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

540s Melanoma/Skin Cancers
LBA8500^ Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing
the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine
(DTIC) in patients with BRAFV600E-mutated melanoma. Presenting Author:
Axel Hauschild, Universitaetsklinikum Schleswig-Holstein, Kiel Schleswig-
Holstein, Germany
The full, final text of this abstract will be available at
abstract.asco.org at 12:01 AM (EDT) on Monday, June 4,
2012, and in the Annual Meeting Proceedings online
supplement to the June 20, 2012, issue of Journal of
Clinical Oncology. Onsite at the Meeting, this abstract will
be printed in the Monday edition of ASCO Daily News.
8502^ Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Updated overall survival (OS) results for BRIM-3, a phase III randomized,
open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem)
with dacarbazine (DTIC) in previously untreated patients with BRAFV600E -
mutated melanoma. Presenting Author: Paul B. Chapman, Memorial
Sloan-Kettering Cancer Center, New York, NY
Background: We previously reported results of the planned OS interim
analysis for BRIM-3 (50% of the planned 196 deaths required for final
analysis) at which time the independent Data Safety Monitoring Board
recommended release of results due to compelling efficacy (hazard ratio
[HR] for death, 0.37 [95% CI 0.26–0.55]); p�0.0001 and PFS HR 0.26
[95% CI 0.20–0.33]; p�0.0001) and that DTIC-treated patients be
permitted to cross over to receive vem. Median follow-up for vem patients
was 3.75 months, and longer follow-up would estimate median OS more
reliably. Updated OS with median 6.2 months follow-up and 199 total
deaths showed HR for death 0.44 (95% CI 0.33–0.59) favoring vem and
median OS for vem not reached. We report here the results of an updated
OS analysis performed in Nov 2011 with ~10 months median follow-up on
vem. Methods: 675 patients with previously untreated, unresectable Stage
IIIC or IV melanoma that tested positive for BRAFV600E mutation by the
cobas 4800 BRAF V600 Mutation Test were randomized (1:1) from Jan to
Dec 2010 to vem (960 mg po bid) or DTIC (1000 mg/m2 IV q3w).
Co-primary endpoints were OS and PFS. OS data for DTIC patients who
crossed over to vem were censored at the time of crossover. Results: Median
lengths of follow-up on vem and DTIC were 10.5 months (range 0.4–18.1)
and 8.4 months (range �0.1–18.3), respectively. There were 334 deaths.
Median OS rates with vem and DTIC were 13.2 months (95% CI
12.0–15.0) and 9.6 months (95% CI 7.9–11.8), respectively. 12-month
OS rates were 55% for vem and 43% for DTIC. HR for death was 0.62 (95%
CI 0.49–0.77) in favor of vem. 81 DTIC patients crossed over to vem. 44
(13%) vem and 65 (19%) DTIC patients received ipilimumab postprogression.
Conclusions: With longer follow-up, vem treatment continues
to be associated with improved OS in the BRIM-3 study. An updated
analysis, with estimated median follow-up of ~13 months and including
response data, will be conducted in Apr 2012 and presented at the
meeting.
8501 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
BREAK-MB: A phase II study assessing overall intracranial response rate
(OIRR) to dabrafenib (GSK2118436) in patients (pts) with BRAF V600E/k
mutation-positive melanoma with brain metastases (mets). Presenting
Author: John M. Kirkwood, University of Pittsburgh Cancer Institute,
Pittsburgh, PA
Background: Melanoma brain mets carry a poor prognosis (median survival
�4 months), for which more effective therapies are needed. Dabrafenib is a
potent, selective oral inhibitor of mutated BRAF that has demonstrated
clinical efficacy in pts with BRAF V600E/K mutant melanoma and
previously untreated brain mets in a phase I study. Therefore, a phase II
study (BREAK-MB) was initiated. Methods: Stage IV pts with � 1 intracranial
met (0.5 cm–4 cm assessed by MRI) without prior brain therapy
(Cohort A) or with progression following prior brain therapy (Cohort B) were
eligible with V600E/K mutation. Pts received dabrafenib 150 mg BID. The
primary endpoint was investigator-assessed OIRR among V600E mutationpositive
pts. Results: Overall, 172 pts were recruited. At interim analysis, of
127 pts enrolled (safety population), 41 (Cohort A n�24; Cohort B n�17)
had reached 8-week disease assessment. Unconfirmed OIRR in Cohort A
was 10/19, (53%; 95% CI: 28.9–75.6%) for V600E and 1/5 (20%; 95%
CI: 0.5–71.6%) for V600K pts. In Cohort B unconfirmed OIRR was 8/15
(53%; 95% CI: 26.6%–78.7%) for V600E and 1/2 (50%; 95% CI:
1.3–98.7%) for V600K pts. Unconfirmed overall response rate (ORR) in
Cohort A was 10/19 (53%; 95% CI: 28.9–75.6%) for V600E and 1/5
(20%; 95% CI: 0.5–71.6%) for V600K pts. In Cohort B unconfirmed ORR
was 6/15 (40%; 95% CI: 16.3–67.7%) for V600E and 1/2 (50%; 95% CI:
1.3–98.7%) for V600K pts. In the safety population, 12/63 pts (19%) in
Cohort A reported an SAE; 1 (2%) was fatal (cerebral hemorrhage). In
Cohort B 15/64 pts (25%) reported an SAE; 1 (2%) was fatal (seizure). In
Cohort A, 47 pts (75%) experienced AEs: 9 grade 3 (14%) and 3 grade 4
(5%). The most common AEs were headache (21%), hyperkeratosis and
rash (17% each). In Cohort B, 47 pts (73%) experienced AEs: 12 grade 3
(19%) and 3 grade 4 (5%). The most common AEs were fatigue or nausea
(22% each) and pyrexia (17%). Conclusions: Dabrafenib shows high
clinical activity both in pts with intra- and extracranial mets with acceptable
toxicity. Final data will be presented.
8503^ Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Analysis of molecular mechanisms of response and resistance to vemurafenib
(vem) in BRAFV600E melanoma. Presenting Author: Jeffrey Alan
Sosman, Vanderbilt-Ingram Cancer Center, Nashville, TN
Background: Vem induces frequent clinical responses (RR �50%) and
improved survival in patients (pts) with BRAF-mutated metastatic melanoma.
Multiple mechanisms of escape from vem have been proposed. We
performed a centralized analysis of pretreatment, cycle 1, day 15 (D15),
and progression (DP) tumor samples collected during the phase II BRIM-2
trial (Sosman et al, NEJM 2012). Methods: Of 132 pts enrolled, archival
tumor samples, biopsies taken at baseline (BL), D15, and DP were
obtained from 84, 38, 26, and 22 pts, respectively, and analyzed by
immunohistochemistry (IHC) for signaling molecules in the MAPK, PI3K/
AKT, and cell cycle pathways. Genetic analyses of signaling genes were
performed using Sequenom MASSarray and direct DNA sequencing.
Results: High levels of ERK phosphorylation were seen at BL indicating
constitutive MAPK signaling due to the BRAF mutation. In 19/22 paired
samples, pERK levels were reduced following vem (BL vs D15). Mean
absolute pERK reduction in pts with clinical response (RECIST criteria) to
vem (n�14) was significantly greater than in non-responders (n�8;
p�0.013). Baseline cytoplasmic PTEN H-score was higher in responders
vs non-responders (H-score�88 vs 68; p�0.042). At progression, upregulation
of pERK (H-score�181) was frequently, but not uniformly found vs
D15 tumors (H-score�48.5). At progression, increases in Cyclin D1 and
Ki67 were seen, without obvious changes in PTEN or pAKT. NRAS
mutations occurred in 3/13 DP; 2 had paired BL samples without NRAS
mutations. Only 1/82 pts had a concomitant NRAS and BRAF mutation at
BL, and did not respond to vem. MAP2K1 (MEK1) codon 124 mutations
occurred in 7/92 BL and 1/20 DP samples. 2 pts with BL MEK1 mutations
had partial responses. Conclusions: MAPK signaling was effectively inhibited
by vem early in treatment, and in the subset of patients with matched
tumor samples the degree of pathway inhibition correlated with clinical
response. MAPK signaling is upregulated in many lesions at progression.
NRAS mutations appear to be a mechanism of acquired resistance in a few
tumors (3/13), while the role of MEK1 mutations in resistance is less clear.
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