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

8512 Poster Discussion Session (Board #1), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Safety of ipilimumab in patients (pts) with untreated, advanced melanoma
alive beyond 2 years: Results from a phase III study. Presenting Author: Luc
Thomas, Lyon 1 University Centre Hospitalier Lyon Sud, Pierre Benite,
France
Background: Ipilimumab (IPI), a fully human monoclonal antibody, blocks
cytotoxic T-lymphocyte antigen-4 to potentiate an antitumor T-cell response.
In a phase 3 study (CA184-024) of previously untreated pts with
stage III or IV melanoma, IPI � dacarbazine (DTIC) significantly improved
overall survival (OS) vs. DTIC alone (Robert et al. NEJM 2011). We now
report safety data of IPI in pts from this study alive � 2 yrs from study
initiation. Methods: Pts with untreated advanced melanoma, were randomized
to IPI (10 mg/kg) � DTIC (850 mg/m2 ) or placebo � DTIC (850
mg/m2 ) given at Wks 1, 4, 7, 10 followed by DTIC q 3 wks through Wk 22.
Eligible pts (stable disease or better) received IPI or placebo q 12 wks as
maintenance. In the population of subjects alive �2 yrs, the appearance of
immune-related adverse events (irAEs) occurring after 2 yrs was evaluated.
Within this group was a subset of subjects still receiving IPI dosing after 2
yrs; safety for these pts was evaluated to assess the impact of prolonged IPI
exposure. Results: In the IPI � DTIC group 68 (28%) pts survived � 2 yrs
compared to 44 (18%) in the DTIC alone group; 11 of the 68 continued IPI
dosing for � 2 yrs. Safety assessment beyond 2 yrs showed 3 of the 11 pts
had any grade irAEs; 1 pt had grade 3/4 rash, pruritus while low grade
events included rash, pruritus (n�2) and elevated ALT / AST (n�1). Overall
among all 68 pts in the Ipi � DTIC group, there were 5 pts (7.4%) with any
grade irAEs including grade 3/4 rash, pruritus (n�1) and low grade rash
(n�3), pruritus (n�2), skin hypopigmentation, and elevated ALT / AST
(n�1). No gastrointestinal or endocrine events (any grade) were observed.
Conclusions: In Study 024, IPI � DTIC treatment improved OS pts with
untreated, advanced melanoma with higher survival rates in the IPI � DTIC
group at 1 yr (47.3% vs. 36.3%), 2 yrs (28.5% vs. 17.9%), and 3 yrs
(20.8% vs. 12.2%) (HR 0.72, p�0.001). The safety profile of pts alive
after 2 yrs suggests that treatment with IPI � DTIC is associated with low
rates of irAEs in these pts. Furthermore, in pts still receiving active IPI
treatment beyond � 2 yrs, the safety profile appears to be consistent and
medically manageable using established safety guidelines (Weber, Oncologist
2007).
8514 Poster Discussion Session (Board #3), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Phase II study of the frontline combination of ipilimumab and temozolomide
in patients with metastatic melanoma. Presenting Author: Sapna
Pradyuman Patel, University of Texas M. D. Anderson Cancer Center,
Houston, TX
Background: Ipilimumab (Ipi) alters the immune system balance by
inhibiting the suppression of T-cell function. In two phase III trials, Ipi has
shown an overall survival benefit alone and in combination with dacarbazine
in previously treated and treatment-naïve patients (pts) with metastatic
melanoma (MM), respectively. We performed a single-institution,
phase II clinical trial of Ipi plus temozolomide (Tem) in pts with MM.
Methods: Pts between the ages of 18 and 75 with previously untreated
unresectable stage III or stage IV MM and an ECOG Performance Status of
0 to 1 were enrolled in a phase II trial of Ipi plus Tem. Induction phase
consisted of Ipi 10mg/kg intravenous on Day 1 and oral Tem 200 mg/m2 on
Days1–4every 3 weeks for 4 doses. Maintenance consisted of Ipi 10
mg/kg intravenous on Day 1 starting week 12 and repeated every 12 weeks
and oral Tem 200 mg/m2 onDays1–5starting week 12 and repeated every
4 weeks until disease progression or unacceptable toxicity occurred. The
primary endpoint was progression-free survival (PFS) rate at 6 months.
Responses were evaluated using immune-related response criteria. Results:
Sixty-four pts were enrolled and received at least one dose of study drug. All
pts were included in the analysis. With a median follow-up of 8.5 months,
the PFS rate at 6 months was 43%, exceeding the proposed rate of 30%,
and the median PFS was 5.1 months. There were 10 (15.6%) confirmed
complete responses and 8 (12.5%) confirmed partial responses. At the
time of this analysis, median overall survival has not been reached.
Immune-related adverse events (irAEs) were experienced by 88% of pts,
most commonly pruritus (88%), rash (83%), diarrhea (56%), transaminitis
(45%), and colitis (11%). Grade 3/4 irAEs seen in more than one patient
were skin rash (11%), diarrhea (9%), pruritus (6%), and transaminitis
(5%). Constipation occurred in 70% of pts and was the most common
gastrointestinal (GI) toxicity. There were no GI perforations or deaths on
study due to treatment. Conclusions: At a median follow-up of 8.5 months,
the best overall response rate in this study is 28%. Ipi at 10 mg/kg in
combination with Tem given in an induction followed by maintenance
fashion is safe, well-tolerated, and efficacious in MM.
Melanoma/Skin Cancers
543s
8513 Poster Discussion Session (Board #2), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Phase II multicenter trial of ipilimumab combined with fotemustine in
patients with metastatic melanoma: The Italian Network for Tumor Biotherapy
(NIBIT)-M1 trial. Presenting Author: Anna Maria Di Giacomo,
Medical Oncology and Immunotherapy, University Hospital of Siena,
Siena, Italy
Background: Ipilimumab (ipi), an antibody against cytotoxic T-lymphocyteassociated
antigen-4, improves survival in patients (pts) with metastatic
melanoma (MM); however, objective tumor responses are limited. NIBIT-M1
aims to investigate the efficacy and safety of ipi plus fotemustine (FTM), a
cytotoxic alkylating drug, in pts with MM. Methods: Eligible pts, with or
without brain metastases, received induction therapy with ipi 10 mg/kg
every 3 weeks (Q3W) for four doses and FTM 100 mg/m2 weekly for 3
weeks. Ipi and FTM maintenance therapy was provided Q12W from Week
24 and Q3W from Week 9, respectively. The primary objective was the
immune-related (ir) disease control rate (irDCR: pts with complete response
[CR], partial response [PR] or stable disease [SD] as determined
using the ir response criteria). Secondary objectives included ir objective
response rate (ORR), duration of response (DOR) and progression-free
survival (PFS); overall survival (OS), and safety. Tumor assessments were
performed Q8W from Week 12 to Week 36 and Q12W thereafter. Results:
Among 86 pts with unresectable stage III (n�3) or stage IV (n�83) MM
treated at 7 NIBIT centers, 42 were previously untreated, 44 had
progressed following first-line treatment and 20 had asymptomatic brain
metastases. As of December 2011, the irDCR was 46.5% (40/86; 95% CI,
35.7–57.6%); the irORR was 29.1% (95% CI, 19.8–39.8%; 5 CRs and
20 PRs) and with a median 8.3 months follow-up, median irPFS was 5.3
months (95% CI, 3.5–7.1). The 1-year OS rate was 51.8% (95% CI,
37.5–66.1%); median OS was not yet reached. Among all pts, 58.1% and
87% completed ipi or FTM induction, respectively. The most common
grade 3/4 drug-related adverse events (AEs) (reported in 54.6% pts overall)
were myelotoxicity (43.5%), increased ALT/AST (14.1/10.6%), gastrointestinal
(4.7%) and skin-related (2.3%). AEs were generally manageable and
reversible per protocol guidance. Conclusions: The study reached its
primary objective with 46.5% of pts achieving disease control. The
combination of ipi plus FTM is safe; the irDCR, 1-year OS rate and median
irPFS warrant its further investigation in MM pts.
8515 Poster Discussion Session (Board #4), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Hypersensitivity skin reactions in melanoma patients treated with vemurafenib
after ipilimumab therapy. Presenting Author: James J. Harding,
Memorial Sloan-Kettering Cancer Center, New York, NY
Background: Ipilimumab (IPI) and vemurafenib (VEM) each improve overall
survival for patients (pts) with metastatic melanoma. Both are FDAapproved
and are being used in pts with BRAFV600E-mutated metastatic
melanoma. We previously described cases of prominent skin eruptions
associated with VEM in pts who had previously received IPI. Methods: We
have updated our experience of BRAFV600E-mutated melanoma pts treated
with VEM who had previously received IPI. Pts were treated at our center
from January 2007 to January 2012. Data were collected under an
approved IRB waiver. Results: Sixteen melanoma pts were treated with VEM
after having received IPI. The most common drug-related adverse event
(AE) associated with VEM was rash, occurring in 13/16 patients (81.3%,
95% CI 56.5-93.2). Four pts developed a severe, Grade 3, maculopapular
rash within 8 days of starting VEM. Biopsies in 2 pts revealed spongiotic
and perivascular dermatitis with eosinophils consistent with a drug hypersensitivity
reaction. Hypersensitivity reactions did not progress to lifethreatening
reactions such as anaphylaxis or Stevens-Johnson syndrome,
nor did they result in VEM dose discontinuation. Reactions were managed
with corticosteroids and dose modifications. Grade 3 rash strongly correlated
with initiating VEM within one month of IPI (Fisher’s exact test, p �
0.007) and was not associated with the dose of prior IPI, the number of
prior doses, or immune-related AEs. The incidence of Grade 3 rash in this
pt cohort was significantly higher than in pts treated on the phase III trial of
VEM (4/16, 25% versus 28/336, 8%; �2 � 5.13, Df � 1, p � 0.02). The
objective overall response for VEM was 50% (95% CI 26.5-73.4), which is
similar to response rates seen on the phase II and III trials. Conclusions: In
pts receiving VEM who have previously received IPI, dermatologic AEs
appear to be more common. This effect seemed most pronounced if VEM
was given within one month of completing IPI. Although more data are
necessary to confirm this apparent association, we speculate that the
release of immune checkpoint inhibition by IPI may predispose pts to
hypersensitivity skin reactions to VEM.
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