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Terapias anti PD1- PDL1 Luis de la Cruz Merino Sº Oncología Médica. HUVMacarena (Sevilla) INDICE • EL EJE PD1/PD-L1 Y LA SINAPSIS INMUNE • ANTICUERPOS MONOCLONALES EN ESTUDIO • DESARROLLO AC MO ANTI PD1 EN MELANOMA • DESARROLLO AC MO ANTI PD1/ ANTI PD-L1 EN OTROS TUMORES • CONCLUSIONES PD1/PDL1: supresión respuesta inmunitaria IFNγ IFNγR MHC TCR TCR (+) PI3K NFκB Other Tumor cell (-) PD-L2 PD-L1 Shp-2 PD-1 Tumor-specific T cell recognition in the periphery MHC CD28 B7.1/2 (-) Dendritic cell T cell Shp-2 PD-1 PD-L2 PD-L1 Lymphocyte priming to tumor antigens SINAPSIS INMUNE Señales entre la APC y el linfocito T Chen and Flies, Nature Reviews Immunology, 2013 MODULADORES DE LA RESPUESTA INMUNE Melero CCR 2013 Clinical Development of Inhibitors of PD-1 Immune Checkpoint Target PD-1 PD-L1 Antibody Molecule Development stage Nivolumab (BMS-936558) Fully human IgG4 Phase III multiple tumors (melanoma, RCC, NSCLCa, HNSCC) Pembrolizumab (MK-3475) Humanized IgG4 Phase I-II multiple tumors Phase III NSCLC/melanoma Pidilizumab (CT-011) Humanized IgG1 Phase II multiple tumors MEDI-4736 Engineered human IgG1 Phase I-II multiple tumors MPDL-3280A Engineered human IgG1 Phase I-II multiple tumors Phase III NSCLC MSB0010718C Fully human IgG1 Phase I solid tumors Long SMR 2014 Robert NEJM 2014 Fases 3 en combinación NCT01783938/ CheckMate 064 NCT01927419/ CheckMate 069 NCT01844505/ CheckMate 067 NCT02224781/ NCI-2014-01747 Nivolumab given Nivolumab + sequentially with ipilimumab vs ipilimumab ipilimumab alone Nivolumab or nivolumab + ipilimumab vs ipilimumab alone Dabrafenib + trametinib followed by ipilimumab + nivolumab or vice versa Phase 2 2 3 Patients Treatment-naive or recurrence after 1 prior regimen Previously untreated Previously untreated BRAFV600 positive Anti-CTLA-4 treatment naive N 140 142 915 300 TBC PD-1 dose Nivolumab 3 mg/kg Nivolumab 1 or 3 mg/kg Nivolumab 1 or 3 mg/kg TBC Nivolumab 3 mg/kg Primary endpoints Safety ORR OS OS rate – Secondary endpoints ORR, progression rates PFS, ORR and PFS in BRAF mutant patients, QoL PFS, ORR, differences PFS, ORR, toxicity in OS, PFS and ORR between arms, OS based on PD-L1, QoL 3 NCT02186249/ CheckMate 218 Nivolumab + ipilimumab Expanded access – www.clinicaltrials.gov 87% ORR 100% CBR NON SMALL CELL LUNG CANCER Median OS Nivolumab Docetaxel 9.2 months 6 months Hazard Ratio 0.59 CI: 0.44, 0.79, p=0.00025] March 04th 2015 FDA approved nivolumab for the treatment of patients with metastatic squamous non-small cell lung cancer with progression on or after platinum-based chemotherapy. Garon NEJM 2015 Garon NEJM 2015 Preliminary Data From a Multi-arm Expansion Study of MEDI4736, <br />an Anti-PD-L1 Antibody Presented By Neil Segal at 2014 ASCO Annual Meeting Dose-Expansion Study in Multiple Tumor Types<br /> Presented By Neil Segal at 2014 ASCO Annual Meeting Majority Remain on Treatment<br /> Presented By Neil Segal at 2014 ASCO Annual Meeting Response in Patient with Pancreatic Cancer<br /> Presented By Neil Segal at 2014 ASCO Annual Meeting Inmunoterapias anti PD1/PD-L1 en desarrollo NHL, AML, CLL, lymphoma Breast Melanoma • • • • • • CTLA-4 pathway targeting agents • LAG-3 protein targeting agents • • • • • • Vaccines PD-1 pathway targeting agents CD40 agents Anti-4-1BB agents Anti-KIR agents Vaccines CTLA-4 pathway targeting agents PD-1 pathway targeting agents LAG-3 protein targeting agents GITR targeting agents CD40 agents NSCLC/SCLC RCC • Vaccines • PD-1 pathway targeting agents • CTLA-4 pathway targeting agents • • • • Vaccines CTLA-4 pathway targeting agents PD-1 pathway targeting agents LAG-3 protein targeting agents HCC • CTLA-4 pathway targeting agents Pancreatic • • • • GIST • CTLA-4 pathway targeting agents CRC Vaccines CTLA-4 pathway targeting agents PD-1 pathway targeting agents CD40 agents Haematologic • CTLA-4 pathway targeting agents • CTLA-4 pathway targeting agents • Targeting CD27 PC/CRPC • Vaccines • CTLA-4 pathway targeting agents • PD-1 pathway targeting agents Cervical • CTLA-4 pathway targeting agents www.clinicaltrials.gov. Accessed September 2014. Ovarian • Vaccine • CTLA-4 pathway targeting agents 49 La respuesta está en el estroma….. Conclusiones • Eje PD1/PD-L1 crítico para frenar la respuesta inmune antitumoral • AcMo dirigidos frente a ambas moléculas permiten “liberar los frenos” induciendo activación de linfocitos T • Estudios fases 1 anti PD1 y anti PD-L1 muy prometedores en una amplia gama de tipos tumorales • Anti-PD1 ya con resultados de estudios fase 3: * Melanoma 1ª línea (vs Ipi/DTIC), impacto OS * Melanoma tras ipilimumab (vs QT), impacto TRO/SLP * CPNCP 2ª línea (vs Docetaxel), impacto OS • AcMo anti PD1 y anti PD-L1 nueva era en el tratamiento del cáncer
