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

8568 General Poster Session (Board #35B), Sun, 8:00 AM-12:00 PM
Ipilimumab-induced hypophysitis in melanoma patients. Presenting Author:
Typhanie Carré, Dermatology Department, Timone Hospital, Aix
Marseille University, Marseille, France
Background: Ipilimumab (Ipi) is a human monoclonal antibody directed
against cytotoxic T-lymphocyte antigene-4 (CTLA-4) recently approved for
the treatment of metastatic melanoma (MM) and currently under investigation
in the adjuvant setting. Methods: Retrospective analysis of patients
treated with ipi between June 2006 and September 2011 in our department
in Marseille. As some patients are still blinded in trials, the exact
number of patient under ipi is unknown. We present a minimal percentage
(�%) assuming that the 120 patients received ipi. Results: A total of 120
patients were treated: 76 stages IV MM, from which 16 in the BMS clinical
trials (CA184-022, -024, and-025 and MDX 010-20) and 44 stages III
MM (in the BMS CA184-029 trial). Stage IV MM were administered 0.3, 3
or 10mg/kg IV dosage, while stages III MM were randomly assigned to
receive 10 mg/ kg or placebo (1:1 ratio). Hypophysitis was diagnosed in 12
patients (�10%): 2/76 patients with stage IV MM (�2. 6 %) and 10/44
patients with stage III MM (�22.7). Diagnosis was performed at the 1st ,3rd and 4th administration in respectively 2 (1.6%), 6 (50%) and 4 patients
(33.3%). Clinical symptoms included headaches (n�11; 91.6%), asthenia
(n�7; 58.3%) and decreased libido (n�2; 1.6%). Adrenal, thyroidal
and gonadal axis were affected in respectively 6 (50%), 9 (75%) and 7
patients (58.3%). MRI changes were observed in 7 patients (58.3%):
pituitary swelling in 5 patients (41.6%) and heterogeneous enhancement
in 4 patients (33.3%) including 2 patients with normal biology. Corticosteroids
supplementation was required in 11 patients and thyroidian supplementation
in 4 patients. Clinical symptoms regressed within one week in 8
patients (66.6%). Conclusions: Ipi-induced hypophysitis is detectable only
if clinicians are aware of these unspecific signs. Only MRI can make
diagnosis in some patients without clinical and/or biological signs. Our data
suggest that it develops especially for 10mg/kg dosage, after the third
administration, and that the rate could be higher in patients with a normal
immune system (adjuvant treatment), than in metastatic ones. Hormonal
supplementation usually controls the disease.
8570 General Poster Session (Board #35D), Sun, 8:00 AM-12:00 PM
Percutaneous hepatic perfusion (PHP or ChemoSat) with melphalan versus
best alternative care (BAC) in patients (pts) with hepatic metastases from
melanoma: A post hoc analysis of PHP-randomized versus BAC-to-PHP
crossover versus BAC-only pts. Presenting Author: H. Richard Alexander,
University of Maryland School of Medicine, Baltimore, MD
Background: PHP (Chemosat, Delcath Systems Inc, New York, NY) allows
repeated delivery of high dose chemotherapy to the liver while limiting
unwanted systemic exposure by extracorporeal filtration of hepatic venous
blood. A prospective randomized multicenter study compared melphalan
PHP versus BAC in pts with unresectable hepatic metastases from ocular or
cutaneous melanoma and showed a highly significant advantage for PHP in
terms of the primary endpoint, hepatic PFS, and multiple secondary
endpoints. We present an exploratory post-hoc analysis of pts assigned to
BAC who crossed over to PHP after disease progression (BAC-to-PHP
crossover) versus those who did not (BAC-only) versus PHP-randomized
pts. Methods: 93 pts were randomized to PHP (n�44) or BAC (n�49). In
the BAC group, crossover to PHP with melphalan was permitted after
hepatic disease progression. Up to 6 PHP treatments with melphalan 3.0
mg/kg ideal body weight were given every 4–8 weeks. Results: In the BAC
group, 28 of 49 pts crossed over to PHP. Updated efficacy findings
(investigator) as of 31 March 2011 are shown in the table. Independent
Review Committee results were similar to investigator-assessed efficacy.
Safety in BAC-to-PHP crossover pts was similar to that seen in PHPrandomized
pts. The most common toxicities in BAC-to-PHP crossover pts
were hematological: peri-procedural thrombocytopenia (71%) and anemia
(57%), and melphalan-related neutropenia (82%) and thrombocytopenia
(79%). Conclusions: Efficacy of melphalan PHP in BAC-to-PHP crossover
pts was consistent with that seen in PHP-randomized pts with hepatic
metastases from melanoma. Crossover from BAC to PHP after hepatic
disease progression led to a median 11-month survival advantage vs BAC
alone.
Endpoint
PHP-randomized
(n�44)
BAC-only
(n�21)
BAC-to-PHP crossover
(n�28)
Median hPFS, months 8.0 1.6 8.8
HR (crossover vs BAC-only) 0.32
Median overall survival, months 9.8 4.1 15.3
HR (crossover vs BAC-only) 0.33
No. alive (f/u 9.7–53.5 mos) 4 3* 7
*One patient crossed over but never received PHP. BAC-only pts: chemoembolization, HAI
nab-paclitaxel, temozolomide.
Melanoma/Skin Cancers
557s
8569 General Poster Session (Board #35C), Sun, 8:00 AM-12:00 PM
Outcomes of patients with malignant melanoma treated with immunotherapy
prior to or after vemurafenib. Presenting Author: Allison Ackerman,
Beth Israel Deaconess Medical Center, Boston, MA
Background: Treatment of patients (pts) with BRAF mutant malignant
melanoma (MM) with vemurafenib (vem), a BRAF inhibitor (BRAFi), is
associated with a high response rate (RR) and improvement in progression
free survival (PFS) and overall survival (OS) compared to standard chemotherapy.
Responses to vem are typically not durable and most pts require
additional therapy. However, there is little data to guide sequencing of vem
with other standard therapies such as ipilimumab (ipi) or interleukin 2
(IL-2). Methods: 43 pts treated with vem as part of clinical trials from
2009-2012 were retrospectively identified. RR of vem was calculated for
all pts as well as for pts treated with immunotherapy (IT) prior to vem. The
OS from first systemic and vem treatment, duration of vem therapy, OS
from when pts came off vem, and PFS and OS for post-vem ipi was
determined using Kaplan-Meier estimates. Results: Of the 43 pts, 11
remain on vem and 32 are off vem (19 deceased) with a median follow up of
19 mo. Pre-vem LDH was elevated in 46% (17/37 evaluable pts). The RR
to vem was 52% (22/42 evaluable pts), the median duration of therapy 5.6
months (mo), and the median OS 19.3 mo, similar to results in trials. The
median OS from initiation of any treatment was 27 mo. 16 pts received IT
(11 IL-2, 4 ipi, 1 IL-2 then ipi) prior to vem with a median OS of 31.2 mo;
the RR of vem following IT was 75% (12/16). At time of vem discontinuation
50% of pts (12/24 evaluable) had an elevated LDH, and the median
OS of the 32 pts who stopped vem was 4 mo from last vem dose. 10 of these
pts then received single-agent ipi; six of whom had an elevated LDH. Five
pts died within 3 mo of last vem dose, and all 10 pts had disease
progression (PD) at 6 months with a median PFS of 0.7 mo and OS of 2.2
mo. The 3 pts who lived beyond 1 year following vem and then ipi were
subsequently treated with a BRAFi following PD on ipi. Conclusions:
Response to vem following IT appears similar to that seen in previously
untreated pts. Median PFS and OS for pts receiving ipi after discontinuation
of vem are poor, possibly due to rapid PD at the time of vem
discontinuation. Prolonged OS is primarily seen with resumption of BRAF
inhibition. Our data suggests that in appropriately selected pts, IT should
be considered prior to BRAFi.
8571 General Poster Session (Board #35E), Sun, 8:00 AM-12:00 PM
Tim-3 expression and function in natural killer cells from advanced
melanoma patients. Presenting Author: Ines Esteves Domingues Pires Da
Silva, New York University Langone Medical Center, New York, NY
Background: The concept of CD8 � T cell exhaustion in the context of
metastatic cancer has been reinforced by the recent success of immunotherapies
targeting the exhaustion markers CTLA-4 and PD-1 in advanced
melanoma. T-cell immunoglobulin 3 (Tim-3), another exhaustion marker,
is also expressed in natural killer (NK) cells, however its role is still
unknown. Recent reports have shown that NK cells, innate immune cells
that eliminate tumors through cytotoxicity and IFN-g production, are
functionally impaired in advanced melanoma patients, although no receptor
has been linked with that phenotype so far. In this study, we
characterize the role of Tim-3 in NK cells, particularly in the presence of its
natural ligand, Galectin-9 (Gal-9), that is known to be expressed/secreted
by some tumor cells including melanoma. Methods: We compared 20
advanced melanoma donors NK cells with 40 healthy donors NK cells as it
relates to Tim-3 expression (by flow cytometry) and function (cytotoxicity,
IFN-� production and proliferation). NK cells cytotoxicity was measured by
lamp-1 expression, and two different target cells were used: i) K562 cells
(Gal-9 - ) and ii) Gmel Gal-9 � and Gmel Gal-9 - sorted melanoma cells.
Proliferation was quantified by CFSE after 6 days in the presence of rhIL-2.
Recombinant rhGal9 effect was tested in cytotoxicity and IFN-� production.
Results: Melanoma patients NK cells express higher levels of Tim-3
compared to healthy donors NK cells (p�0.05). Melanoma patients NK
cells have a defect in cytotoxicity, proliferation and IFN-� production.
Tim-3 expression by itself (without engagement of specific ligands) does
not negatively affect NK cell functions (p�0.05). However, when rhGal9 is
added to the system, a decrease in NK cell cytotoxicity and IFN-�
production (p�0.05) was observed. Finally, the expression of Gal-9 by the
target cells induces a defect in NK cell cytotoxicity (Gmel Gal-9 � vs Gmel
Gal-9 - ). Conclusions: These data suggest that advanced melanoma patients
NK cells are exhausted, although it still remains unclear if Tim-3 is involved
in this phenotype. In addition,the expression/secretion of Galectin-9,
immunosuppressive for NK cells, may be a possible mechanism for tumors
to evade immune surveillance.
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