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

8528 Poster Discussion Session (Board #17), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Association of high T-cell immune infiltrate and low hemorrhage in
melanoma brain metastases (MBMs) with prolonged survival. Presenting
Author: Michal Tadeusz Krauze, University of Pittsburgh Melanoma Program,
UPCI, Pittsburgh, PA
Background: Despite the poor prognosis of patients (pts) with MBM several
pts have prolonged survival. We hypothesized that the heterogeneity of
BrMM is determined by differences in melanoma biology and its brain
microenvironment. Methods: We identified pts who have undergone craniotomy
for MBMs. Evaluation entailed complete clinical information, acquisition
of archived melanoma brain metastases, histopathologic analysis of
hematoxylin and eosin-stained sections (n�101), whole genome expression
profiling (WGEP, Illumina DASL) in 29 archived tissues. Results were
validated by immunohistochemistry (IHC) or in situ hybridization (ISH).
Results: In univariate analysis (log-rank) factors significantly associated
with prolonged survival were high immune infiltrate (HII) plus low hemorrhage
(hazard ratio, HR, 2.71, p�0.001), present melanin (1.67, p�0.03),
and recursive partitioning analysis (RPA) class 1 (0.37, p�0.0001). No
association between HII and use of immunotherapy prior to craniotomy was
noted. Only RPA class 1 (p�0.029) and HII plus low hemorrhage
(p�0.002) remained significant in Cox proportional hazards model analysis.
Gene set analysis of WGEP data confirmed that Encarta pathways
related with T-cell activation and differentiation were significantly associated
with prolonged survival whereas Y branching of actin filaments,
presenilin action in Notch and Wnt signaling, G-protein signaling through
tubby protein, lissencephaly gene in neuronal migration and development
are among the gene categories associated with worse survival. IHC and ISH
analysis of tumor sections for various markers (n�40) showed that high
peritumoral CD3� (3.31, p�0.009), high peritumoral CD4� (4.41,
p�0.014), and high peritumoral CD8� (3.02, p�0.030) are associated
with prolonged survival whereas neither CD14� nor FoxP3� infiltrate, nor
high melanoma expression of antigen presentation molecules are associated
with survival. Conclusions: Our study is the first to document that high
peritumoral T-cell infiltrates are associated with prolonged survival. High
tumor hemorrhage, an adverse prognostic sign, reflects aggressive melanoma
cells that migrate and invade in the brain.
8530 Poster Discussion Session (Board #19), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Clinical activity and safety of combination therapy with temsirolimus and
bevacizumab for advanced melanoma: Phase II trial with correlative
studies. Presenting Author: Craig L. Slingluff, University of Virginia,
Charlottesville, VA
Background: A CTEP-sponsored phase II trial was performed to evaluate
safety and clinical activity of combination therapy with CCI-779 (temsirolimus)
and bevacizumab in patients with advanced melanoma. Correlative
studies assessed mTOR signaling in tumor biopsies and evidence of
induced immunologic dysfunction systemically. Methods: 17 patients with
stage III or IV melanoma were enrolled and treated with temsirolimus (25
mg IV weekly) and bevacizumab (10 mg/kg IV every 14d, starting d.8) for
up to 13 months. Clinical response was determined by RECIST criteria.
Adverse events were assessed (CTCAE v3.0). Blood was collected d.1, 2,
and 23 (to assess immune function), and tumor biopsies were obtained (to
assess protein kinase activity and melanoma cell proliferation). Results:
Treatment-related grade 3 or 4 adverse events occurred in 5 and 1 patients,
respectively; 1 patient developed reversible leukoencephalopathy. In 16
patients evaluable for clinical response, best overall response was a partial
response (PR) in 3 patients (19%), stable disease at 8 weeks (SD) in 9
patients (56%), and progressive disease in 4 patients. Thus, disease
control rate (DCR � PR � SD) was 75%. Ten of the patients had BRAF
wild-type (BRAFwt ) melanomas: these accounted for the 3 PRs (30%), and
a DCR of 100%. Maximal response duration has exceeded 3 years for a
BRAFwt patient. mTOR signaling was inhibited in melanoma metastases,
based on decreased phospho-S6 kinase after 24h temsirolimus. Ki67� melanoma cells in tumor biopsies decreased significantly by day 23 (p �
0.007, F-test), most notably in clinical responders. There was no significant
alteration of T cell and NK function with combination treatment, by
ELIspot and cytotoxicity assays. Conclusions: Combination therapy with
temsirolimus and bevacizumab is well-tolerated in patients with advanced
melanoma and has intriguing clinical activity. The most notable responses
were in patients with BRAFwt tumors, a population with no accepted
effective targeted therapy. Decreases in Ki67� melanoma cells may be
associated with clinical response. The lack of immunologic dysfunction
supports future combination with immune therapies.
Melanoma/Skin Cancers
547s
8529 Poster Discussion Session (Board #18), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
The NIBIT-M1 trial: Activity of ipilimumab plus fotemustine in patients
with melanoma and brain metastases. Presenting Author: Michele Maio,
Medical Oncology and Immunotherapy, University Hospital of Siena,
Siena, Italy
Background: Patients (pts) with metastatic melanoma (MM) often develop
treatment-resistant brain metastases (mets). Treatment includes fotemustine
(FTM), which crosses the blood-brain barrier. Ipilimumab (ipi) has
shown activity in pts with MM and asymptomatic brain mets (Heller et al.
ASCO 2011; abs 8581). In the phase II NIBIT-M1 trial, MM pts with
asymptomatic brain mets were eligible for treatment with ipi plus FTM.
Here, data from this pt subset are reported. Methods: Eligible pts received
induction therapy with ipi 10 mg/kg every 3 wks (Q3W) x4 and FTM 100
mg/m2 weekly for 3 wks, followed by ipi Q12W from Week (W) 24 and FTM
Q3W from W9. The primary objective was the immune-related (ir) disease
control rate (irDCR: complete/partial response [CR/PR] or stable disease
[SD] using the ir response criteria). Secondary objectives included ir
objective response rate (ORR) and progression-free survival (PFS); overall
survival (OS), and safety. Tumor assessments were performed Q8W from
W12 to W36 and Q12W thereafter. Results: Among 86 enrolled pts, 20 had
brain mets. Of these, 7 had prior whole brain radiotherapy (n�4) or
radiosurgery (n�3). As of December 2011, the irDCR was 50% (10/20;
95% CI, 27.2–72.8%) with an irORR of 40% (95% CI, 19.1–63.9%: 2
CRs and 6 PRs). Pts with irDC also had stability/reduction (n�5) or
disappearance (n�5) of brain mets. Among pts with progressive disease, all
but one had progression in the brain. With median follow-up of 8.3 months
(range: 0.4–16.9), median irPFS was 4.6 months (95% CI, 0.7–12.3).
The 1-year OS rate was 52.9% (95% CI, 26.6–79.2); median OS was not
reached. Induction with ipi and FTM was completed by 55% and 85% pts,
respectively. Grade 3/4 drug-related adverse events (AEs) occurred in 60%
pts; most commonly myelotoxicity (50%), increased ALT/AST (5%) and
gastrointestinal (5%). AEs were generally manageable and reversible per
protocol guidance. CNS AEs of any grade (i.e., haemorrhage, headache and
seizure) occurred in 25% pts (grade 3/4 in 2 pts) and were attributed to
disease progression. Conclusions: The combination of ipi plus FTM is active
and safe in pts with MM and brain mets, regardless of prior treatment, and
will be further explored in the phase III NIBIT-M2 trial.
8531 Poster Discussion Session (Board #20), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Activity of cabozantinib (XL184) in metastatic melanoma: Results from a
phase II randomized discontinuation trial (RDT). Presenting Author:
Michael S. Gordon, Pinnacle Oncology Hematology, Scottsdale, AZ
Background: MET and VEGF signaling are implicated in angiogenesis,
invasion, and metastasis. Cabozantinib (cabo) is an oral, potent inhibitor of
MET and VEGFR2. A RDT evaluated activity and safety in 9 tumor types.
Here we report on the metastatic melanoma cohort, including the ocular
subtype. Methods: Eligible patients (pts) were required to have progressive
measurable disease per RECIST. Pts received cabo at 100 mg qd over a 12
wk Lead-in stage. Tumor response (mRECIST) was assessed q6 wks.
Treatment � wk 12 was based on response: pts with PR continued
open-label cabo, pts with SD were randomized to cabo vs placebo, and pts
with PD discontinued. Primary endpoint in the randomized phase was
progression free survival (PFS). Results: Enrollment to this cohort is
complete (n � 77); all pts are unblinded. Baseline characteristics: median
age 66 years; melanoma subtype: cutaneous/mucosal 70% and ocular
30%; known BRAF mutation 32%; LDH � 1.1 x upper limit normal 35%;
bone metastases 19%; median prior lines of therapy 1 (range 0-5). Median
follow-up was 2.8 months (range 0.3 - 25). 35 pts (45%) completed the
open-label Lead-in stage with 25 pts randomized to continue cabo (n�12)
or to placebo (n�13). Median PFS from randomization was 5.7 months for
cabo vs. 3 months for placebo (HR�0.3, p �0.055). Median PFS from
Study Day 1 was 4.4 months. The estimate of PFS at month 6 (PFS6) is
44%. Evidence of objective tumor regression was observed in 39/65 pts
(60%) with � 1 post-baseline tumor assessment including 11/23 pts
(48%) with ocular melanoma. Two bone scan evaluable pts demonstrated
partial resolution of bone lesions at wk 6 accompanied by pain relief. Most
common Grade 3/4 AEs were fatigue (14%), HTN (9%), constipation (4%),
and diarrhea (3%); one related Grade 5 AE of diverticular perforation and
peritonitis reported during Lead-in stage. Conclusions: Cabo demonstrates
activity in metastatic melanoma pts, regardless of subtypes or BRAF
mutation status, with improvement in PFS relative to placebo, and high
rates of PFS6 and objective tumor regression. The safety profile of cabo was
comparable to that of other VEGFR TKIs.
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