IV REUNIÓN GIDO-GGCP Dr. José Muñoz Langa Servicio Oncología Médica Hospital Universitario y...
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IV REUNIÓN GIDO-GGCP Dr. José Muñoz Langa Servicio Oncología Médica Hospital Universitario y Politécnico La Fe Inmunoterapia en Cáncer de Pulmón Baiona,
IV REUNIN GIDO-GGCP Dr. Jos Muoz Langa Servicio Oncologa Mdica
Hospital Universitario y Politcnico La Fe Inmunoterapia en Cncer de
Pulmn Baiona, 25 Abril 2015)
Slide 2
1st-line combination with chemotherapy After failure of 1 prior
chemotherapy Maintenance treatment after 1st-line chemotherapy
1st-line or unspecified setting single agent 1970198019902000
Erlotinib 2004 Docetaxel 1999 Gefitinib 2003 2010 Pemetrexed 2004
Erlotinib 2010 Pemetrexed 2009 Crizotinib 2011 (US)/2012 (EU)
Erlotinib** 2013 Median OS, months 12+ ~810 ~6 ~24 13+ Carboplatin*
1989 Gemcitabine 1996 Vinorelbine 1994 Docetaxel 2002 Bevacizumab
2006 Pemetrexed 2008 Paclitaxel 1998 Nab-Paclitaxel 2012 Cisplatin*
1978 Despite advances, only small incremental OS benefits in
overall patient population * Not approved in NSCLC, but commonly
used; Restricted to patients participating in a clinical trial or
continuing to benefit from treatment already initiated;
Non-squamous NSCLC only; ALK-positive NSCLC only; **EGFR exon 19
deletions or exon 21 (L858R) substitution mutations only; #
Afatinib is approved for the treatment of patients with activating
EGFR mutations but only PFS data have been published (May 2014).
U.S. Food and Drug Administration. Available at www.fda.gov.
Accessed September 2014; European Medicines Agency. Available at
http://www.ema.europa.eu. Accessed September 2014; NCCN Guidelines.
Non-small cell lung cancer. v3.2014.www.fda.gov
http://www.ema.europa.eu Afatinib**,# 2013
Slide 3
Immuno-Oncology (I-O): can it address unmet needs in lung
cancer? Immunotherapy represents a new hope for NSCLC patients,
Cancer patient The field of immunotherapy has exploded in the last
decade, and more and more patients are benefiting, Steven O'Day,
USC The PD-1 antibodies stop lung cancer cells from blocking the
body's natural immune response to cancer. A drug that can inhibit
PD-1 may be able to treat a variety of cancers, which is very
exciting, Myron Bednar, Hunterdon Regional Cancer Center We look
forward to the potential for the combination of checkpoint
inhibitors, like nivolumab, with small molecule inhibitors in
patients with EGFR mutated lung cancer, Naiyer Rizvi, Memorial
Sloan Kettering Cancer Center The high level of excitement around
this space is that immune checkpoint inhibitors may apply to a very
broad range of cancer types, as both monotherapies and combination
therapies. The data we are seeing so far, including recently
released at ASCO, also indicates the mechanism works in patients
who have failed previous cancer therapies., Stephen Dunn, LifeTech
Capital In any trial you get the odd patient who does very well,
but this is an order of magnitude above that., Mick Peake,
Glenfield Hospital
Slide 4
Objetivos de la Charla: Revisar los fundamentos cientficos de
la inmuno-oncologa en el cncer de pulmn y en qu se diferencia de
otras modalidades de tratamiento. Discutir los ltimos avances en
inmunoterapia para el tratamiento del cncer de pulmn. Analizar el
problema de la identificacin de biomarcadores para las terapias
inumono-oncolgicas y su potencial valor predictivo. Valorar el
potencial de la inmunoterapia sola o en combinacin con otras
modalidades de tratamiento en la prctica clnica.
Slide 5
Dunn GP et al. Immunity. 2008; 21:137-148. Inmuno-edicin del
Cncer: Las Tres E.
Slide 6
The Cancer-Immunity Cycle Chen DS and Mellman I. Immunity.
2013;39.
Slide 7
Stimulatory and Inhibitory Factors in the Cancer-Immunity Cycle
Chen DS and Mellman I. Immunity. 2013;39.
Slide 8
Mecanismos Tumorales para Escapar del Sistema Inmune Goldman et
al, Nature Biotechnology, 2009
Slide 9
Mecanismos Tumorales para Escapar del Sistema Inmune
Slide 10
Duray et al, J of Immunol Research, 2010
Slide 11
Activacin Clula T Proliferacin Supervivencia Produccin
Citoquinas APC MHC Clula T TCR CD28B7 Molculas coestimulatorias
Inmunidad Adaptativa: Activacin del Linfocito T Abbas AK et al.
Cellular and Molecular Immunology. 6th ed. Philadelphia, PA:
Elsevier Saunders, 2010
Slide 12
CTLA-4 Anti cpo MHC TCR Seales Activacion Seales Inhibitorias
CD28B7 Cel Dendritica T cell F. Presentacion Ag G.LinfaticoTejidos
perifericos F. Efectora o citotxica T cellCancer cell MHC TCR Anti
cpo PD-L1 Regulacin Negativa PD-1 Anti cpo Cancer cell T cell
Blocking CTLA-4 and PD-1 pathways
Slide 13
Sinapsis Inmunolgica: Regulacin funcin Linfocitos T
Slide 14
Nirschl CJ Clin Cancer Res 2013
Slide 15
Glennie M. BJCP 2013 Sinapsis Inmunolgica: Regulacin funcin
Linfocitos T
Slide 16
Regulating the T cell immune response T cell responses are
regulated through a complex balance of inhibitory (checkpoint) and
activating signals Tumours can dysregulate checkpoint and
activating pathways, and consequently the immune response Targeting
checkpoint and activating pathways is an evolving approach to
cancer therapy, designed to promote an immune response PD-1 CTLA-4
Inhibitory receptors Activating receptors TIM-3 LAG-3 Antagonistic
(blocking) antibodies Agonistic antibodies T cell stimulation CD28
OX40 CD137 a The image shows only a selection of the
receptors/pathways involved. CD = cluster of differentiation;
CTLA-4 = cytotoxic T-lymphocyte antigen-4; LAG-3 =
lymphocyte-activation gene 3; PD-1 = programmed cell death TIM-3 =
T-cell immunoglobulin domain and mucin domain 3. Adapted from
Mellman I, et al. Nature. 2011:480;481489; Pardoll DM. Nat Rev
Cancer. 2012;12:252264.
Slide 17
Objetivos de la Charla: Revisar los fundamentos cientficos de
la inmuno-oncologa en el cncer de pulmn y en qu se diferencia de
otras modalidades de tratamiento. Discutir los ltimos avances en
inmunoterapia para el tratamiento del cncer de pulmn. Analizar el
problema de la identificacin de biomarcadores para las terapias
inumono-oncolgicas y su potencial valor predictivo. Valorar el
potencial de la inmunoterapia sola o en combinacin con otras
modalidades de tratamiento en la prctica clnica.
Slide 18
Immuno-Oncology: an emerging immunotherapy strategy for NSCLC.
EGFR = epidermal growth factor receptor. www.clinicaltrials.gov.
Accessed September 2014; NCCN Guidelines. Non-small cell lung
cancer. v3.2014; Peters S, et al. Ann Oncol. 2012;23:vii56vii64.
Therapeutic vaccines Enhancing immune cell function Adoptive
Anti-tumour mAbs Bavituximab EGFR inhibition Adoptive cell transfer
Modulate T cell function Cytokines GSK1572932A TG4010
Belagenpumatucel-L Tergenpumatucel-L Racotumomab L-BLP25 CIMAvax
Passive (adoptive) Designed to act at tumour; immune-based
mechanism Active Designed to act on the immune system itself
Immunotherapy Antigen dependent Antigen independent Immuno-Oncology
CTLA-4 inhibition PD-1 inhibition PD-L1 inhibition
Slide 19
Blocking CTL4 and PD-1/PD-L1 Patway Un agente nico es capaz de
proporcionar beneficio clnico en mltiples lneas de tratamiento y
con largos supervivientes.
Slide 20
Dose (mg/kg) Died/ Treated ORR, % (n/N) Median OS (95% CI) OS
rate, % (95% CI) [patients at risk] 1-year OS2-year OS 126/33 3.0
(1/33) 9.2 (5.3, 11.1) 32 (16, 49) [8] 12 (3, 27) [2] 320/37 24.3
(9/37) 14.9 (7.3, ) 56 (38, 71) [17] 45 (27, 61) [9] 1048/59 20.3
(12/59) 9.2 (5.2, 12.4) 40 (27, 52) [23] 19 (10, 31) [9]
061218243027211593333642485439455157 0.0 0.2 0.4 0.6 0.8 1.0
Overall survival Months since treatment initiation 33 Patients at
risk 2185200000015616260000 373 mg/kg26171291111104111321341110
5910 mg/kg35231493220004121629512100 1 mg/kg Anti-PD-1 demonstrates
encouraging survival in pre-treated patients: Nivolumab as an
example 70% of patients had 35 prior lines of therapy; 46% of these
patients had received 1 2 prior lines of therapy and 54% had
received 3 5 prior lines of therapy. Gettinger NS et al. J Clin
Oncol. 2015; 33 CA209-003: phase 1 follow-up study, up to 5 prior
lines of therapy, stage IIIB/IV squamous and non-squamous NSCLC
cohort
Slide 21
Most common treatment-related AE: fatigue 20% 10% experienced 1
grade 3 5 treatment-related AEs Incidence of fatigue, arthralgia
and nausea,
Select adverse events (1%) in patients with NSCLC treated with
nivolumab Demonstrates a safety profile managed by protocol
algorithms No new safety signals emerging; all patients >1 year
of follow-up Patients, n (%) [N = 129] Any grade Grade 3 4 Any
treatment-related select adverse event*41 (53)5 (6) Skin16 (20)0
Gastrointestinal12 (15)1 (1) Pneumonitis8 (6)3 (2) Pulmonary7 (9)2
(3) Endocrinopathies6 (8)0 Hepatic5 (6)1 (1) Infusion reaction4
(5)1 (1) Renal3 (4)0 *Defined as an event with potential
immunological aetiologies that require more frequent monitoring
and/or unique intervention. 2/3 cases were fatal. Brahmer J, et al.
Poster presented at ASCO 2014 (Abstract 8112).
Slide 32
Toxicidad clase especfica con un perfil de seguridad manejable
Inhibition of CTL4 and PD-1/PD-L1 Patway Un agente nico es capaz de
proporcionar beneficio clnico en mltiples lneas de tratamiento y
con largos supervivientes. Respuestas rpidas y duraderas
independientes del tipo histolgico y de la presencia
mutaciones.
Slide 33
Anti-PD-1 response by histology: nivolumab as an example
Responses were durable and occurred early 50% of patients (11/22)
with ORs demonstrated response at first assessment (8 weeks)
Responses ongoing in 45% of patients (10/22) at time of analysis
38% of responders (6/16) who discontinued for reasons other than PD
responded for >30 weeks after last nivolumab dose; responses in
83% of patients (5/6) ongoing at the time of reporting Brahmer J,
et al. Poster presented at ASCO 2014 (Abstract 8112). Time to and
duration of response while on treatment Time to response Ongoing
response Response duration following latest reported dose of
therapy Time, weeks 0163248648096112128144 160 Squamous (n = 9)
Non-squamous (n = 13) CA209-003: phase 1 follow-up study, up to 5
prior lines of therapy, stage IIIB/IV NSCLC cohort
Slide 34
Anti-PD-1 survival rates appear independent of histology:
nivolumab as an example Brahmer J, et al. Poster presented at ASCO
2014 (Abstract 8112).
Slide 35
Response to anti-PD-1 by EGFR or KRAS mutation status:
nivolumab as an example Brahmer J, et al. Poster presented at ASCO
2014 (Abstract 8112). SubgroupORR, % (n/N) [95% CI] EGFR status
Mutant17 (2/12) [2.1, 48.4] Wild-type20 (11/56) [10.2, 32.4]
Unknown15 (9/61) [7.0, 26.2] KRAS status Mutant14 (3/21) [3.0,
36.3] Wild-type25 (9/36) [12.1, 42.2] Unknown14 (10/72) [6.9, 24.1]
Change in tumour size, % -100 -80 -60 -40 120 -20 0 20 40 60 80 100
Patients EGFR mutation status Mutant Unknown Wild-type -100 -80 -60
-40 120 -20 0 20 40 60 80 100 Patients Change in tumour size, %
KRAS mutation status Mutant Unknown Wild-type CA209-003: phase 1
follow-up study, up to 5 prior lines of therapy, NSCLC cohort
Slide 36
Objetivos de la Charla: Revisar los fundamentos cientficos de
la inmuno-oncologa en el cncer de pulmn y en qu se diferencia de
otras modalidades de tratamiento. Discutir los ltimos avances en
inmunoterapia para el tratamiento del cncer de pulmn. Analizar el
problema de la identificacin de biomarcadores para las terapias
inumono-oncolgicas y su potencial valor predictivo. Valorar el
potencial de la inmunoterapia sola o en combinacin con otras
modalidades de tratamiento en la prctica clnica.
Slide 37
Understanding of NSCLC subtyping has evolved in parallel with
treatment strategies *Bronchioloalveolar carcinoma 6%,
adenosquamous 2%; Of all histologies. 1. Carney DN. N Engl J Med.
2002;346:12628; 2. American Cancer Society. Lung Cancer (Small
Cell). Available from http://www.cancer.org/cancer/lungcancer-
smallcell/detailedguide/small-cell-lung-cancer-what-is-small-cell-lung-cancer.
Accessed September 2014; 3. Chansky K, et al. J Thorac Oncol.
2009;4:792-801; 4. Pao W, et al. Lancet Oncol. 2011;12:175180; 5.
Molecular profiling of lung cancer. Available at
http://www.mycancergenome.org/content/disease/lung-cancer. Accessed
September 2014; 6. American Cancer Society. Lung Cancer (Non-Small
Cell); What is non-small cell lung cancer? Available at
http://www.cancer.org/cancer/lungcancer-non-
smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer.
Accessed September 2014; 7. Kim HS, et al. Lung Cancer.
2013;80:249255; 8. The Cancer Genome Atlas Research Network.
Nature. 2012;489:519525. NSCLC >85% SCLC
AgentAssayAnalysisDefinition of positivityPD-L1 expression
Nivolumab (anti-PD-1) 1 4 Dako automated IHC assay (28-8 rabbit Ab)
Analytically validated Archival FFPE1% and 5% cut-off among >100
evaluable tumour cells 56%: 1% cut-off 49%: 5% cut-off
Pembrolizumab (anti-PD-1) 5,6 Dako automated IHC assay (22C3 mouse
Ab) New tumour biopsy within 60 days prior to first dose of
pembrolizumab Tumour dependent: - Melanoma > 1% - NSCLC PD-L1
(+): Strong (50%) and weak staining (149%) PD-L1 (): no staining
~25%: 50% staining ~4570%: 1% staining MPDL3280A (anti-PD-L1) 7,8,9
Ventana automated clinical research IHC assay Archival FFPEPD-L1
(+): IHC 3 (10%), IHC 2,3 (5%), IHC 1,2,3 (1%) PD-L1 (): IHC 0
(