Manejo de pacientes con EGFR mutado a la progresio n tras una 1 a li nea con EGFR-TKI Dra. E.Felip, Hospital Vall Hebrón, Barcelona Dra. N.Reguart, Hospital Clínic, Barcelona
Caso clínico Mujer de 44 años, madre de 2 hijos, sin antecedentes patológicos de interés. Nunca fumadora Primer síntoma en Marzo 2011 con dolor dorsal En Septiembre 2011 se diagnostica de adenocarcinoma pulmonar con afectación ósea metastásica (E IVb) Estudios genéticos: Del Exon 19 EGFR Septiembre 2011 inicia primera línea de tratamiento con Gefitinib con primera valoración de RP Seis meses después (Abril 2012), presenta progresión asintomática de las adenopatias mediastínicas con estabilidad a nivel óseo Biopsia de las adenopatias mediastínicas: Del Exon 19, T790M+
Caso clínico Que tratamiento te plantearias? 1.EC con inhibidor T790M 2.Suspender gefitinib e iniciar quimioterapia 3.Mantener gefitinib e iniciar quimioterapia 4.Mantener gefitinib y realizar RDT mediastínica
Caso clínico La paciente realizó RDT mediastínica obteniéndose control local de la enfernedad y continuó con Gefitinib con respuesta mantenida. Diez meses después (Febrero 2013) presenta progresión ósea multifocal sintomática
Caso clínico Que tratamiento te plantearias? 1.Carbo-paclitaxel-bevacizumab con gefitinib 2.Carbo-paclitaxel-bevacizumab 3.Cisplatino-pemetrexed 4.Cisplatino-pemetrexed con gefitinib
Caso clínico Se suspendió el tratamiento con gefitinib La paciente realizó tratamiento con cisplatino-pemetrexed x 6 ciclos que completó en Junio 2013 con valoración de RP
Types of EGFR TKI resistance in EGFR+ NSCLC PRIMARY DE NOVO RESISTANCE ACQUIRED RESISTANCE TKI No response at all TKI TKI Response and regrowth 10-30% of EGFR+ Diverse molecular causes of resistance: T790M+, EMT, ALK, BIM, KRAS, Met Lee et al, Annals of Oncology 2013 Jackman D. et al. JTO 2010
Diverse Clinical Patterns of EGFR-TKI failure Dramatic Symptomatic Progression Baseline 4M PR 8M Symptomatic PD Gradual Asymptomatic Progression Baseline 11 M 29 M 41 M CR PD First Symptom Local Progression Baseline 3M 10M PR 10.13 Local PD Case Reports from N. Reguart
EGFR+ Resistant Lung Tumors Endorse High Heterogeneity T, T790M mutation; M, MET gene amplification; m, MET gene copy number gain Suda, et al, CCR 2010; Chmielecki, Sci Transl Med 2011
EGFR+ tumors with acquired resistance may encompass different diseases challenging the subsequent treatment approaches 1. When do we have to stop the TKI and consider another treatment strategy?
RECIST
New Definition of Prognostic EGFR TKI-failure Models Variables: Duration of disease control Evolution of tumor burden (VTD) Clinical symptoms Groups: Dramatic progression Gradual progression Local progression Yang J.J, Lung Cancer 2013
Alternative Management Algorism based on Clinical Factors Rebiopsy T790M Rebiopsy T790M? No Rebiopsy Yang J.J, Lung Cancer 2013
Local Intervention for Oligoprogressive Disease 45% could delay change of therapy > 3mo after RECIST PD 21% delay change of therapy > 12mo Patients delaying change of therapy more commonly had no cancer-related symptoms at PD and had no new metastases Median TTP 10 mo Median OS 41 mo Oxnard, ASCO 2012;, Yu HA et al. JTO 2013
RECIST v 1.1 PD ASPIRATION Trial: Phase II of continued Erlotinib Beyond RECIST progression in Asian EGFR+ patients based on clinical factors Asian advanced EGFR + NSCLC 1 measurable lesion ( 10mm) EGFR+ PS 0-2 N=204 Erlotinib 150 mg/d vo QD Primary endpoint: PFS Secondary endpoints: ORR, DCR, OS and safety * Pts continuing erlotinib who present with second RECIST PD will discontinue. GRADUAL PROGRESION Slow PD (>6 months of PR/SD) Asymptomatic minimal PD Brain mets controlled locally. DRAMATIC PROGRESSION Extracranial PD with symptoms Rapid PD and/or worsening of PS Life-threatening complications Continue Erlotinib* Discontinue Erlotinib Park K. et al, J Clin Oncol 30, 2012 (suppl; abstr TPS7614), (NCT01310036)
EGFR+ tumors with acquired resistance may encompass different diseases challenging the subsequent treatment approaches 1. When do we have to stop the TKI and consider another treatment strategy? 1. Do we have to maintain the TKI if chemotherapy is started?
Dramatic Progression: Role of Chemotherapy and TKI?? Oxnard et al. Clin Cancer Res 2011
Oncogene Addiction In oncogenic tumors, should targeted therapy be stopped? Other tumors such as prostate (hormonotherapy) or breast (trastuzumab) targeted treatment is maintained after PD PROSTATE GNRH GNRH + CHEMO BREAST HER2+ TRASTUZUMAB + CHEMO A TRASTUZUMAB + CHEMO B LUNG EGFR+ ERLOTINIB ERLOTINIB + CHEMO? Chaft J.E, CCR 2011
In vitro sinergistic effect of chemotherapy with TKI in T790M+ resistant models EGFR-mutant cell lines with acquired resistance are more sensitive to chemotherapy when given with TKI Chmielecki J. et al Sci Transl Med. 2011
Rational to sustain TKI inhibition: Disease Flare-Up Flare after EGFR TKI cessation in 23% (n=14/61) leading to hospitalization or death The median time to disease flare after TKI discontinuation was 8 days (range 3 21). Chaft J.E, CCR 2011
Dramatic Progression: Role of Chemotherapy and TKI Oxnard et al. Clin Cancer Res 2011
In vitro restoration of TKI sensitivity after drug holiday T790M+ After TKI withdrawal, resistant cells overcome again sensitive through clonal selection T790M+ Chmielecki J. et al Sci Transl Med. 2011
Chemotherapy +/- TKI Author Study N (C/C+TKI) Goldberg, et al. Retrospective 78 (44/34) Halmos, et al. Phase II 46 (24/22) Faehling, et al. Retrospective 41 (16/25) Mut + (%) RR % (C vs C+TKI) PFS, OS (C + C+TKI) all 18 vs 41 ns 85% (17/14) 57% (9/4) - ns - Favours C+TKI Retrospective data with few patients Selection in some cases base on TKI sensitivity not EGFR mutation Toxicity might increase with combination strategy (Halmos, ASCO 2013) Goldberg, Oncologist 2013, Halmos, ASCO 2013, Faehling, Lung Cancer 2013
Double-blind Iressa Mutation Positive Multicentre Treatment Beyond Progression: IMPRESS Trial Advanced EGFR + NSCLC Failure to Gefitinib > 6 mo No prior chemotherapy ECOG 0/1 EGFR+ Random N=250 EU & Asia Primary endpoint: PFS Secondary endpoints: OS, RR, DCR Symptoms & QoL Pemetrexed, IV, 500mg/m2 Cisplatin, IV, 75mg/m2 q 21 days x 6 cycles plus Gefitinib 250 mg QD Pemetrexed, IV, 500mg/m2 Cisplatin, IV, 75mg/m2 q 21 days x 6 cycles plus placebo Mok T, Soria J.C, NCT01544179
Post-Progression Erlotinib For Erlotinib Resistance: PREFER Trial Advanced EGFR + NSCLC Progression on first line Erlotinib EGFR+ PS 0-2 Stratification Factors: EGFR mut type exon 19 vs 21 TTP on TKI (< 1 y vs > 1 y) PS 0-1 vs 2 Random N=180 Carbo (AUC 5, 6) pemetrexed 500 mg/m2 x 4 cycles + Erlotinib Carbo (AUC 5, 6) pemetrexed 500 mg/m2 x 4 cycles Manteinance Pemetrexed+ Erlotinib Manteinance pemetrexed Primary endpoint: PFS Secondary endpoint: ORR, Non-progression 12 w OS, safety PI Leora Horn, Vanderbilt
Many Other Unsolved Questions.. When do we have to re-biopsy for T790M assessment? at RECIST progression or at clinical symptomatic progression? When do we have to consider a resistant-molecular-targeted T790M drug inhibitor? Always or only at dramatic progression?
Caso clínico En Agosto 2013 la paciente presenta inestabilidad cefálica y aumento de los dolores óseos Un TAC evidencia progresión de la enfermedad pulmonar y ósea con aparición de metastasis hepáticas, SNC y letálides cutáneas La paciente realiza radioterapia holocraneal Una rebiopsia de LOE hepática demuestra Del Exon 19, T790M+
Caso clínico Que tratamiento te plantearias? 1.Segunda línea quimioterapia 2.Inhibidor irreversible TK 3.EC con inhibidor T790M 4.Reinducción con inhibidor reversible TK
Caso clínico Se valora a la paciente para EC fase I AURA con inhibidor selectivo T790M, AZD9291 En Septiembre 2013, se inicia tratamiento a dosis de 240 mg/dia (cohorte escalada). La paciente presenta ECOG 1, sin sintomatologia neurológica asociada A las 48h de tratamiento objetiva desaparición de la letálide cutánea Primera valoración RECIST a los dias de tratamiento es de RP Última valoración Febrero 2014, RP máxima mantenida con disminución 83% de las lesiones diana
Caso clínico Eventos Diagnóstico ADC EGFR+ 1ª PD Asintomática Ganglionar T790M+ 2ª PD Sintomática ósea 3ª PD Sintomática hepática/snc T790M+ Cronología Sept 11 Abr 12 Febr 13 Agosto 13 Alive on treatment Ttos RDT mediastínica GEFITINIB QTP WBRT AZD9291 ongoing Mejor respuesta RP RP RP
Mechanisms of resistance in EGFR mutant NSCLC Yu HA. Clin Cancer Res 2013;19:2240-2247
Acquired point mutation resulting in threonine-tomethionine amino acid change at positive 790 What do we know about T790M? ~50% of p who develop AR have T790M that coexist with the primary EGFR mut Kobayashi NEJM 06
Incidence of de-novo T790M Study Technique # cases / #EGFRm Inukai, CR 06 Sequencing Enriched PCR 1/98 (1%) 4/98 (4%) Sequist, JCO 08 Sequencing 2/34 (6%) IPASS, NEJM 09 SARMS 7/261 (3%) Maheswaran, NEJM 09 SARMS 10/36 (28%) Rosell, CCR 14 Taqman + PNA probe 45/95 (65%) Hata, JTO 10 PNA-LNA clamp 3/318 (1%) Direct sequencing might underestimate the prevalence of T790M
Side-roads EGFR pathways shown to be activated - MET amplification - HGF overexpression - EGFR amplification - PIK3CA mut - PTEN loss - FGRF overexpression - AXL overexpression - HER2 amplification - CRKL amplification - NFkB activation Yano JTO 2011; Sos Cancer Res, 2011; Ware PLoS one 2010, Zhang Nat Gen 2012; Ohashi PNAS 2012; Tabara Plos one 2012; Ng Nat Med 2012
MET amplification as mechanism of AR to EGFRTKI In up to 20% of specimens which have developed AR Can coexist with T790M Cells with EGFRTKI resistance rely on MET signaling to activate AKT through ERBB3-mediated activation of PI3K MET amplification observed at low frequency pre-treatment Engelman Science 07; Engelman, CCR 08; Turke Cancer Cell 10
Other EGFRTKI resistance processes - Epithelial to mesenchimal transition and histological transformation to SCLC o Histological transformation into SCLC in 14% of EGFR mutant lung cancer p (5 of 37) associated with a response to treatment with standard SCLC CT (Sequist Science Translational Medicine 11) - Anti-apoptotic pathway (BIM)
Role of BIM important in apoptotic mechanism in cells that depend on survival in targeted treatment BIM (BH3 only protein): activates cell death by opposing the function of anti-apoptotic proteins of the BCL2 family or binding to the pro-apoptotic proteins of the BAX family BIM, a critical mediator of targeted therapy-induced apoptosis Li Med Oncol 11
Clinical studies for acquired resistance Study Agent Phase RR % TTP/PFS Riely. CCR 07 Gefi/Erl & Everolimus II 0% 3m Reguart. Lung Cancer 14 Erl &Vorinostat I/II 0% NR Janjigian. CCR 11 Erlotinib & cetuximab II 0% 3m Sequist. JCO 10 Neratinib (2gen TKI) II 3% 3.6m Pietanza. JTO 12 XL647 (2gen TKI) II 3% 3.5m Sequist. JCO 10 IPI-504 (HSP90i) II 4% 2.8m Wakelee. ASCO 10 Erl & Cabozantinib I/II 8% NR Miller. Lancet O. 10 Afatinib (2gen TKI) III 7% 3.3m Felip. ESMO 12 AUY922 (HSP90i) II 20% NR Janjigian. ESMO 12 Afatinib & Cetuximab I/II 30% 4.7m Soria. WCLC 13 CO-1686 (3gen TKI) I 67% NR Ranson. ECCO 13 AZD9291 (3gen TKI) I 46% NR
Cabozantinib (Exelixis/BMS) MET inhibitors A potent inhibitor of MET and VEGFR2 that also inhibits RET, KIT, AXL and FLT Phase Ib/II of cabozantinib +/- erlotinib, encouraging activity in erlotinib-pretreated population, including PR in one p with MET amplification (Wakelee H, ASCO 2012) Responses to cabozantinib in p with RET fusion-positive lung ADC (Drilon A, Cancer Discov 2013) INC280 (Novartis) An oral highly selective TKI of c-met receptor Phase I trial of INC280/gefitinib in p with EGFR mutation and METpositive (IHC) expression, ongoing
Onatuzumab/erlotinib in advanced NSCLC Phase II o Tumor tissue evaluated by IHC (using CONFIRM anti-met monoclonal antibody, Ventana); MET-positive defined as a score of 2+ or 3+ o P with MET-positive tumors seem to benefit from onatuzumab/erlotinib Phase III, erlotinib +/- onartuzumab, in MET-positive, negative Stop randomized trial in 1 st line EGFR-mutated, MET-positive p, comparing erlotinib/onartuzumab vs erlotinib/placebo
Best % change in target lesions AUY922 response: EGFR-mutant patients (n=25 /35) 100 80 60 40 EGFR-mutant (n=35) ORR (any PR) 7 (20%) DCR (CR/PR or SD) 20 (57%) PFS (18 weeks [95% CI]), % 35.2 (18.7, 52.2) 20 0-20 -40-60 -80 * * * * * * -100 Felip ESMO 12
EGFRTKI-resistant p treated with cetuximab-afatinib: update Confirmed PR 30% (29 of 96 p), identical in T790M subgroups Median duration of response 8 mo Clinical benefit (PR or SD) 75% (72 of 96 p) Janjigian ESMO 2012
AZD9291 preclinical data AZD9291 is a potent oral, irreversible inhibitor of EGFR that contains EGFR- TKI sensitising (EGFR m+) and resistance mutations (T790M) Model Wildtype A431 cells EGFRm+ PC9 cells EGFRm+/ T790M H1975 cells AZD9291 IC50 μm 0.411 0.012 0.0115 AstraZeneca data on file
AZD9291 Ranson. ECCO 2013
Summary Most patients with EGFR mutation respond to targeted agents but all progress later Potential molecular mechanisms of resistance have been determined in several studies Some of the known resistance mechanisms are targetable Importance of repeat biopsies - To understand the underlying biology - To direct our p to the appropriates clinical trials ESMO SYMPOSIUM ON SIGNALING PATHWAYS IN CANCER
Response to TKI according to Tumour Heterogeneity Chmielecki, Sci Transl Med 2011
Clinical & Molecular Heterogeneity of Acquired Resistance Diverse Molecular Mechanisms of Acquired Resistance Diverse Clinical Patterns of Progression Yu, H, et al. CCR 2013, Gandara D., Clinical Lung Cancer 2014