Transcript Diapositiva 1

2010 ASCO
Annual Meeting
Abstracts
AIOM post ASCO review: updates
and news from the Annual Meeting in
Chicago
Bologna, 19 - 20 giugno 2010
MELANOMA
Ruggero Ridolfi
IRST Meldola, Forlì
AIOM post ASCO review:
updates and news from the Annual
Meeting in Chicago
HIGH LIGHTS:
Improved Survival with
Ipilimumab
in Patients with
Metastatic Melanoma
F. S. Hodi et Al.
AIOM post ASCO review: updates and
news from the Annual Meeting in
Chicago
Chemotherapy
Carbo+Tax + Sorafenib vs Carbo+Tax + Placebo
820 Ptz 18% vs 16 % OR NEGATIVO (K. Flaherty)
Local-regional treatment for melanoma hepatic metastases
Melphalan in meta epatiche da melanoma oculare
29 Ptz ; 62% OR; No >OS (JF. Pingpank)
Immune-Therapy
- adjuvant treatment
- treatment for stage IV
Targeted Therapies
-genomic predictive biomarkers
- combinations
Adjuvant treatments
-Interferon alpha 2b: PEG-IFN-2b 36months
vs IFNalpha2b
18months. “low dose” PEG-IFN did
not show superiority over “low” dose IFNalpha in a
population of stage I to IIIb melanoma. Grade 3-4 SAE more
frequent in PEG-IFN arm. Treatment in the PEG-IFN arm was not of
prolonged duration due to high discontinuation rate. (Grobb JJ et.
Al. EADO trial)
-GM-CSF +/- peptide vaccination in HLAA2+ patients or GM-CSF vs placebo in HLAA2- patients: neither GM-CSF or peptide vaccination
achieved significant improvement in OS and DFS. Suggestion of
favorable effect of GM-CSF on DFS (0.04), largest in stage IV
subjects (subsets analysis). 815 Ptz (Lawson DH.)
Immune-Therapy
TIL + Hd IL-2
Good Results (MD Anderson –Texas )
Cytokines
IL-21): RR 22%, PFS 4.3 months. Inhibits CD8
IND 189 study (
effector differentiation ,
increased secondary expansion (T. Petrella)
-Checkpoint blokade
Re-induction with ipilimumab, gp100 peptide
vaccine after or a combination of both froma a phase III
randomized trial: 40 Ptz (10%) who recieved reinduction: (7/40)
durable objective response/ (15/40) stable disease are achieved in
subjects who recieved re-induction upon PD. (Hodi)
Targeted Therapies
Melanoma Genomics
45% BRAF mutations
25% NRAS mutations
15% PTEN loss
- Clinical responses to AZD6244 based combination therapy stratified by gene mutations
(Phase I, 25 melanoma pts): AZD6244+DTIC or Docetaxel or Erlotinib or temsirolimus. RR plus
chemotherapy 28%.
BRAF mutation: 56% RR (predict clinical benefit?)
NRAS mutation: 0% RR
Wild-type: 0% RR
(Patel Sp. Et al.)
-Randomized Phase II trial of sorafenib with temsirolimus or Tipifarnib (NRAS
farnesyltransferase): only arm A with temsirolimus met the criteria to open second stage
accrual with 2 PR and 11 PFS among first 30 accrued.
(Margolin K. Et al)
-Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant of BRAF Kinase in
patients with metastatic melanoma and other solid tumors: AEs most common pyrexia, SAE most
common pyrexia and skin squamous cell carcinoma. Confirms target in selective BRAF inhibitors,
efficacy in CNS metastases, durability, effecto on survival (?).
(Kefford r. et al)
AIOM post ASCO review: updates and
news from the Annual Meeting in
Chicago
HIGH LIGHTS CONCLUSIONS…..
-Molecular Profiling for ptz selection
- BRAF-
inhibitors selectivity
-Understand Mechanisms of resistance
- Combination therapy:
MAPK pathway: BRAF+MEK inhibitors
MAPK pathway+P13K/AKT pathway inhibitors
-Selectivity and potency of agents
……..BUT………
ASCO
HIGH LIGHTS
STAR
Improved Survival with
Ipilimumab
in Patients with Metastatic
Melanoma
MECCANISMI DI IMMUNOSOPPRESSIONE TUMORALE
FAS
FAS - L
Linfocita T
?
p56lck
TGF-
cat
IL-6
X
cat
X
IL-10
X
TCR
CD28
ANERGIA
X
VEGF
HLA
Cellula tumorale
Antigene
Cellula dendritica
Linfocita T CD4+/25+ FoxP3+
immunoregolatore/immunosoppressivo
X
X
CTLA-4
?
B7
IL-2
CTLA-4
B7
IL-2
(Activation)
CD28
(Blocking)
ANERGIA
APC
T-cell
CTLA-4
T-reg
Improved Survival with Ipilimumab
in Patients with Metastatic Melanoma
F. Stephen Hodi, M.D., Steven J. O'Day, M.D., David F. McDermott, M.D., Robert W. Weber, M.D.,
Jeffrey A. Sosman, M.D., John B. Haanen, M.D., Rene Gonzalez, M.D.,
Caroline Robert, M.D., Ph.D., Dirk Schadendorf, M.D., Jessica C. Hassel, M.D., Wallace Akerley, M.D.,
Alfons J.M. van den Eertwegh, M.D., Ph.D., Jose Lutzky, M.D., Paul Lorigan, M.D., Julia M. Vaubel, M.D.,
Gerald P. Linette, M.D., Ph.D., David Hogg, M.D., Christian H. Ottensmeier, M.D., Ph.D., Celeste Lebbé, M.D.,
Christian Peschel, M.D., Ian Quirt, M.D., Joseph I. Clark, M.D., Jedd D. Wolchok, M.D., Ph.D.,Jeffrey S. Weber, M.D.,
Ph.D., Jason Tian, Ph.D.,Michael J. Yellin, M.D., Geoffrey M. Nichol, M.B., Ch.B., Axel Hoos, M.D., Ph.D.,
and Walter J. Urba, M.D., Ph.D.
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PAST
Methods: A total of 676
HLA-A*0201–positive patients with
unresectable stage III or IV melanoma, whose disease had
progressed while they were receiving therapy for metastatic disease,
were randomly
assigned, in a 3:1:1 ratio, to receive
• ipilimumab
plus gp100 (403 patients),
•ipilimumab alone (137), or
•gp100 alone (136).
Ipilimumab, at a dose of 3 mg per kilogram of body weight, was
administered with or without gp100 every 3 weeks for up to four
treatments (induction).
The median overall survival was 10.0 months
among patients receiving ipilimumab plus
gp100, as compared with 6.4 months among
patients receiving gp100 alone (hazard ratio
for death, 0.68; P<0.001).
Grade 3 or 4 immune-related adverse events
occurred in 10 to 15% of patients treated with
ipilimumab and in 3% treated with gp100
alone.
Conclusions Ipilimumab, with or without a
gp100 peptide vaccine, as compared with
gp100 alone, improved overall survival in
patients with previously treated metastatic
melanoma.
Clin Cancer Res. 2009 Dec 1;15(23):7412-20. Epub 2009 Nov 24.
Guidelines for the evaluation of immune therapy
activity in solid tumors: immune-related response
criteria.
Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbé C, Maio M, Binder M,
Bohnsack O, Nichol G, Humphrey R, Hodi FS.
The core novelty of the
irRC (immune-related Response Criteria) is
the incorporation of measurable new lesions
into
“total tumor burden”
and comparison of this variable to baseline
measurements
Caso Clinico 6 TA38
INIZIO IPILIMUMAB
AGOSTO 2006
Dicembre 2006
Febbraio 2008
15/12/06
23/06/07
Caso Clinico 6 TA38
Marzo 2010
Dicembre 2009
COMPARISON between
WHO and irRC Criteria
WHO
irCR
New lesions
Always PD
Incorporated into tumor
burden
CR
Disappearance of all lesions
Disappearance of all lesions
PR
≥ 50% decrease of all index
lesions, in absence….of PD
≥ 50% decrease in tumor
burden
SD
50% decrease nor 25%
increase…
50% decrease in tumor
burden nor 25% increase…
PD
> 25% increase also in nonindex lesions and appearance of
new lesions
>25% increase in tumor
burden in two consecutive
observations at least 4 wks
apart
irAEs and their Treatment
•The most common grade 3 and 4 class-related irAEs were
dermatitis and colitis
• Other serious but less common events included uveitis,
hepatitis and hypophysitis
•The NCI Surgery Branch reported that, among 198
patients treated with Ipilimumab, 41 (21%) developed
enterocolitis
•The majority also presented diarrhea, fever and abdominal
pain.
•Histolpathology reports of bowel biopsies showed striking
lymphocytic and neutophilic infiltration.
•Five patients were refractory to corticosteroids and
infliximab and underwent surgery for bowel perforation.
irAEs and their Treatment




Most irAEs were manageable with systemic
steroids or other treatment.
Steroid treatment did not appear to affect
antitumor efficacy The management of irAEs is
different from that of other immunotherapies, such as
IL-2 or IFN- α, or cytolitic chemotherapies:
Grade 1 and 2 toxicities generally resolve
spontaneously.
Grade 3 or 4 toxicities require early intervention
with agents not typically used for AEs associated
with antineoplastic therapy: the objective is to reduce
the number of life-threatening outcomes (eg.
corticosteroids to prevent diarrhea/colitis
resulting in bowel perforation/colectomy).
irAEs and their Treatment

Guidelines for the management of
Ipilimumab-associated diarrhea and
hepatotoxicities have recently been
published (Weber J. Oncologist 12(7),
864-872 (2007)

In 2007, NCI and ACS proposed some
algorithms to manage colitis/diarrhea
and hepatotoxicity that have been used
in clinical trials (O'Day SJ, Cancer
110(12), 2614-2627 (2007).
CONCLUSIONS
The Clinical Responses and the
improved Survival in Patients
with Metastatic Melanoma
with anti-CTLA-4 Monoclonal
Antibody are testing the
effectiveness of Cancer
Immunotherapy….
…SI PUO’ FARE !!