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

8536 Poster Discussion Session (Board #25), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Impact of comorbidities on overall survival of high-risk and advanced
melanoma. Presenting Author: Prashanth Peddi, University of Texas M. D.
Anderson Cancer Center, Houston, TX
Background: Comorbidities have been shown to adversely affect survival
among patients with cancer. Currently, the most important prognostic
factor in patients with melanoma is AJCC stage. However, little is known
regarding the impact of comorbidities on melanoma prognosis. The aim of
our study was to determine the impact of the severity of concurrent
comorbidities on the overall survival of patients with high-risk and advanced
melanoma (defined as AJCC stages IIc, III and IV). Methods: We
conducted a retrospective cohort study of eligible adult melanoma patients
available in the MelCore prospective database at MD Anderson Cancer
Center (MDACC) from 01-2003 to 12-2006 who were diagnosed and
completed staging within 3 months of presentation to MDACC. Patients
with ocular melanoma were excluded. Demographic, AJCC staging, and
survival data were collected. The Adult Comorbidity Evaluation-27 (ACE-
27) was utilized to collect comorbidity information and grade its severity. A
Cox proportional hazards model was used. Results: Of 444 patients that met
enrollment criteria, 176 (39.6%) had grade 0 (no comorbidities), 222
(50%) had grade 1 or 2 (mild or moderate comorbidities) and 46 (10.4%)
had grade 3 (severe comorbidities). The median age of the entire cohort was
56.4 years (19.7-98.9), 141 (32%) were female, and 406 (91.4%) were
white. The median overall survival after presentation to MDACC was 5.0
years for the entire cohort. Adjusted hazard ratios are shown in the table.
Comorbidity and AJCC Stage were significantly associated with survival.
Age, gender and race did not have a significant impact on overall survival.
Conclusions: In our study, the presence of comorbidities at presentation
were independent predictors of decreased survival, even when adjusted for
AJCC stage. Our findings suggest that comorbidity should be incorporated
into prognostic models and therapeutic decision-making for patients with
high-risk or advanced melanoma.
Multivariate Cox model (adjusted for age, sex, gender and stage).
Grade Hazard ratio 95% CI p value
ACE-27 0
1or2
3
AJCC stage IIC
III
IV
1.0
1.5
1.7
1.0
0.7
3.2
----
1.1-2.0
1.1-2.7
---
0.4-1.2
2.0-5.2
---
0.01
0.02
---
0.27
�0.001
8538 General Poster Session (Board #31D), Sun, 8:00 AM-12:00 PM
A prospective study investigating the impact of definitive chemoradiation in
locoregionally advanced squamous cell carcinoma of the skin. Presenting
Author: Michelle K. Nottage, Royal Brisbane Hospital, Brisbane, Australia
Background: Our state, Queensland, Australia, has the highest rate of
cutaneous squamous cell cancer (SCC) in the world. Spread to regional
lymph nodes or more distant sites occurs in 5-10%. A proportion of
patients can not undergo surgical resection but complete response rates
with radiotherapy alone are low. This led to the hypothesis that combined
chemoradiation (CRT) may be of benefit. We decided to document the
outcomes of concurrent chemoradiation by means of a prospective trial.
Methods: This was a single arm, phase II study with planned sample size 30
patients. The primary endpoint was complete response rate (CRR), estimate
60%. Patients with locally/regionally advanced (non-metastatic)
cutaneous SCC deemed unresectable or unsuitable for surgery by consensus
of the multidisciplinary Head and Neck Cancer Clinic, with measurable
disease, aged over 18, performance status 0-2, received definitive radiotherapy
(XRT) (70Gy in 35#) and concurrent weekly platinum based
chemotherapy (CT) (cisplatin 40mg/m2 or carboplatin AUC 2). Results: 14
patients were enrolled (Feb 2008-June 2011), median age 66 (48-84),
64% ECOG PS 0, 64% stage IV, 57% nodal disease only. Cisplatin/
carboplatin was administered in 64%/36% respectively. 42% received all
planned CT while 58% had 1 or 2 weeks omitted. 2 patients had dose
reductions. XRT was completed as planned in 93%. The CRR was 57%
(8/14) at analysis in December 2011 (median follow-up 13.5m). 2 further
patients with partial response (PR) achieved CR after undergoing salvage
surgery. Six (43%) patients had a PR; 4(29%) did not receive surgery and
later progressed. Median overall survival was not reached, with 3 year
survival 54%. The most frequent toxicities were dermatitis, mucositis,
thrombocytopenia, nausea, anaemia, dysphagia. 28% had grade 3/4
toxicity, mainly cytopenias, infection, dehydration and nausea. Conclusions:
This is the only prospective series of CRT for cutaneous squamous cell
cancer. A high complete response rate was documented in patients with
loco-regionally advanced disease and multiple co-morbidities, with acceptable
toxicity, making this a reasonable alternative for patients unable to
undergo surgery.
Melanoma/Skin Cancers
8537 General Poster Session (Board #31C), Sun, 8:00 AM-12:00 PM
Suppression of apoptosis by BRAF inhibitors through off-target inhibition
of JNK signaling. Presenting Author: Kenneth Yee Tsai, University of Texas
M. D. Anderson Cancer Center, Houston, TX
Background: The advent of targeted therapy has revolutionized the treatment
of cancer. The mutant BRAFV600E protein is found in over 50% of
melanomas and thyroid carcinomas, resulting in elevated kinase activity,
increased mitogen-activated protein kinase (MAPK) pathway signaling, and
cell proliferation. Vemurafenib and PLX4720 were designed to selectively
inhibit the BRAF kinase, and clinical trials of vemurafenib in metastatic
melanoma have demonstrated a response rate of over 50% and an overall
survival advantage over standard dacarbazine therapy. Approximately
20-30% of individuals treated with vemurafenib develop cutaneous squamous
cell carcinoma (cSCC) highlighting the importance of understanding
toxicities associated with this drug. Paradoxical ERK activation in BRAF
wild-type, RAS-mutant cells is thought to be the major mechanism by
which this occurs, as evidenced by the presence of RAS mutations in 60%
of such lesions. Methods: Using a combination of BRAF-wild-type cSCC cell
lines, primary human keratinocytes, as well as a UV mouse model of cSCC
and human cSCC samples, we identified novel effects of BRAFi on
apoptosis. Results: Here we show an unexpected and novel effect of
vemurafenib and PLX4720 in suppressing apoptosis through the inhibition
of multiple off-target kinases. JNK signaling and apoptosis are suppressed
in cSCC lesions arising in vemurafenib-treated patients as well as in
irradiated mouse skin. This occurs independently of paradoxical ERK
signaling and in the presence of MEK inhibitor. Treatment with PLX4720
greatly accelerates the development of UV-induced cSCC in mice without
Ras mutations. Kinome screening identified ZAK and MKK4 (MEK4 /
MAP2K4) kinases as inhibited by vemurafenib, leading to suppression of
MKK4 and MKK7 (MAP2K7) phosphorylation. Knockdown of inhibited
off-target kinases recapitulates these anti-apoptotic effects of vemurafenib.
Conclusions: Our results implicate suppression of JNK signaling,
independent of ERK activation, as an additional, complementary mechanism
of adverse effects of vemurafenib. This has broad implications for
combination therapies with other modalities that induce apoptosis and for
the long-term use of vemurafenib in the adjuvant setting.
8539 General Poster Session (Board #31E), Sun, 8:00 AM-12:00 PM
Outcomes of ipilimumab treatment-related adverse events in patients with
metastatic melanoma (MM) who received systemic corticosteroids in a
phase III trial. Presenting Author: Jean-Francois Baurain, Oncologie
Médicale Cliniques Universitaires Saint-Luc, Brussels, Belgium
Background: Ipilimumab (ipi) is a fully human monoclonal antibody that
blocks cytotoxic T-lymphocyte antigen-4 to augment antitumor immune
responses. In a phase III trial, ipi at 10 mg/kg plus dacarbazine (DTIC)
improved overall survival in previously untreated patients (pts) with MM. In
ipi studies, the most common drug-related adverse events (AEs) were
immune-related, which were generally reversible using treatment guidelines
involving prompt recognition, intervention (corticosteroids, and rarely,
alternative immunosuppressive agents), and possible discontinuation of
therapy. The purpose of this analysis is to evaluate outcomes of ipi
treatment-related AEs with use of systemic corticosteroids. Methods: AEs
were reported from the first ipi dose up to 70 days after the last dose.
Immune-mediated adverse reactions (imARs) were used to characterize
inflammatory AEs in previously untreated pts with MM who received ipi plus
DTIC in a phase III trial. This analysis includes the imAR categories of
hepatitis, dermatitis, enterocolitis, and endocrinopathies. Results: More
than 70% of pts who received corticosteroids had complete resolution of
the imAR, ie, last reported Grade (Gr) of 0 (Table). In pts for whom a
high-grade imAR had not completely resolved at the last report, �50% had
improved to Gr 1. Conclusions: In the majority of pts treated with ipi at 10
mg/kg plus DTIC who received corticosteroids for the management of
imARs, as recommended per treatment guidelines, the most common
imARs had completely resolved or improved to Gr 1.
ImAR
Resolution or
last Gr reported
Outcomes of imARs, N (%)
Ipi � DTIC,
worst Gr�2
549s
Ipi � DTIC,
worst Gr >2
Hepatitis N who received steroids N�10 N�63
Outcomes Gr 0 8 (80.0) 45 (71.4)
Gr 1 2 (20.0) 12 (19.0)
Gr 2 0 (0.0) 2 (3.2)
Gr 3 0 (0.0) 3 (4.8)
Gr 4 0 (0.0) 1 (1.6)
Dermatitis N who received steroids N�29 N�6
Outcomes Gr 0 24 (82.8) 2 (33.3)
Gr 1 2 (6.9) 2 (33.3)
Gr 2 3 (10.3) 1 (16.7)
Gr 3 0 (0.0) 1 (16.7)
Enterocolitis N who received steroids N�5 N�10
Outcomes Gr 0 4 (80.0) 7 (70.0)
Gr 1 0 (0.0) 2 (20.0)
Gr 2 1 (20.0) 0 (0.0)
Gr 3 0 (0.0) 1 (10.0)
Endocrinopathies N who received steroids N�3 N�0
Outcomes Gr 0 0 (0.0) 0 (0.0)
Gr 1 0 (0.0) 0 (0.0)
Gr 2 3 (100.0) 0 (0.0)
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