Tratamiento inicial de mNSCLC: visión panorámica
•Download as PPTX, PDF•
0 likes•106 views
Presentación por Zoom para el Hospital de la Fundación Cardioinfantil, invitado por William Mantilla
Recommended
Recommended
More Related Content
What's hot
What's hot (20)
Similar to Tratamiento inicial de mNSCLC: visión panorámica
Similar to Tratamiento inicial de mNSCLC: visión panorámica (20)
More from Mauricio Lema
More from Mauricio Lema (20)
Recently uploaded
Recently uploaded (20)
Tratamiento inicial de mNSCLC: visión panorámica
- 1. Tratamiento inicial de cáncer de pulmón de células no pequeñas metastásico: visión panorámica Mauricio Lema Medina MD Clínica de Oncología Astorga / Clínica SOMA - Medellín, Colombia Zoom, 06.05.2020
- 2. Mauricio Lema Medina MD Clínica de Oncología Astorga / Clínica SOMA Medellín Inspirado en: Michael Bierut, 2013, Logo para Mohawk Fine Papers
- 3. @onconerd
- 4. Conflictos de interés Mauricio Lema Honorarios por conferencias y consultoría de: Boehringer-Ingelheim, BMS, MSD, Pfizer, ROCHE, Aztra-Zeneca, Eli Lilly, NOVARTIS
- 5. Biopsy: Establish Diagnosis, Determine Histologic Subtype, Biomarker Testing Histologic subtyping: squamous or nonsquamous?[1] For biomarker testing: ‒ Primary tumors and metastatic lesions equally suitable[2] ‒ Bone biopsy suboptimal due to decalcification and degradation of DNA[2] ‒ Liquid biopsies (cell-free DNA in plasma) when tissue not available[3] Testing for PD-L1 expression indicated in all NSCLC[4] Testing for EGFR, ALK, ROS1, BRAF V600E indicated in all nonsquamous NSCLC[4] ‒ Broad NGS testing encouraged to detect a wider range of mutations (eg, NTRK) using least amount of tissue[4,5] ‒ For squamous NSCLC, consider testing in young, never or light smokers, or if biopsy specimen is small or of mixed histology[2] Completion of testing within 10-14 working days of biopsy recommended[4,6] ‒ TAT for PD-L1 much shorter than for NGS ‒ Wait for results of NGS results before acting on PD-L1 testing results! Slide credit: clinicaloptions.com 1. Masters. JCO. 2015;33:3488. 2. Lindeman. J Thorac Oncol. 2013;8:823. 3. Bernabé. Eur J Cancer. 2017;81:66. 4. Pennell. ASCO Educ Book. 2019;39:351. 5. Kalemkerian. JCO. 2018;36:911. 6. Bernicker. J Oncol Pract. 2017;13:221.
- 6. Lista de chequeo para el manejo de NSCLC Caja de herramientas Diagnóstico tisular Histología. Morfología Escamoso Adeno NSCLC NOS SCLC. Inmunohistoquímica Escamoso: p63-p40 Adeno: TTF+, Napsin PD-L1 expresión (mNSCLC) SCLC: Ki67 alto, Cromogranina, sinaptofisina Genotipificación Especialmente en no escamosos EGFR ALK/EML4 ROS1, y otros.
- 7. Comparison of Alternative Molecular Testing Approaches Single Gene Testing Multigene Testing (eg, by NGS) Advantages Routine in practice Potential local implementation Minimizes use of tumor tissue Facilitates testing of multiple biomarkers, including emerging biomarkers for clinical trial enrollment Easy—just need to know to test vs which biomarkers to test for More cost-effective than sequential testing Limitations Tumor tissue samples often inadequate for multiple necessary tests May lead to repeat biopsy Multiple platforms available using different methodology that affect types of alterations detected (eg, amplicon-based NGS does not detect gene fusions/rearrangements) Analysis of complex biomarker reports Preauthorization requirements May not be easily accessible in community practice Hirsch. Clin Lung Cancer. 2018;19:331. Pennell. ASCO 2018. Abstr 9031. Slide credit: clinicaloptions.com
- 8. Liquid Biopsy What is liquid biopsy? ‒ Blood sample containing cell-free DNA from multiple sources, including DNA shed from tumor When do we use liquid biopsy? ‒ Molecular testing is needed but amount of available biopsy tissue is inadequate or tissue biopsy not possible ‒ Resistance to TKIs Advantages ‒ Minimally invasive ‒ May overcome tumor heterogenicity Limitations ‒ Sensitivity: 70%-80%; specificity: near 100% ‒ Negative result is noninformative Bauml. Clin Cancer Res. 2018;24:4352. Lowes. Int J Mol Sci. 2016:17:E1505. Figure 1 of given citation is used in its original form under the terms and conditions of the Creative Commons Attribution 4.0 International license (CC BY 4.0: https://creativecommons.org/licenses/by/4.0/). Slide credit: clinicaloptions.com
- 9. Current Paradigm for Immunotherapy in Advanced NSCLC Without an Actionable Mutation For PD-L1 low (1%-49%) or negative (< 1%), SoC is combination ICI + CT For ≥ 50% PD-L1, choice of single-agent ICI or ICI + CT ‒ Single-agent ICI approved for ≥ 1% PD-L1 but not broadly recommended by experts Nivolumab/ipilimumab is under priority FDA review for first-line treatment of advanced NSCLC Lim. Immune Netw. 2020;20:e10. Slide credit: clinicaloptions.com PD-L1 high (≥ 50%) PD-1 inhibitor or CT + PD-1 inhibitor PD-L1 low (1%-49%) or negative (< 1%) Squamous histology Nonsquamous histology CT + PD-1 inhibitor CT + PD-(L)1 inhibitor
- 10. Lack of Efficacy With Immune Checkpoint Inhibition in EGFR Mutation–Positive NSCLC Phase II study of pembrolizumab in patients with PD-L1–positive EGFR-mutated advanced NSCLC (planned N = 25); stopped for futility at 11 patients ‒ Only 1 patient, where report of EGFR mut was in error, with objective response to pembrolizumab Lisberg. J Thorac Oncol. 2018;13:1138. Slide credit: clinicaloptions.com Best Response for Target Lesions Subsequent Therapies and Reasons for Treatment Discontinuation *AE led to discontinuation. †Completed tx, under surveillance. ‡Died while on erlotinib (1 by fatal pneumonitis). EGFR-WT 20 10 0 -10 -20 -30 -40 -50 ChangeFromBaseline(%) * † Mos 0 2 4 6 8 10 12 * * * ‡ ‡ † Pembrolizumab No therapy Erlotinib Afatinib Chemotherapy Clinical trial PD Tx ongoing *Patient with dural thickening on brain MRI deemed to have PD. †Patient had CR of target lesion but nontarget progression on first scan. EGFR-WT
- 12. NSCLC as one disease Squamous 34% Other 11% Adenoca 55% Non-Small-Cell Lung Cancer: Not One Disease, but Many! Slide credit: clinicaloptions.comLi. JCO. 2013;31:1039. Tsao. J Thorac Oncol. 2016;11:613. Then Histology-Based Subtyping Now Adenocarcinoma KRAS 25% ALK 7% EGFR Sensitizing 17% No Known Oncogenic Driver Detected 31% EGFR Other 4% MET 3% > 1 Mutation 3% HER2 2% ROS1 2% BRAF 2% RET 2% NTRK < 1% PIK3CA 1% MEK1 < 1%
- 13. Tratamiento de cáncer de pulmón con mutaciones “accionables”
- 14. mEGFR
- 15. Kinase domain N-lobe EGFR mutations in human cancer CR2 476-621 L1 1-163 N-lobe 686-769 L2 310-475 CRD 961-1211 CR1 164-309 TM 622-644 JM 645-685 C-lobe 773-960 L858R lung R108K neuronal L861Q lung Frequency of mutation: ≥40% <5% 5-40% Ligand bs Ligand bs A1048V stomach R677H neuronal C624F neuronal P598V glioblastoma, neuronal P596L glioblastoma, neuronal R324L neuronal D1012H lung 686 960 Kinase domain C-lobe E709K lung, prostate E709A lung E709G lung G719S lung, intestine G719C lung G719A lung L833V lung T790M lung, neuronal, oesophagus L858R lung L858Q lung L858M lung H835P breast H835L breast, lung T710I breast E872K breast E872X oesophagus L861Q lung, neuronal L861R lung L861V lung E866K breast, lung delL747-A751insP lung delL747-A751insS lung delL747-T751 lung delL747-S752 lung delE747-A750insP lung delL747-P753 lung delL747-P753insQ lung delL747-P753insS lung delE746-T751insA lung delE746-T751insI lung delE746-A751 lung delE746-T750insRP lung delK745-E749 lung delE746-A750 lung delE746-S752insA lung delE746-S752insV lung delE746-S752insVA lung EGFRvIII: delV30-R297insG glioblastoma, lung, breast Catalytic site R108K neuronal T263P glioblastoma, neuronal A289V glioblastoma, neuronal A289D glioblastoma, neuronal A289T glioblastoma, neuronal delD770-N771insSVD lung delD770-N771insG lung delH773_V774insNPH lung delV774_C775insHV lung delV769-D770insASV lung S768I lung, neuronal, oesophagus S768ins lung H774M lung H773R lung
- 16. Y920 Y891Y845 EGF Stepwise EGFR ligand binding and tyrosine phosphorylation 1 Y1146Phosphotyrosine EGF TM N C TM L1 L2 CR2 CR1 N C monomers tethered, inactive TM N C TM N C EGFR CR1 L2 CR2 L1 2 predimer extended, symmetric, inactive EGF TMTM EGFR CR1 L2 CR2 L1 3 dimer extended, asymmetric EGF TM EGFR CR1 L2 CR2 L1 4 dimer extended, asymmetric, active EGF 5 dimer extended, asymmetric switched EGF CR1 L2 CR2 L1 TMTM Y845 Y920 Y891 Y992 Y1045 Y1068 Y1086 Y1173 Y1148 Y1148 Y1086 Y1173 Y1068 Y1045Y992 EGF CR1 L2 CR2 L1 TMTM Y1148 Y1086 Y1173 Y1068 Y1045Y992 Y845 Y920 Y891 Y1148 Y1086 Y1173 Y1068 Y1045 Y992 Y891 Y920Y845 6 dimer extended, asymmetric active activated kinase activating kinase kinase inactive tethered, inactive extended, active kinase inactive receptor kinase donor kinase activating kinase activated kinase receptor kinase donor kinase EGF EGF EGF EGFR TM EGFR
- 17. EGF receptor family signaling specificity (Human) ErbB1 EGFR GEP100 ErbB4ErbB3 ErbB2 HER2 TK Ligand CRD Ligand CRD TGF EGF HB-EGF Epiregulin Amphiregulin -Cellulin Epigen Neuregulin-1 Neuregulin-2 Neuregulins NRG 1,2,3,4 Epiregulin -cellulin HB-EGF ? Ligand CRD Ligand TK CRD TK Ligand CRD Ligand CRD Ligand CRD Ligand CRD FAK Ligand CRD Ligand TK CRD TK Ligand CRD Ligand CRD Ligand CRD Ligand CRD TK Ligand CRD Ligand CRD PI3K PDK PKB Src Cbl GAB1 Grb2 Ras Raf MEK1/2 Erk1/2 STAT 3 P P P P P P P P PSOS Grb2 SHCGrb2 Ras Raf MEK1/2 Erk1/2 PSOSSHC Nck PAK1 JNKK JNK STAT 3 P SHCGrb2 Ras Raf MEK1/2 Erk1/2 PSOS Grb2Crk Abl SOS Ras Raf MEK1/2 Erk1/2 Grb2 P SOS Ras Raf MEK1/2 Erk1/2 Grb2 P SOS Ras Raf MEK1/2 Erk1/2 PLC1 Arf6 Grb2 P SOS Ras Raf MEK1/2 Erk1/2 p85 PI3K PDK PKB p85 PI3K PDK PKB p85 PI3K PDK PKB p85 PI3K PDK PKB PI3K PDK PKB GAB1P Grb2 STAT 5A P TK 4ICD secretase ER ER TK 4ICD AP-1AP-1 PP SRFElk Ets PPP C-Myc P TCFNFkBNFkB E2F 1-3 FOXO1 P PP P STAT 3 STAT 5A Lyn P Nck PAK1 JNKK JNK p85 PI3K PDK PKB RhoA Rac1 RhoA Rac1 Shp2 P SYK ITK
- 18. Análisis combinados de los estudios LUX-Lung 3 y LUX-Lung 61 mEGFR+ /mNSCLC Sin tratamiento previo PS 0/1 Asiáticos Metástasis cerebrales asintomáticas (no excluidas) 1. Yang JC, Lancet Oncol, 2015 R 2:1 Afatinib 40 mg Vía oral cada día Cisplatino + Gemcitabina Desenlace secundario a observar: supervivencia global mEGFR del19 mEGFR+ /mNSCLC Sin tratamiento previo PS 0/1 Global Metástasis cerebrales asintomáticas (no excluidas) R 2:1 Afatinib 40 mg Vía oral cada día Cisplatino + Pemetrexed LUX-Lung 6 LUX-Lung 3
- 19. Estomatitis Pneuminitis Fatigue ≤5% Afatinib Rash Acné Diarrea Paroniquia >10% Yang JC, Lancet Oncol, 2015 40 mg vía oral cada día. Eficaz en: mEGFR del19 mEGFR L858R Otras mutaciones Estudios Estudios LUX-Lung Toxicidades Grado 3 o 4
- 20. Análisis combinados de los estudios LUX-Lung 3 y LUX-Lung 61 1. Yang JC, Lancet Oncol, 2015 mEGFR del19
- 21. FLAURA1 mEGFR (del19/L858R) mNSCLC Sin tratamiento previo PS 0/1 Metástasis cerebrales estables (no excluidas) 1. Ramalingam SS, NEJM, 2020 R Gefitinib o Erlotinib cada día Osimertinib 80 mg cada día Desenlace secundario reportado: supervivencia global
- 22. AST Alopecia ALT Prurito Tos Estreñimiento Náuseas Disnea Anemia Cefalea Vómito Pirexia QT largo 10% - 20% Osimertinib Exantema Diarrea Piel seca Paroniquia Estomatitis Disminución del apetito >20% <10% Algún grado de toxicidad: 98% Grado 3: 30% Grado 4: 2% Soria JC, NEJM, 2018 80 mg vía oral cada día. Eficaz en: Metástasis cerebrales mEGFR T790M+ mEGFR L858R mEGFR del19 Estudios AURA(1-3) FLAURA
- 23. FLAURA1 1. Ramalingam SS, NEJM, 2020
- 24. RELAY1 mEGFR mNSCLC PS 0/1 No tratamiento previo con TKI anti EGFR No T790M No Metástasis cerebrales 1. Nagakawa K, Lancet Oncol, 2019 R Placebo + Erlotinib cada día Ramucirumab + Erlotinib Desenlace principal: supervivencia libre de progresión
- 25. 1. Nagakawa K, Lancet Oncol, 2019 RELAY1
- 26. Hiporexia Náuseas Prurito Edema Tos Pirexia Disgeusia Hipertensión ALT Estomatitis AST Piel seca Alopecia Epistaxis Bilirrubina 30% - 50% Erlotinib más ramucirumab Diarrea Dermatitis acneiforme Paroniquia >50% 15% - 30% Algún grado de toxicidad: 100% Grado 3 Hipertensión (23%) Dermatitis (15%) Diarrea (7.2%) ALT Eficaz en: mEGFR (no en T790M) Estudio RELAY Nagakawa K, Lancet Oncol, 2019
- 27. Hiporexia Náuseas Prurito Edema Tos Pirexia Disgeusia Hipertensión ALT Estomatitis AST Piel seca Alopecia Epistaxis Bilirrubina 30% - 50% Erlotinib más ramucirumab Diarrea Dermatitis acneiforme Paroniquia >50% 15% - 30% Algún grado de toxicidad: 100% Grado 3 Hipertensión (23%) Dermatitis (15%) Diarrea (7.2%) ALT Eficaz en: mEGFR (no en T790M) Estudio RELAY Nagakawa K, Lancet Oncol, 2019 Toxicidades de terapia antiangiogénica
- 28. ALK+
- 29. ALK+ Pal, P. Pulmonary Adenocarcinoma: Approaches to Treatment. (2019) Características No siempre fumadores Mujeres Adenocarcinoma Mucinosos Arquitectura acinar / cribiforme Células en anillo de sello Calcificaciones de PsammomaDiagnóstico FISH: Hibridización fluorescente in-situ RT-PCR: Reacción en cadena de polimerasa – tiempo real Inmunohistoquímica NGS: secuenciación de próxima generación
- 30. ALK+ Acinar/cribiforme Mucina / anillo de sello Inmunohistoquímica – Clona 5A4 Pal, P. Pulmonary Adenocarcinoma: Approaches to Treatment. (2019)
- 34. Tumor Responses to Crizotinib for Patients With ALK-Positive NSCLC Camidge DR. Lancet Oncol. 2012;1011-1019. Slide credit: clinicaloptions.com Crizotinib in ALK-Positive NSCLC (N = 143)100 80 60 40 20 0 -20 -40 -60 -80 -100 ChangeFromBaseline(%) PD SD PR CR
- 35. ALEX1 ALK+ mNSCLC Sin tratamiento previo PS 0/1 Metástasis cerebrales asintomáticas (no excluidas) 1. Peters S, NEJM, 2017 R Crizotinib 250 mg cada 12 horas Alectinib 600 mg cada 12 horas Desenlace principal: supervivencia libre de progresión
- 36. Crizotinib Solomon BJ, NEJM, 2014 250 mg vía oral: 2 veces por día. Eficaz en: ALK mutado ROS1 Estudios PROFILE ALT/AST (14%) Neutropenia (11%) Fatiga Dolor abdominal Cefalea Neutropenia Pirexia Mareo Dolor extremidad 15% - 30% Visual (71%) Diarrea (61%) Edema (49%) Vómito (46%) Constipación (43%) Aminotransferasas (36%) Infección respiratoria (32%) >30% Grado 3-4 Toxicidades
- 37. Alectinib Peters S, NEJM, 2017 600 mg vía oral: 2 veces por día. Eficaz en: ALK mutado Metástasis cerebrales Estudios ALEX Vómito Mareo Disgeusia Visuales Fotosensibilidad 1-10%Anemia Edema Mialgia Náusea Diarrea ALT AST Bilirrubina Aumento de peso 10-20% Toxicidades Grado 3: 41% Serios: 38% Fatales: 3%
- 38. ALEX1 1. Peters S, NEJM, 2017
- 39. ALEX1 1. Peters S, NEJM, 2017
- 40. Otras
- 41. Crizotinib in ROS1 Rearrangement–Positive NSCLC Best % Change From Baseline in Target Lesion Size (N = 51) Best overall response: CR PR Stable disease Progressive disease 20 ChangeFromBaseline(%) 40 60 80 100 0 -20 -40 -60 -80 -100 * * * *Indicates tumor assessment by RECIST v1.1. aExcludes 2 patients: one with early death and one with indeterminate response. ROS1-Rearranged NSCLC (N = 53) Shaw et al 2014 (N = 50) BOR, n (%) CR PR SD PD NEa 6 (11.3) 32 (60.4) 10 (18.9) 3 (5.7) 2 (3.8) 3 (6) 33 (66) 9 (18) 3 (6) 2 (4) ORR, % 95% CI 71.7 57.7-83.2 72.0 58-84 Median TTR, wks (range) 7.9 4.3-103.6 7.9 4.3-32.0 Responses could not be evaluated in 2 patients because of early death or indeterminate response. Slide credit: clinicaloptions.comShaw. NEJM. 2014;371:1963.
- 42. Crizotinib in ROS1 Rearrangement–Positive NSCLC Median follow-up for OS: 62.6 mos 14 patients (26%) remain in follow-up ROS1-Rearranged NSCLC (N = 53) Deaths, n (%) 26 (49.1) Median OS, mos (95% CI) 51.4 (29.3-NR) 40 OS(%) Mos 60 80 100 20 0 0 4020 60 80 53Pts at Risk, n 48 42 37 31 27 23 20 18 17 9 5 4 02033 13 3 1-yr OS rate: 79% 4-yr OS rate: 51% Censored Slide credit: clinicaloptions.comShaw. Ann Oncol. 2019. [Epub]
- 43. Gliomas Infantile fibrosarcoma Thyroid cancer Congenital nephroma Spitz nevi Sarcoma (multiple) Brain cancers (glioma, GBM, astrocytoma) Thyroid cancer Salivary (MASC) Lung cancer (< 1%) Secretory breast cancer Pancreatic Cholangiocarcinoma GIST Colon Melanoma Sarcoma (multiple) NTRK Rearrangements and TRK Fusions in Cancer Normal role in neuronal development in utero and postnatal neuronal differentiation, survival, function; expression limited to CNS In cancer, rearrangement of NTRK gene couples TK domain with a 5’ fusion partner to generate a chimeric TRK protein lacking LBD Cocco. Nat Rev Clin Oncol. 2018;15:731. Hyman. ASCO 2017. Abstr LBA2501. Gatalica. AACR-NCI-EORTC 2017. Abstr A047. Slide credit: clinicaloptions.com Leads to overexpression or constitutive activation of kinase domain NTRK Fusions Are Rare Events: 0.21% Across 11,116 Patients With Tumors of All Types Promoter 5’ partner LBD Kinase domain TRK kinase domain5’ partner NTRK1/2/3 Tyr Tyr Fusion Protein DNA Common cancer with low TRK fusion frequency Rare cancer with high TRK fusion frequency
- 44. Testing for NTRK Fusions Options: IHC, RNA or DNA NGS, FISH, RT-PCR ‒ Advantages/disadvantages with each ‒ RNA NGS most sensitive ‒ IHC widely available; fast TAT Choice of assay will depend on institution, resources, clinical context ‒ Reflexing to NGS vs IHC reasonable for NSCLC due to low prevalence of NTRK fusions Important to qualify negative results: limitations of sample or testing Marchiò. Ann Oncol. 2019;30:1417. Slide credit: clinicaloptions.com ESMO Working Group Recommendations: A Potential Approach for NTRK Fusion Testing in NSCLC FISH RT-PCR RNA NGS NTRK Testing Desired YES NO* NO YES Use IHC as a screening tool No TRK expression Detection of TRK expression IHC to confirm protein expression in positive cases Use frontline NGS, preferably with RNA testing when possible Is there a sequencing platform available? Is the histologic tumor type known to harbor highly recurrent NTRK fusions? *Likely to include any advanced malignancy proven to be WT for other known standard genetic alterations, especially if diagnosed in a young patient.
- 45. † * Efficacy of Pan-TRK Inhibitors Regardless of Tumor Type DoR: 10.4 mos with entrectinib (n = 31); 35.2 mos with larotrectinib (n = 44) Hyman. ESMO 2019. Abstr 445PD. Demetri. ESMO 2018. Abstr LBA17. Slide credit: clinicaloptions.com Entrectinib (N = 54) ORR: 57.4% (95% CI: 43.2%-70.8%) ORR in NSCLC (n = 10): 70% ORR: 79% (95% CI: 72%-85%) Larotrectinib (N = 55) ORR in NSCLC (n = 12): 75% 0 -30 -50 -90 BestChangeinTumorSLD FromBL(%) 15 -80 -70 -60 -40 -20 -10 20 30 40 -100 50 CRC NSCLCSarcoma Neuroendocrine tumors PancreaticThyroid MASC Breast CholangiocarcinomaGynecologic Appendix Cancer of unknown primary Congenital mesoblastic nephroma Lung Salivary gland Bone sarcoma Cholangiocarcinoma GIST Melanoma Other soft tissue sarcoma Breast Colon IFS Pancreas Thyroid MaximumChangeinTumorSize(%) 50 40 30 20 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 ‡ † † † † † † † † † † * * n = 6 excluded. n = 10 excluded. *Patients with pathCR. †Patients with brain mets. ‡Max tumor size change: +93.2%.
- 46. PROFILE 1001: Crizotinib in MET Exon 14–Altered NSCLC Crizotinib: multikinase TKI approved for treatment of ALK+ and ROS+ NSCLC Open-label, multicohort phase I study evaluating efficacy, safety of crizotinib in NSCLC, including a METex14 expansion cohort (n = 69) MET inhibition with crizotinib a viable off-label option for patients with MET exon 14–altered NSCLC Drilon. Nat Med. 2020;26:47. Paik. ASCO 2019. Abstr 9005. Wolf. ASCO 2019. Abstr 9004. Slide credit: clinicaloptions.com Best % Change in Target Lesion Size from Baseline (n = 52*) ORR: 32% Median DoR: 9.1 mos Median PFS: 7.3 mos *Of 65 response-evaluable patients, 13 excluded from waterfall plot. †METex14 alteration by local testing; ROS1+, WT MET by central testing.† MET TKI Potency Comparison Crizotinib Cabozantinib Savolitinib Tepotinib Capmatinib IC50, nM 22.5 7.8 2.1 ~1.7-3.0 0.6 CR PR SD PD ChangeFromBaseline(%) 100 80 60 20 0 40 -20 -40 -60 -80 -100 †
- 47. Efficacy of New Generation MET Inhibitors for Advanced MET Exon 14–Altered NSCLC MET inhibitors are well tolerated, with peripheral edema being a common on target effect Paik. ASCO. 2019. Abstr 9005. Wolf. ASCO 2019. Abstr 9004. Lu. AACR 2019. Abstr CT031. Slide credit: clinicaloptions.com MET Inhibitor Trial and Cohorts ORR, % DCR, % Median DoR, Mos Median PFS, Mos CNS Activity Capmatinib Phase II GEOMETRY mono-1[1] Pretreated (2L/3L) (n = 69) Treatment naive (1L) (n = 28) 40.6 67.9 78.3 96.4 9.7 11.1 5.4 9.7 Yes Tepotinib Phase II VISION[2] METex14+ by liquid biopsy (n = 48) •2L/3L (n = 31) •1L (n = 17) METex14+ by tissue biopsy (n = 51) •2L/3L (n = 33) •1L (n = 18) 50.0 45.2 58.8 45.1 45.5 44.4 66.7 -- -- 72.5 -- -- 12.4 12.4 -- 15.7 12.4 -- 9.5* -- -- 10.8† -- -- Yes Savolitinib 51.6 93.5 -- -- -- Data shown for capmatinib and tepotinib by IRC. *n = 57. †n = 58.
- 48. RET Receptor Tyrosine Kinase and RET Fusions in NSCLC Normal role in neural, genitourinary development In cancer, RET gene rearrangements give rise to chimeric, cytosolic proteins with constitutively active RET kinase domain ‒ 1%-2% of nonsquamous NSCLC ‒ 10%-20% of papillary thyroid carcinoma Majority of RET fusions can be detected by DNA NGS but increased sensitivity with RNA NGS Gautschi. JCO. 2017;13:1403. Ferrara. J Thorac Oncol. 2018;13:27. Kato. Clin Cancer Res. 2017;23:1988. Wang . JCO. 2012;30:4352. Airaksinen. Nature Rev Neuroscience. 2002;3:383. Slide credit: clinicaloptions.com Heterodimerization of ligand–coreceptor complex and RET leads to autophosphorylation and downstream activation Most Common RET Translocation in Lung Adenocarcinoma: KIF5B-RET Wild-type RET Lipid raft P P GFRα family receptors/ GDNF family ligands P P 713575KIF5B KIF5B exon 15 RET exon 12
- 49. Phase I/II LIBRETTO-001: Efficacy With Selpercatinib (LOXO-292) in RET Fusion–Positive NSCLC Durability of response in primary analysis set ‒ DoR: 20.3 mos ‒ PFS: 18.4 mos ‒ ORR, DoR, and PFS similar regardless of prior therapy Treatment-naive (n = 34) ‒ ORR: 85% ‒ DoR and PFS not reached Slide credit: clinicaloptions.comDrilon. WCLC 2019. Abstr PL02.08. Best Tumor Response in Primary Analysis Set (N = 105 Patients With Prior Platinum Doublet CT) ORR, % (95% CI) CR PR SD PD NE 68 (58-76) 2 66 26 2 5 40 20 0 -20 -40 -60 -80 -100 BestTumorResponse(%) Prior therapy CT ICI MKI* *Includes MKIs with anti-RET activity.
- 50. Phase I/II ARROW: Efficacy With Pralsetinib (BLU-667) in RET Fusion–Positive NSCLC Slide credit: clinicaloptions.comGainor. ASCO 2019. Abstr 9008. n = 4 excluded. *Confirmed responses on 2 consecutive assessments as per RECIST 1.1. Durability of response in response evaluable patients ‒ DoR: not reached Anti-tumor activity regardless of prior ICI, RET fusion genotype, or presence of CNS mets 5/7 (71%) of treatment-naive patients had confirmed PR Anti-Tumor Activity With Pralsetinib (BLU-667) 400 mg QD in Response Evaluable Population (N = 48)40 20 0 -20 -40 -60 -80 -100 Maximum%ReductionFromBaselineSum ofDiametersofTargetLesions Plt naive Prior Plt Best Response All Patients (N = 48) Prior Plt (n = 35) ORR, % (95% CI) CR* PR* SD PD 58 (43-72) 1 27 18 2 60 (42-76) 1 20 14 -- DCR, % (95% CI) 96 (86-99) 100 (90-100)
- 51. 1. Fakih. ASCO 2019. Abstr 3003. 2. Biernacka. Cancer Genet. 2016;209:195. 3. Tsao. J Thorac Oncol. 2016;11:613. 4. Baraibar. Crit Rev Oncol Hematol. 2020;148:102906. Other Emerging Biomarkers in the Treatment of Advanced NSCLC For many patients diagnosed with advanced NSCLC, the best therapeutic option may be a clinical trial If identify an emerging biomarker, patient referral to a location with an appropriate study is encouraged Mutation Incidence Investigational Inhibitor(s) Ongoing Trials KRASG12C[1-3]* 13% AMG510 MRTX849 NCT03600883, NCT04185883, NCT04303780 NCT03785249, NCT04330664 EGFR/HER2 exon 20 insertions[4] 0.3%- 3.7%/ 2%-4% Poziotinib TAK-788 Pyrotinib NCT03066206, NCT03318939, NCT04044170 NCT04129502 NCT04063462 HER2 mutations, including exon 20 insertions[4] 2%-4%† Trastuzumab/pertuzumab Trastuzumab deruxtecan NCT03845270 NCT03505710 Slide credit: clinicaloptions.com *Incidence of KRAS mutations in NSCLC: 25% to 33%. †90% of HER2 mutations are in exon 20.
- 52. Current Treatment Paradigm for Molecular Biomarker– Positive Advanced NSCLC ALK positive Progression EGFR mutation positive Advanced NSCLC (molecular biomarker positive) ROS1 positive Crizotinib, ceritinib, or entrectinib Follow treatment options for adenocarcinoma or squamous cell carcinoma without actionable biomarker Osimertinib EGFR T790M mutation negative or previous osimertinib Alectinib, brigatinib, ceritinib, or lorlatinib dependent on previous therapy Alectinib (preferred), ceritinib, or crizotinib† Osimertinib (preferred) erlotinib, afatinib, gefitinib, or dacomitinib* EGFR T790M mutation positive BRAF V600E positive Dabrafenib/ trametinib‡ Firstline Second lineand beyond Slide credit: clinicaloptions.com *Afatinib, dacomitinib, erlotinib, gefitinib, osimertinib approved for EGFR exon19del, exon 21 L858R; afatinib for EGFR G719X, S768I, L861Q. †Brigatinib under priority review by the FDA for first-line ALK positive NSCLC.‡Or as second line after CT. Entrectinib or larotrectinib NTRK positive
- 53. Tratamiento de cáncer de pulmón SIN mutaciones “accionables” Inmunoterapia
- 54. CTLA-4 and PD-1/PD-L1 Checkpoint Blockade for Cancer Treatment Ribas. NEJM. 2012;366:2517. Slide credit: clinicaloptions.com Anti–PD-1: Nivolumab Pembrolizumab Anti–PD-L1: Atezolizumab Avelumab Durvalumab Anti–CTLA-4: Ipilimumab Priming Phase (Lymph Node) Effector Phase (Peripheral Tissue) T-Cell Migration
- 55. Tumor Cell Cytotoxic T8 Lymphocyte PD-L1 PD-1 - - - Tumor Cell Cytotoxic T8 Lymphocyte - - - Tumor Cell Cytotoxic T8 Lymphocyte + + + Pembrolizumab Nivolumab Atezolizumab Durvalumab…
- 56. Immune-Related Adverse Events Majority of irAEs are mild to moderate Severity can be asymptomatic to life threatening; prompt recognition is crucial Onset is variable; can occur after cessation of therapy Most reversible with steroids; some require discontinuation of therapy Important to educate care team, patient, and caregivers on signs and symptoms of irAEs Uveitis Pneumonitis Thyroiditis Hypo/hyperthyroidism Hepatitis Rash and vitiligo Pancreatitis Autoimmune diabetes Adrenal insufficiency Enterocolitis Arthralgia Dry mouth, mucositis Encephalitis, aseptic meningitis Hypophysitis Myocarditis Nephritis Vasculitis Thrombocytopenia Anemia Neuropathy Slide credit: clinicaloptions.comBrahmer. 2018;36:1714. Postow. NEJM. 2018;378:158. Puzanov. JIC. 2017;5:95. Michot. EJC. 2016;54:139.
- 57. Positive First-line Immunotherapy Trials Trial Comparison Selection ORR, % PFS HR OS HR KEYNOTE-024[1,2] Pembrolizumab vs platinum-doublet CT PD-L1 ≥ 50% 44.8 vs 27.8 0.50* 0.63* KEYNOTE-042[3] Pembrolizumab vs platinum-doublet CT PD-L1 ≥ 1% 32 vs 39 0.81† 0.69* KEYNOTE-189[4] Pembrolizumab or placebo + carboplatin/pemetrexed PD-L1 unselected; nonsquamous 47.6 vs 18.9* 0.52* 0.49* IMpower150[5] Atezolizumab + carboplatin/paclitaxel + bevacizumab vs CT alone PD-L1 unselected; nonsquamous 64 vs 48 0.62* Positive‡ KEYNOTE-407[6] Pembrolizumab or placebo + carboplatin/paclitaxel or nab-paclitaxel PD-L1 unselected; squamous 57.9 vs 38.4* 0.56* 0.64* CheckMate 227[7] Nivolumab + ipilimumab vs platinum-doublet CT TMB high (≥ 10 mut/Mb) 45.3 vs 26.9 0.58* Immature 1. Reck. NEJM. 2016;375:1823. 2. Reck. J Clin Oncol. 2019;37:537. 3. Mok. Lancet. 2019;393:1819. 4. Gandhi. NEJM. 2018;378:2078. 5. Socinski. NEJM. 2018;378:2288. 6. Paz-Ares. NEJM. 2018;379:2040. 7. Hellmann. NEJM. 2018;378:2093. *P < .01. †Not significant. ‡Interim analysis. Slide credit: clinicaloptions.com
- 58. Tratamiento de cáncer de pulmón SIN mutaciones “accionables” No-escamoso
- 59. PD-L1 ≥ 50%
- 60. PD-L1 expression in NSCLC
- 61. KEYNOTE-024: First-line Pembrolizumab for Advanced NSCLC Primary endpoint: PFS by BICR Secondary endpoints: ORR, OS, and safety Patients with untreated stage IV NSCLC; ECOG PS 0/1; no actionable EGFR/ALK mutations; PD-L1 TPS ≥ 50%*; no untreated CNS mets or active autoimmune disease requiring tx (N = 305) Pembrolizumab 200 mg IV Q3W for up to 35 cycles (n = 154) Plt-doublet CT (histology based) for 4-6 cycles (n = 151) Until PD or unacceptable toxicity Stratified by ECOG PS (0 vs 1), histology (squamous vs nonsquamous), and enrollment region Until PD (crossover to pembrolizumab allowed) *≥ 50% tumor cell staining using 22C3 companion diagnostic IHC assay. Slide credit: clinicaloptions.com Open-label, randomized phase III study Reck. NEJM. 2016;375:1823. Reck. J Clin Oncol. 2019;37:537.
- 62. KEYNOTE-024: PFS Pembrolizumab (n = 154) Chemotherapy (n = 151) Median PFS, mos (95% CI) 10.3 (6.7-NR) 6.0 (4.2-6.2) 6-mo PFS, % 62 50 12-mo PFS, % 48 15 Reck. ESMO 2016. Abstr LBA8_PR. Reck. NEJM. 2016;375:1823. Slide credit: clinicaloptions.com HR: 0.50 (95% CI: 0.37-0.68; P < .001) Mos PFS(%) Patients at Risk, n Pembrolizumab CT 154 151 104 99 89 70 44 18 22 9 3 1 1 0 100 90 80 70 60 50 40 30 20 10 0 0 3 6 9 12 15 18
- 63. KEYNOTE-024: OS (Updated) Reck. J Clin Oncol. 2019;37:537. Mos 154 151 136 123 121 107 112 88 106 80 89 61 83 55 22 16 5 5 Slide credit: clinicaloptions.com Pembrolizumab (n = 154) Chemotherapy (n = 151) Median OS, mos (95% CI) 30.0 (18.3-NR) 14.2 (9.8-19.0) 12-mo OS, % 70.3 54.8 24-mo OS, % 51.5 34.5 HR: 0.63 (95% CI: 0.47-0.86; P = .002) Patients at Risk, n Pembrolizumab CT OS(%) 96 70 52 31 0 0 100 80 60 70 60 50 40 30 20 10 0 330 3 6 9 12 15 18 21 24 27 30
- 64. Entre 5-10% Hipotiroidismo Hipertiroidismo Pneumonitis Reacción infusional Pembrolizumab Diarrea Fatiga Pirexia Náuseas Anemia Hiporexia 5% - 15% Inmunorelacionados: 29.2% Algún grado de toxicidad: 73.4% Grado 3 (9.7%) Cutánea Pneumonitis Colitis Eficaz en: PD-L1 ≥ 50% Estudio KN 024 Reck M, NEJM, 2016
- 66. KEYNOTE-189: First-line Pembrolizumab + CT vs Placebo + CT in Stage IV Nonsquamous NSCLC Randomized, double-blind, international phase III study Patients with previously untreated stage IV nonsquamous NSCLC; ECOG PS 0/1; any PD-L1 status; no actionable EGFR/ALK mutations; no symptomatic CNS mets or pneumonitis requiring tx (N = 616) Pembrolizumab 200 mg Q3W + Plt*/pemetrexed† Q3W (n = 410) Placebo Q3W + Plt*/pemetrexed† Q3W (n = 206) 4 cycles Pembrolizumab‡ + Pemetrexed† Q3W Placebo‡ + Pemetrexed† Q3W Stratified by PD-L1 TPS (≥ 1% vs < 1%), platinum agent (carboplatin vs cisplatin), smoking history (never vs former/current) Until PD or unacceptable toxicity; crossover from placebo allowed *Carboplatin AUC 5 or cisplatin 75 mg/mm2.†500 mg/m2. ‡Up to total of 35 cycles. Gandhi. NEJM. 2018;378:2078. Primary endpoints: OS, PFS by BICR Secondary endpoints: ORR, DoR, safety No PD No PD Slide credit: clinicaloptions.com
- 67. KEYNOTE-189: OS in Patients With PD-L1 Tumor Proportion Score ≥ 50% Slide credit: clinicaloptions.comGandhi. NEJM. 2018;378:2078. Pembrolizumab + CT (n = 127) Placebo + CT (n = 63) Events, % 25.8 51.4 Median OS, mos (95% CI) NR (NE-NE) 10.0 (7.5-NE) TPS ≥ 50% 132 70 122 64 114 50 96 35 56 19 25 13 6 4 0 0 HR: 0.42 (95% CI: 0.26-0.68) Pembro + CT Pbo + CT 0 20 40 60 80 100 0 3 6 9 12 15 18 21 Mos 73.0% 48.1% Patients at Risk, n Pembro + CT Pbo + CT OS(%)
- 68. Hiporexia Neutropenia Vómito Tos Disnea Astenia Rash Pirexia Edema Pembrolizumab más pemetrexed más platino Náuseas Anemia Fatiga Constipación Diarrea 30% - 56% 15% - 30% Algún grado de toxicidad: 99.8% Eficaz en: No-escamoso, metastásico Estudio KN 189 Gandhi L, NEJM, 2018 Anemia Neutropenia Trombocitopenia Astenia/fatiga Pneumonitis (4.4%) Diarrea Nefritis Rash Grado 3-5 Muertes tóxicas: 6.9% Hipotiroidismo Pneumonitis Hipertiroidismo R. Infusional Colitis Nefritis Hepatitis De interés especial 22.7%
- 69. Hiporexia Neutropenia Vómito Tos Disnea Astenia Rash Pirexia Edema Pembrolizumab más pemetrexed más platino Náuseas Anemia Fatiga Constipación Diarrea 30% - 56% 15% - 30% Algún grado de toxicidad: 99.8% Eficaz en: No-escamoso, metastásico Estudio KN 189 Anemia Neutropenia Trombocitopenia Astenia/fatiga Pneumonitis (4.4%) Diarrea Nefritis Rash Grado 3-5 Hipotiroidismo Pneumonitis Hipertiroidismo R. Infusional Colitis Nefritis Hepatitis De interés especial 22.7% Toxicidades de inmunoterapia Gandhi L, NEJM, 2018
- 70. Inmunoterapia más quimioterapia en PD-L1 <50%
- 71. KEYNOTE-189: First-line Pembrolizumab + CT vs Placebo + CT in Stage IV Nonsquamous NSCLC Randomized, double-blind, international phase III study Patients with previously untreated stage IV nonsquamous NSCLC; ECOG PS 0/1; any PD-L1 status; no actionable EGFR/ALK mutations; no symptomatic CNS mets or pneumonitis requiring tx (N = 616) Pembrolizumab 200 mg Q3W + Plt*/pemetrexed† Q3W (n = 410) Placebo Q3W + Plt*/pemetrexed† Q3W (n = 206) 4 cycles Pembrolizumab‡ + Pemetrexed† Q3W Placebo‡ + Pemetrexed† Q3W Stratified by PD-L1 TPS (≥ 1% vs < 1%), platinum agent (carboplatin vs cisplatin), smoking history (never vs former/current) Until PD or unacceptable toxicity; crossover from placebo allowed *Carboplatin AUC 5 or cisplatin 75 mg/mm2.†500 mg/m2. ‡Up to total of 35 cycles. Gandhi. NEJM. 2018;378:2078. Primary endpoints: OS, PFS by BICR Secondary endpoints: ORR, DoR, safety No PD No PD Slide credit: clinicaloptions.com
- 72. KEYNOTE-189: Frequency of PD-L1 TPS Categories Gandhi. NEJM. 2018;378:2078. Pembrolizumab + plt/pemetrexed Placebo + plt/pemetrexed Slide credit: clinicaloptions.com 50 45 40 35 30 25 20 15 10 5 0 Frequency(%) < 1% 1% to 49% ≥ 50% Not Evaluable 31.0% 30.6% 31.2% 28.2% 32.2% 34.0% 5.6% 7.3%
- 73. KEYNOTE-189: Survival by PD-L1 Tumor Proportion Score TPS < 1% TPS ≥ 50%TPS 1% to 49% 0 20 40 60 80 100 0 3 6 9 12 15 18 21 Mos OS(%) 127 63 113 54 104 45 79 32 42 21 20 6 6 1 0 0 HR: 0.59 (95% CI: 0.38-0.92) Pembro + CT Pbo + CT Patients at Risk, n Pembro + CT Pbo + CT 128 58 119 54 107 47 84 32 52 17 21 5 5 2 0 0 HR: 0.55 (95% CI: 0.34-0.90) Pembro + CT Pbo + CT 132 70 122 64 114 50 96 35 56 19 25 13 6 4 0 0 HR: 0.42 (95% CI: 0.26-0.68) Pembro + CT Pbo + CT 0 20 40 60 80 100 0 3 6 9 12 15 18 21 0 20 40 60 80 100 0 3 6 9 12 15 18 21 Mos Mos Slide credit: clinicaloptions.comGandhi. NEJM. 2018;378:2078. 61.7% 52.2% 71.5% 50.9% 73.0% 48.1% Pembro + CT Placebo + CT Events, % 38.6 55.6 mOS, mos (95% CI) 15.2 (12.3-NE) 12.0 (7.0-NE) Pembro + CT Placebo + CT Events, % 28.9 48.3 mOS, mos (95% CI) NR (NE-NE) 12.9 (8.7-NE) Pembro + CT Placebo + CT Events, % 25.8 51.4 mOS, mos (95% CI) NR (NE-NE) 10.0 (7.5-NE)
- 74. IMpower150: Addition of Atezolizumab to Carbo/Pac + Bevacizumab in Advanced NSCLC Randomized phase III study Patients with stage IV or recurrent, chemotherapy- naive nonsquamous NSCLC (PD on or intolerance to targeted agents allowed); available tumor tissue (N = 1202) Atezolizumab 1200 mg IV Q3W + Carboplatin/Paclitaxel (n = 510) Carboplatin/Paclitaxel Q3W + Bevacizumab 15 mg/kg IV Q3W (n = 336; control arm) Atezolizumab 1200 mg IV Q3W + Carboplatin/Paclitaxel Q3W + Bevacizumab 15 mg/kg IV Q3W (n = 356) Atezolizumab until PD or loss of benefit and/or bevacizumab until PD Atezolizumab Bevacizumab Atezolizumab + Bevacizumab Stratified by sex, PD-L1 expression, liver mets 4-6 cycles Reck. ESMO I-O Congress 2017. Abstr LBA1_PR. Kowanetz. AACR 2018. Abstr CT076. Socinski. NEJM. 2018;378:2288. Slide credit: clinicaloptions.com Maintenance therapy (no crossover allowed) Primary endpoints: PFS, OS Secondary endpoints: PFS (IRF), ORR, OS at Yrs 1 and 2, QoL, safety, PK
- 75. IMpower150: Updated PFS in ITT WT Population* (Coprimary Endpoint) Socinski. ASCO 2018. Abstr 9002. Slide credit: clinicaloptions.com Data cutoff: January 22, 2018. *ITT WT: patients without EGFR or ALK alterations; 87% of randomized patients. Atezolizumab + Carbo/Pac + Bev (n = 359) Carbo/Pac + Bev (n = 337) Median PFS, mos (95% CI) 8.3 (7.7-9.8) 6.8 (6.0-7.1) 6-mo PFS, % 66 56 12-mo PFS, % 38 20 18-mo PFS, % 27 8 HR: 0.59 (95% CI: 0.50-0.70; P < .0001) Median follow-up: ~ 20 mos Patients at Risk, n PFS(%) Mos 100 90 80 70 60 50 40 30 20 10 0 340 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 Atezolizumab + Carbo/Pac + Bev Carbo/Pac + Bev 359 337 336 323 315 294 301 263 293 244 267 215 234 180 213 148 190 127 168 103 154 89 146 78 125 61 112 50 85 35 80 29 69 21 68 18 53 14 50 13 37 6 33 6 24 5 20 5 12 1 11 1 6 3 1 1 1 + + + ++ ++ + + +++ ++ +++++ +++++++++++ + ++ + +++ ++++ ++ +++++ +++++ ++ + ++ ++ + ++ + +++++++ ++++ +++ + ++ ++ + + +++ +
- 76. IMpower150: Landmark OS in ITT Population (Including Patients With EGFR and ALK Aberrations) Clinically meaningful OS benefit with atezolizumab + bevacizumab + chemotherapy vs bevacizumab + chemotherapy was observed in all patients Socinski. ASCO 2018. Abstr 9002. Slide credit: clinicaloptions.com HR: 0.76 (95% CI: 0.63-0.93) Median follow-up: ~ 20 mos 100 90 80 70 60 50 40 30 20 10 0 OS(%) Mos 340 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 Atezolizumab + Carbo/Pac + Bev (n = 400) Carbo/Pac + Bev (n = 400) Median OS, mos (95% CI) 19.8 (17.4-24.2) 14.9 (13.4-17.1) 12-mo OS, % 68 61 18-mo OS, % 54 42 24-mo OS, % 45 36
- 77. IMpower150: OS by Subgroup Socinski. ASCO 2018. Abstr 9002. Slide credit: clinicaloptions.com Favors Atezolizumab + Carbo/Pac + Bev Favors Carbo/Pac + Bev *For prevalence, ITT WT (n = 696) used for PD-L1, liver metastases groups; ITT (n = 800) for rest. Median OS, Mos 25.2 20.3 17.1 13.2 19.8 19.8 NE 19.2 15.0 16.4 14.1 9.1 16.7 14.9 17.5 14.7 Subgroup PD-L1 high (TC3 or IC3) WT PD-L1 low (TC1/2 or IC1/2) WT PD-L1 negative (TC0 and IC0) WT Liver metastases WT No liver metastases WT ITT (including EGFR/ALK+) EGFR/ALK+ only ITT WT n (%)* 136 (20) 226 (32) 339 (49) 94 (14) 602 (86) 800 (100) 104 (13) 696 (87) 0.2 1.0 2.0 HR HR 0.70 0.80 0.82 0.54 0.83 0.76 0.54 0.78 ABCP BCP
- 78. Tratamiento de cáncer de pulmón SIN mutaciones “accionables” Escamoso
- 79. KEYNOTE-407: Carboplatin + Paclitaxel/nab-Paclitaxel ± Pembrolizumab in NSCLC Randomized, double-blind phase III trial Primary endpoint: PFS by RECIST v1.1 (BICR), OS Secondary endpoints: ORR and DoR by RECIST v1.1 (BICR), safety Paz-Ares. NEJM. 2018;379:2040. Slide credit: clinicaloptions.com Pembrolizumab + Carboplatin + Paclitaxel or nab-Paclitaxel 3-wk cycles x 4 (n = 278) Patients with untreated stage IV squamous NSCLC, ECOG PS 0/1, available tumor biopsy for PD-L1 assessment, no brain mets, and no pneumonitis requiring systemic steroids (N = 559) Stratified by PD-L1 TPS (< 1% vs ≥ 1%), taxane (paclitaxel vs nab-paclitaxel), region (east Asia vs other) Carboplatin AUC 6 Q3W, nab-paclitaxel 100 mg/m2 QW, paclitaxel 200 mg/m2 Q3W, pembrolizumab 200 mg Q3W. *Upon confirmation of PD and safety criteria by BICR, optional crossover could occur during combination or monotherapy. Placebo + Carboplatin + Paclitaxel or nab-Paclitaxel 3-wk cycles x 4 (n = 281) Pembrolizumab up to 31 cycles Placebo up to 31 cycles Pembrolizumab up to 35 cycles Crossover allowed* PD
- 80. KEYNOTE-407: OS (ITT) Paz-Ares. NEJM. 2018;379:2040. Slide credit: clinicaloptions.com MosPatients at Risk, n Pembro + CT CT OS(%) Median OS, Mos (95% CI) 15.9 (13.2-NE) 11.3 (9.5-14.8) 100 80 60 40 20 0 0 3 6 9 12 15 18 21 Pembro + CT CT HR: 0.64 (95% CI: 0.49-0.85; P < .001 ) 278 281 256 246 188 175 124 93 62 45 17 16 2 4 0 0
- 81. KEYNOTE-407: OS by Subgroup Paz-Ares. NEJM. 2018;379:2040. Slide credit: clinicaloptions.com Subgroup Overall Age Sex ECOG PS Region of enrollment PD-L1 tumor proportion score Choice of taxane 0.64 (0.49-0.85) 0.52 (0.34-0.80) 0.74 (0.51-1.07) 0.69 (0.51-0.94) 0.42 (0.22-0.81) 0.54 (0.29-0.98) 0.66 (0.48-0.90) 0.44 (0.22-0.89) 0.69 (0.51-0.93) 0.61 (0.38-0.98) 0.65 (0.45-0.92) 0.57 (0.36-0.90) 0.64 (0.37-1.10) 0.67 (0.48-0.93) 0.59 (0.36-0.98) HR (95% CI) CT BetterPembro + CT Better 0.1 0.5 1.0 < 65 yrs ≥ 65 yrs Male Female 0 1 East Asia Rest of world < 1% ≥ 1% 1% to 49% ≥ 50% Paclitaxel nab-Paclitaxel Deaths/Patients, n/N 205/559 88/254 117/305 167/455 38/104 48/163 157/396 34/106 171/453 73/194 129/353 76/207 53/146 140/336 65/223
- 82. KEYNOTE-407: PFS (ITT) Paz-Ares. NEJM. 2018;379:2040. Slide credit: clinicaloptions.com Mos PFS(%) Median PFS, Mos (95% CI) 6.4 (6.2-8.3) 4.8 (4.3-5.7) 100 80 60 40 20 0 0 3 6 9 12 15 18 21 Pembro + CT CT 278 281 223 190 142 90 57 26 23 12 5 4 0 0 0 0 HR: 0.56 (95% CI: 0.45-0.70; P < .001 ) Patients at Risk, n Pembro + CT CT
- 83. KEYNOTE-407: Infusion Reactions and irAEs Paz-Ares. NEJM. 2018;379:2040. Slide credit: clinicaloptions.com AEs of Interest in As-Treated Population,* n (%) Pembrolizumab† (n = 278) Placebo (n = 234) Any Grade Grade ≥ 3 Any Grade Grade ≥ 3 Any 80 (28.8) 30 (10.8) 24 (8.6) 9 (3.2) Hypothyroidism 22 (7.9) 1 (0.4) 5 (1.8) 0 Hyperthyroidism 20 (7.2) 1 (0.4) 2 (0.7) 0 Pneumonitis 18 (6.5) 7 (2.5)† 6 (2.1) 3 (1.1)† Infusion reaction 8 (2.9) 4 (1.4) 6 (2.1) 1 (0.4) Colitis 7 (2.5) 6 (2.2) 4 (1.4) 3 (1.1) Hepatitis 5 (1.8) 5 (1.8) 0 0 Severe skin reaction 5 (1.8) 3 (1.1) 1 (0.4) 1 (0.4) Hypophysitis 3 (1.1) 2 (0.7) 0 0 Thyroiditis 3 (1.1) 1 (0.4) 0 0 Nephritis 2 (0.7) 2 (0.7) 2 (0.7) 2 (0.7) *All randomized patients who received ≥ 1 dose; regardless of whether attributed to trial regimen or to be immune-related by investigator. †n = 1 (0.4%) grade 5 pneumonitis in each arm.
- 84. Immunotherapy Treatment Algorithm for NSCLC in 2019 NonsquamousSquamous Slide credit: clinicaloptions.com Pembrolizumab or Pembrolizumab + CT Pembrolizumab + Carboplatin/Pemetrexed -or- Chemotherapy Alone Pembrolizumab + Carboplatin/Pemetrexed Pembrolizumab or Pembrolizumab + CT Pembrolizumab + Carboplatin/Paclitaxel or nab-Paclitaxel Pembrolizumab + Carboplatin/Paclitaxel or nab-Paclitaxel PD-L1 ≥ 50% PD-L1 ≥ 1-49% PD-L1 < 1% Atezolizumab+ Carboplatin/Pemetrexed+ Bevacizumab
- 85. Supervivencia a largo plazo con inmunoterapia
- 86. LT OS & Impact of Early Response/Disease Control With Nivolumab in 2L+ NSCLC Figure 1. OS in all nivolumab-treated patients from CheckMate 003/ 063/ 017/ 057a 86 Nivolumab (N = 664) Median OS (95% CI), mo 10.3 (9.2, 11.9) 6 18 24 36 42 54 60 72 78 90 96 102 Months 12 30 48 66 84 108 62664 430 299 164 104 92 28 16 13 2 1 0214 123 82 16 4 1 46% 26% 17% 14% 100 0 40 60 80 20 0 OS(%) No. at risk Nivolumab aMedian duration of response in all patients with a CR/PR (n = 122) was 19.1 months (95% CI, 14.7−29.9). CI, confidence interval.
- 87. LT OS & Impact of Early Response/Disease Control With Nivolumab in 2L+ NSCLC Figure 2. OS with nivolumab vs docetaxel in CheckMate 017/ 057a 87 Nivolumab (n = 427) Docetaxel (n = 427) Median OS (95% CI), mo 11.1 (9.2, 13.1) 8.1 (7.2, 9.2) 427 264 145 84 45 34 1957 26 11 1 0 100 0 40 60 80 20 34% 14% 8% 5% 14%17% 48% 27% 427 280 205 150 84 70 55113 64 37 9 0 Nivolumab Docetaxel No. at risk Nivolumab Docetaxel Months 0 6 18 24 30 42 48 6012 36 54 66 OS(%) aIn the nivolumab and docetaxel arms, 4.0% (17/427) and 10.1% (43/427) of patients, respectively, received subsequent immunotherapy (includes 23 patients who crossed over from the docetaxel arm to the nivolumab arm); 5 of 19 patients (26.3%) originally randomized to docetaxel and still alive at database lock received immunotherapy as subsequent therapy.
- 88. LT OS & Impact of Early Response/Disease Control With Nivolumab in 2L+ NSCLC Figure 5. OS from time of response with nivolumab vs docetaxel in CheckMate 017/ 057a 88 Nivolumab (n = 83) Docetaxel (n = 48) Median OS post response (95% CI), mo NR (26.4, NR) 16.5 (11.8, 22.1) Median DOR (95% CI), mo 23.8 (11.4, 36.1) 5.6 (4.4, 7.0) OSpostresponse(%) Months 65% 33% 23% 12% 54%57% 87% 65% Nivolumab Docetaxel 83 78 71 62 47 46 3653 40 17 2 48 45 31 22 15 11 616 10 3 0 0 0 No. at risk Nivolumab Docetaxel 100 0 6 18 24 30 42 48 60 0 40 60 80 20 12 36 54 66 aOS was calculated from the time of response (CR/PR) for each responder.
- 89. Conclusiones 89 mNSCLC – candidato a tratamiento Mutación accionable Terapia blanco-dirigida PD-L1 ≥ 50% Considerar pembrolizumab PD-L1 <50% - Alta carga tumoral Quimio + IO Sí Sí Sí Sí No No mEGFR Lux-Lung 3/6 FLAURA RELAY ALK+ ALEX PROFILE1014 KEYNOTE-24 No-escamosos IMpower150 KEYNOTE-189 Escamosos KEYNOTE-407 Arte
- 90. @onconerd