T790M como marcador predictivo de respuesta Mariano Provencio
CASO 1 Provencio et al submitted.
Provencio et al submitted.
C + 450 días: Progresión Taponamiento cardiaco Distress respiratorio ingreso por Urgencias Sensitizing minimamente elevada T790M negativa
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Noviembre 2016 T790M: plasma: negativa T790M: líquido pericárdico: positiva Osimertinib Marzo 2017
At the time of progression, about 60% of patients (regardless of race or ethnic) are found to have a Thr790Met point mutation (T790M) in the gene encoding EGFR. The presence of T790M variant reduces bindings to the ATP binding pocket, reducing EGFR-TKI-mediated inhibition of downstream signaling. There are minor clones with T790M + with low allelic frequencies identified in naïve tumors very rare: T790M in patients with a germline polymorphism associated with familial cancer syndromes
Proof-of-concept clinical studies validating AZD9291 as a mutant-selective EGFR kinase T790M inhibitor. 2014 by American Association for Cancer Research Darren A.E. Cross et al. Cancer Discovery 2014;4:1046-1061
All the patients: at least one prior EGFR tyrosine kinase inhibitor and 80% prior chemotherapy ORR: 51% (IC 95%, 45-58) Disease Control Rate: 84% (95% CI, 79-88)
ORR T790M +: 61% (95% CI, 52-70) DCR: 95% (95% CI, 90-98) ORR T790M - : 21% (95% CI, 12-34) DCR: 61% (95% CI, 47-73)
T790M +: median progression-free survival: 9.6 months (maturity:30%) 88% response > 6 months
NEJM 2017
Response Rate: AZD: 71% Cis-Pem: 31%
T790M status is associated with outcome Patients with T790M + status have dramatically longer PFS with Osimertinib Oxnard GR, et al. JCO 2016
Median age at diagnosis 61 years (30-83) Sex Women 23 56% Men 18 44% Smoking status Former/quit 19 46.34% Never 22 53.66% Histology Adenocarcinoma 39 95.12% squamous cell carcinoma 2 4.88% UICC Stage III 4 9.76% IV 37 90.24% EGFR mutation exon 19 deletion 24 58.54% exon 20 insertion 3 7.32% G719X 4 9.76% L858R 10 24.39% Treatmet 1st line TKI treatment 37 90.24% Gefitinib 12 32.43% Erlotinib 20 54.05% Afatinib 5 13.51% 2nd line TKI treatment 4 2% AZD9291 1 25% Afatinib +cetuximax 1 25% Erlotinib+Pemetrexed 1 25% Gefitinib+Pemetrexed 1 25% Tumor Mutation PFS (months) deletion exon 19 13.5 G719X 7.5 L858R 7 insertion exon 20 5.5 Overall 10 Patient outcome N Positive plasma T790M (N) P Increase in EGFR sensitizing mutation Progressive disease 25 17 <0.0005 23 <0.0005 Other 16 1 5 P Provencio M, & Romero A et al submitted.
Provencio et al submitted.
Provencio M. & Romero A et al submitted.
Intra-tumor Spatial and Temporal Heterogeneity contributed to the Complexity of Resistant mechanism of EGFR-TKIs EGFR M only 70%- 80% Around 20% both EGFRM and other mutations Around 20%-30% EGFR mutants presented heterogeneity. Tumor heterogeneity contributes to drug resistances 46% of EGFR-TKIsresistance mutations are heterogeneous(co-existence of T790M and other drugresistance genes ) Meacham CE,et al. Nature. 2013 Sep 19;501(7467):328-37 ASCO ANNUAL MEETING 2016 Jake Chabon
Tissue, plasma, and urine testing identify unique subsets of T790M+ patients that are responsive to rociletinib Urine and plasma testing combined identify more T790M+ cases than tumor alone Tissue (therascreen) 170 T790M-positive cases 5 21 19 100 5 16 4 Plasma (Trovera) Urine (Trovera) 174 matched tissue, plasma and urine specimens Positive by any one specimen type Positive by plasma and urine combined % T790M positive 97.7 94.8 Negative/invalid by all three specimens 2.3 Positive by tissue 83.3 Positive by plasma 81.6 Positive by urine 79.9 Investigator-assessed objective response rate is not significantly different between T790M+ patients detected by liquid versus tumor biopsy (ORR 33-43%; 95% CI, 25-51%) Abstract 4637: A highly sensitive next-generation sequencing platform for detection of NSCLC EGFR T790M mutation in urine and plasma - H. Wakelee
Non-invasive urine and plasma T790M detection is highly sensitive EGFR T790M Tissue Positive Negative Inadequate* Total Positive 121 8 13 142 Plasma Negative 21 5 3 29 Invalid* 3 0 0 3 Total 145 13 16 174 Specimen Type Sensitivity (%) 95% CI Plasma (Trovera) 83.4 (121/145) 76.4-89.1 Tissue Plasma (BEAMing) 81.5 (106/130) 73.8-87.8 EGFR T790M Positive Negative Inadequate* Total Urine (Trovera) 82.1 (119/145) 74.8-87.9 Positive 119 9 11 139 Combined Plasma and Urine (Trovera) 96.6 (140/145) 92.1-98.9 Urine Negative 25 4 5 34 Invalid* 1 0 0 1 Total 145 13 16 174 Abstract 4637: A highly sensitive next-generation sequencing platform for detection of NSCLC EGFR T790M mutation in urine and plasma - H. Wakelee
Duration of Response and Progression-Free Survival:<br />Results Independent of Sample Type Used to Identify T790M Positivity Presented By Heather Wakelee at 2016 ASCO Annual Meeting
Plasma and tumor genotyping can have complementary roles for T790M testing 23% inadequa te tissue Conventional paradigm: 3 weeks Alternate paradigm: 3 days
T790M Clara relación entre tratamiento específico y marcador Aumento supervivencia: osimertinib y T790M, sigue la senda de EGFR y TKIs Test necesario en todas las progresiones de EGFR Debe tenerse en cuenta heterogeneidad de la enfermedad Las determinaciones de distintos fluidos o tejidos pueden ser complementarias y no influyen en la supervivencia
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Gracias!! mprovencio.hpth@salud.madrid.org
PFS by tumor and plasma T790M Osimertinib All patients with plasma information Oxnard GR, et al. JCO 2016
PFS by tumor and plasma T790M Osimertinib All patients with plasma information Patients with T790M plasma negative In plasma T790M negative: tumor genotyping can distinguish patients with better or worse outcomes Oxnard GR, et al. JCO 2016
PFS by tumor and plasma T790M Osimertinib Patients with T790M plasma negative All patients with plasma information also in T790M positive cases Patients with T790M plasma positive Oxnard GR, et al. JCO 2016