan J. Sullivan, Massachusetts
General Hospital Cancer Center, Boston, MA
Background: Many patients (pts) with metastatic melanoma (MM) who
progress on BRAF inhibitors (BRAFi) develop rapidly progressive disease
(PD) which is difficult to manage. Identification of an early marker of PD
may allow for therapeutic intervention prior to clinical deterioration. We
have developed a highly sensitive and inexpensive assay in our laboratory
which can detect as little as 1 BRAFV600E mutant melanoma cell in
400,000 peripheral blood lymphocytes (PBL). We aimed to determine the
utility of our assay as a tool to follow pts with BRAF mutant MM who are
being treated with a BRAFi. Methods: Every pt had a BRAFV600E mutation
detected from a tumor sample in a CLIA-approved laboratory prior to
commencing BRAFi therapy. 20 pts with stage IV BRAFV600E MM underwent
serial venopunctures before and every 4 weeks during treatment with
a BRAFi. BRAFV600E level was quantified using our proprietary assay (Panka
et al Melanoma Research 2010). Serial BRAFV600E levels were generated
for every pt and normalized to the pre-treatment value. BRAFV600E level was
then correlated with response to therapy and PD. Results: BRAFV600E was
detected in the PBL of each pt. To date, 10 pts have had BRAFV600E levels
quantified at 3 or more time points (data for all 20 pts will be available at
time of presentation). Relative BRAFV600E levels reduced by half following
the first and second cycles of treatment in 7 pts, which correlated with
disease regression in each pt. Following the third cycle of treatment, the
relative BRAFV600E levels varied greatly with a subset of pts having
continued suppression while others having a rise in their BRAFV600E levels.
In each pt with PD, the BRAF assay showed an increase � 4 wks in advance
of clinically or radiographically defined PD. Conclusions: Our assay is able to
quantify changes in BRAFV600E levels in the blood of pts with BRAF mutant
MM receiving BRAFi therapy. In these pts, the BRAFV600E levels are
reduced in the setting of initial disease regression and increase well in
advance of clinical or radiographic PD. While further development is
necessary, such a test could be used to identify pts who may be selected to
receive alternative therapy prior to clinical or radiographic PD.
8518 Poster Discussion Session (Board #7), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Tumor-specific circulating cell-free DNA (cfDNA) BRAF mutations (muts)
to predict clinical outcome in patients (pts) treated with the BRAF inhibitor
dabrafenib (GSK2118436). Presenting Author: Georgina V. Long, Melanoma
Institute Australia, Westmead Institute for Cancer Research and
Westmead Hospital, The University of Sydney, Sydney, Australia
Background: Tumor specific cfDNA levels in blood increase with tumor
burden and decrease following treatment. cfDNA can harbor muts consistent
with the tumor. Thus cfDNA could be a useful biomarker of therapeutic
response. BREAK-2, an open label, single arm, Phase II study evaluated
efficacy, safety and tolerability of dabrafenib in BRAF V600E/K mut�
metastatic melanoma pts. Exploratory objectives of BREAK-2 were to
evaluate whether (i) tumor and cfDNA BRAF muts are correlated; (ii) cfDNA
levels correlate with baseline tumor burden and (iii) cfDNA muts predict
clinical outcome with dabrafenib. Methods: BRAF mut status was established
for 92pts using an allele-specific PCR assay in tumor samples.
Baseline plasma samples were available for 91/92 pts. cfDNA BRAF mut
status was evaluated by Inostics GmBH using the BEAMing technology.
Spearman correlation coefficients (R) were used to determine the association
between cfDNA fraction (mut DNA molecules � 0.01%) and estimated
baseline tumor burden, calculated by the sum of RECIST measurements of
target lesions. Logistic regression and Cox proportional hazards models
were used to assess the association between cfDNA mut status and
objective response rate (ORR) and progression free survival (PFS), respectively.
Results: The overall agreement between tumor and cfDNA BRAF
V600E and V600K mut status was 83%, and 96% respectively. Higher
cfDNA V600E mut fraction was associated with higher baseline tumor
burden (R�0.73; p-value � 0.0001; n�60); lower ORR (O.R. � 0.83;
95% CI � 0.72, 0.96; p-value�0.0134; n�46) and shorter PFS
(H.R.�1.09; p-value�0.0006; n�46). Median PFS was 27.4 weeks in the
overall V600E pt population (n�76) and 20.0 weeks in the cfDNA V600E
pt population (n�46). Otherwise, the response endpoints were comparable
between the two populations. There was no correlation between V600K mut
fraction (n�14) and any efficacy endpoints. Conclusions: cfDNA was useful
for detecting BRAF muts in pts treated with dabrafenib and increasing
V600E mut fraction was associated with reduced ORR and shorter PFS,
suggesting higher amounts of mut cfDNA in V600E mut� pts predicts
poorer clinical outcome.
8517 Poster Discussion Session (Board #6), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
An open-label, multicenter safety study of vemurafenib (PLX4032,
RO5185426) in patients with metastatic melanoma. Presenting Author:
James M. G. Larkin, Royal Marsden Hospital, London, United Kingdom
Background: Vemurafenib, a BRAF inhibitor, is associated with improved
PFS and OS in patients (pts) with BRAFV600-mutant metastatic melanoma
(mM). We present preliminary safety and efficacy findings from a safety
study of vemurafenib in pts with unresectable stage IIIC/IV mM with
BRAFV600 mutations. Methods: Pts with untreated or previously treated
stage IIIC/IV BRAFV600 mutation-positive (cobas 4800 BRAF V600 Mutation
Test) melanoma were enrolled. Pts received continuous oral vemurafenib
960 mg bid. Primary study endpoint was safety; efficacy (RECIST V
1.1) was a secondary endpoint. Results: Of 1,964 screened pts between
Mar and Sep 2011, 914 (47%) were enrolled and 834 were evaluable for
safety. Median age was 53 (21–88 years), 55% males. Median time since
first mM diagnosis was 7.6 months (0–18 years). At baseline, 80% of pts
had ECOG PS 0–1, 11% ECOG PS 2 (missing 9%); 27% of pts had brain
metastases, and 31% had elevated LDH. Most pts had received prior
systemic therapy (70%) including ipilimumab (14%), MEK and BRAF
inhibitors (2%). At data cut-off (Sep 30, 2011), median treatment duration
was 68 days (1–223 days) with 87% of pts still on treatment. Of 834 pts,
553 (66%) to date have reported AEs. Of 553 pts reporting AEs, 88% were
related to vemurafenib, 33% Grade 3, and 1.9% Grade 4. The most
common (�1%) Grade 3/4 AEs were rash (3.6%), arthralgia (3.1%), and
cutaneous squamous cell carcinoma/keratoacanthoma (4.3%). Most common
AEs (�10%) of any grade were arthralgia (31%), rash (29%), fatigue
(22%), photosensitivity (21%), nausea (15%), and were similar irrespective
of brain metastases and ECOG PS. AEs caused treatment interruption
in 141 (17%) pts. Of 109 pts who discontinued treatment (13%), main
reasons for withdrawal were progressive disease (60%), death (20%), AEs
(6%; most commonly arthritis and abdominal pain). Tumor assessments at
Week 8 of treatment were available for 302/834 (36%) pts, 61% pts
achieved CR or PR, and 29% had SD. Conclusions: In a setting representative
of routine clinical practice, vemurafenib is seen to be well tolerated and
both safety profile and activity resemble the phase I–III data although this
analysis is limited by the study duration.
8519 Poster Discussion Session (Board #8), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Safety and efficacy of MET inhibitor tivantinib (ARQ 197) combined with
sorafenib in patients (pts) with NRAS wild-type or mutant melanoma from a
phase I study. Presenting Author: Julie A. Means, Vanderbilt University
Medical Center, Nashville, TN
Background: The MET receptor tyrosine kinase is implicated in tumor cell
proliferation, invasion, and metastasis, and is activated in NRAS mutant
melanoma. Tivantinib is an oral, selective MET inhibitor currently in phase
II/III clinical trials. Tivantinib plus sorafenib exhibited synergistic antitumor
activity vs single-agent activity in several tumor models. This phase I
dose-escalation study assessed the safety of tivantinib plus sorafenib in pts
with advanced solid tumors. Methods: Endpoints were safety, the recommended
phase II dose (RP2D) of tivantinib plus sorafenib, and antitumor
activity. Dose escalation previously established the RP2D as tivantinib 360
mg twice daily (BID) plus sorafenib 400 mg BID. Extension cohorts
enrolled � 20 pts each with melanoma or other tumors. Pts were treated
until disease progression or unacceptable toxicity. Results: 16 pts with
melanoma (median age, 66 yr) received treatment at the RP2D, and 3 pts
are still on study. 12 pts received � 1 previous systemic anticancer
treatment (median, 1.2; range, 0-5) including ipilimumab (2 pts) or MEK
inhibitor (1 pt). Common adverse events (� 25%) were rash (50%),
diarrhea and fatigue (44% each), anorexia (38%), stomatitis and nausea
(31% each), and anemia, weight decrease, and hypophosphatemia (25%
each). Best responses were complete response (CR) in 1 pt, partial
response (PR) in 3 pts, and stable disease (SD) in 3 pts. 4 pts had
progressive disease and 5 pts were not evaluable (3 pts had not reached
first assessment time, 1 pt withdrew consent, and 1 pt had unacceptable
toxicity). The overall response rate and disease control rate were 25% and
44%, respectively. Median progression-free survival (mPFS) was 5.3 mo
(95% CI, 1.6-12.9 mo). Among 8 pts with NRAS mutations, mPFS was 9.2
mo (95% CI, 5.3-12.9 mo) and responses were 1 CR, 1 PR, and 2 SD.
Conclusions: Tivantinib plus sorafenib combination therapy was well
tolerated and exhibited preliminary anticancer activity in pts with melanoma.
Dual inhibition of MET and angiogenesis may be an effective
treatment strategy in NRAS-mutant melanoma.
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