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

542s Melanoma/Skin Cancers
8508 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Ipilimumab (Ipi) expanded access program (EAP) for patients (pts) with
stage III/IV melanoma: 10 mg/kg cohort interim results. Presenting Author:
Omid Hamid, The Angeles Clinic and Research Institute, Santa Monica, CA
Background: The EAP (CA184-045), begun in 8/07, currently provides the
largest safety database for Ipi outside of controlled clinical trials (CCTs)
and included pts with brain metastases (BM) and primary ocular (OM) and
mucosal (MM) melanoma. The EAP was amended in 10/08 to administer a
3 mg/kg dose based on the current label (Hodi et al. NEJM 2010). We now
report interim data from pts treated in the US at 10 mg/kg from
8/07-10/08. Methods: Pts with unresectable Stage III or IV melanoma who
progressed on at least 1 systemic therapy or had no alternate treatment
options were eligible. Pts received 10 mg/kg Ipi i.v. q 3 wks up to 4 doses
(induction) followed by 10 mg/kg q 12 wks (maintenance) until no longer
clinically benefiting or unacceptable/unmanageable toxicity occurred. All
serious adverse events (SAEs) and on-study deaths were collected; overall
survival (OS) was assessed retrospectively. Results: Of 906 treated pts, 830
were included in the analysis; 39 from prior Ipi trials � 37 from sites whose
IRB did not agree to collect OS were excluded. Pts got a median of 4 doses;
31% got �5 doses. ECOG 0/1/2 was 53%/39%/8% (1 pt was ECOG 3);
27% had BM, 5% had OM, and 4% MM. Primary reasons for discontinuation
were disease progression (67%) and drug toxicity (11%). Incidence of
drug-related SAEs was 27% with diarrhea 10%, colitis 8%, endocrinopathies
4%, and dermatitis 0.8%. 2 pts (0.24%) had on-study hepatitis
SAEs, both considered drug-related and resulted in discontinuation. There
were 3 (0.36%) drug-related intestinal perforations. 2 deaths (0.24%)
were the outcome of drug-related SAEs; 1 multi-organ failure and 1 acute
respiratory distress syndrome (both �70 days from last induction dose). 72
(9%) pts currently remain on treatment (i.e. �3 years). Available OS data
showed that 138 pts (17%) were still at risk after 3 years. For 27% of pts
the last known alive date was �30 days before data cutoff (with most �2
yrs). Conclusions: Data from the US EAP must be interpreted with caution
compared to CCTs. To date, incidence of SAEs for hepatitis and intestinal
perforation, and drug-related death at 10 mg/kg Ipi monotherapy is
consistent with that seen in BMS clinical trials. Durable OS (�3 yrs) was
observed in at least 17% of pts.
8510 Clinical Science Symposium, Mon, 3:00 PM-4:30 PM
Updated safety and efficacy results from a phase I/II study of the oral BRAF
inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2
inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic
melanoma. Presenting Author: Jeffrey S. Weber, Comprehensive
Melanoma Research Center, H. Lee Moffitt Cancer Center, Tampa, FL
Background: In preclinical models, the BRAFi/MEKi combination has
demonstrated enhanced activity against BRAF-mutant cancer cells compared
with either drug alone, delayed emergence of BRAFi resistance, and
prevented BRAFi-related proliferative skin lesions. A 3-part study investigating
the dabrafenib/trametinib combination was conducted in patients (pts)
with V600 BRAF mutant solid tumors. Interim data from the study were
previously reported (Infante, ASCO 2011); updated safety and efficacy
data are presented. Methods: In Part 2, 125 pts with V600 BRAF mutant
solid tumors enrolled, including 77 melanoma pts with no prior BRAFi, and
measurable disease according to RECIST 1.1. Pts were treated on 4
escalating dose levels of dabrafenib/trametinib (mg BID/mg QD): 75/1,
150/1, 150/1.5, 150/2. Demographic and efficacy data for the 77
melanoma pts with no prior BRAFi and safety data for all 125 Part 2 pts are
reported. Results: Among 77 melanoma pts, median age was 52 years, 61%
male, 57% ECOG PS of 0, 91% V600E, 65% M1c stage, 26% prior brain
metastases, and 52% LDH � ULN. Confirmed ORR was 56% (95% CI:
44.1%-67.2%) with 4 CR, 39 PR, 29 SD and, 3 PD. Confirmed response
rate for each dose level, respectively, was 67% (n�6), 64% (n�22), 48%
(n�25), and 54% (n�24). Median PFS (months) for each dose level,
respectively, was: 8.7, 8.3, 5.5; PFS is not mature for 150/2. Overall PFS
was 7.4 (95% CI: 5.5-9.2). Among the 125 pts, there were 2 grade (G) 5
adverse events (AEs), pneumonia and hyponatraemia. The most common
G3/4 AEs were pyrexia (n�6, 5%), fatigue (n�6, 5%) and dehydration
(n�6, 5%). Skin toxicity � G2 occurred in 17 (14%) pts. Cutaneous
squamous cell carcinoma occurred in 3 (2%) pts and actinic keratoses in 2
(2%). Conclusions: The combination of dabrafenib/trametinib has an
acceptable safety profile, with a lower incidence of MEKi-related rash and
BRAFi-induced hyperproliferative skin lesions compared with the single
agents. The clinical activity of dabrafenib/trametinib observed in pts with
V600 BRAF mutant metastatic melanoma is encouraging and will be
investigated further in a phase III trial.
LBA8509 Clinical Science Symposium, Mon, 3:00 PM-4:30 PM
METRIC phase III study: Efficacy of trametinib (T), a potent and selective
MEK inhibitor (MEKi), in progression-free survival (PFS) and overall
survival (OS) compared with chemotherapy (C) in patients (pts) with
BRAF mutant advanced or metastatic melanoma (MM). Presenting
V600/k
Author: Caroline Robert, Institut Gustave Roussy, Villejuif, France
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.
8511 Clinical Science Symposium, Mon, 3:00 PM-4:30 PM
Efficacy and safety of oral MEK162 in patients with locally advanced and
unresectable or metastatic cutaneous melanoma harboring BRAFV600 or
NRAS mutations. Presenting Author: Paolo Antonio Ascierto, Unit of
Medical Oncology and Innovative Therapy, Istituto Nazionale Tumori
Fondazione Pascale, Napoli, Italy
Background: BRAF and NRAS mutations occur in 50-60% and 15-20% of
cutaneous melanomas, respectively. MEK162, a selective inhibitor of the
kinases MEK1 and MEK2, has shown pre-clinical activity in BRAF and
NRAS mutant (mt) melanoma models. This open label, phase II study
assessed the antitumor activity of MEK162 in patients (pts) with BRAFV600
and NRAS mt advanced cutaneous melanoma. Methods: MEK162 was
administered orally at a starting dose of 45 mg twice daily. Treatment was
until unacceptable toxicity, disease progression (PD) or investigator or
patient refusal. Tumor response was assessed by CT imaging every 8 weeks
(RECIST 1.0) until PD. Results: As of 16 Sept 2011, the full analysis and
safety populations comprised 66 pts: 42 BRAF mt and 24 NRAS mt.
Median age 58.0 years; 57.6% male; 72.7% WHO performance status 0.
All NRAS pts and all but 2 BRAF (1 each stage IIIB and IIIC) pts had stage
IV disease, and 87.5% of NRAS pts and 66.7% of BRAF pts had received
prior therapy at study entry. Median time from 1st diagnosis to 1st dose of
drug was 40.4 months. Median time on study was 10.4 and 8.5 weeks for
the BRAF and NRAS arms. Relative dose intensities of 80–�100% were
received by 71.4% and 70.8% of pts, respectively. Among 29 BRAF mt
and 13 NRAS mt pts evaluable for efficacy, 1 confirmed and 6 unconfirmed
partial responses (PRs) and 9 pts with stable disease (SD) were recorded in
the BRAF arm and 2 confirmed PRs, 1 unconfirmed PR and 4 pts with SD
recorded in the NRAS arm. Common treatment–related adverse events
(AEs), all grades (Gs) and all pts, were rash (40.9%), diarrhea (33.3%),
acneiform dermatitis (27.3%), creatine phosphokinase (CK) elevation
(25.8%), fatigue (18.2%) and peripheral edema (21.2%). Central serous
retinopathy-like retinal events (G 1/2 only) were reported in 8 (12.1%) pts
(6 G1, 2 G2). All retinal events were reversible. G3/4 AEs in �1pt were
diarrhea (4.5%) and CK elevation (15.2%). 5 pts discontinued due to
toxicity. 34 pts are ongoing with more responses under current review.
Conclusions: MEK162 showed clinical activity and good tolerability in pts
with BRAF and NRAS mt advanced melanoma. This is the 1st targeted
therapy to show activity in pts with NRAS mt melanoma.
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