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SESSIONE IV - Oncogene-addicted NSCLC:
Criteri di risposta durante terapie con TKI:
criteri clinici o molecolari?
Emilio Bria
U.O.C. Oncologia Medica, U.O.S. Neoplasie Toraco-Polmonari,
Comprehensive Cancer Center,
Fondazione Policlinico Universitario Agostino Gemelli IRCCS,
Università Cattolica del Sacro Cuore, Roma
emilio.bria@unicatt.it
Roma, 20 Maggio 2019
Disclosures • Advisory Boards / Honoraria / Speakers’ fee / Consultant for: – MSD, Astra-Zeneca, Celgene, Pfizer, Helsinn, Eli-Lilly, BMS, Novartis, Roche • Research Support / Grants from: – A.I.R.C. (Associazione Italiana Ricerca sul Cancro) – I.A.S.L.C. (International Association for the Study of Lung Cancer) – L.I.L.T. (Lega Italiana per la Lotta contro i Tumori) – Fondazione Cariverona – Astra-Zeneca – Roche – Open Innovation
Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Presentation Outline: Response Criteria
• Clinical Response Criteria:
– Objective Response Rate (ORR)
– Symptoms Improvement
• Pathological
– pCR (for neoadjuvant approach)
– MPR (Major Pathological
Response)
• Molecular
– ctDNA
– Driver Gene Clearance
Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Presentation Outline: Response Criteria
• Clinical Response Criteria:
– Objective Response Rate (ORR)
– Symptoms Improvement
• Pathological
– pCR (for neoadjuvant approach)
– MPR (Major Pathological
Response)
• Molecular
– ctDNA
– Driver Gene Clearance
Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
‘Operative’ Classification according to Molecular Biology
ONCOGENE Addiction NON-ONCOGENE ADDICTION
[‘Stupid’ Disease] [‘Smart’ Disease]
• Single Dominant Driver • Multiple Drivers & Passengers
• Small Mutational Load (LOW Tumor Mutation • Large Mutational load (HIGH Tumor Mutation
Burden) Burden)
• Targeted TKIs COULD work • (Un)Targeted TKIs are NOT effective
• Immunotherapy MAY NOT • Immunotherapy MAY effective
• Low Early Resistance Rate • High Early Resistance Rate (common/frequent)
• Always Late Acquired Resistance (same/other • Few Late Acquired Resistance (long-term
pathways) survivors, cured patients?)
• Traditional Intermediate End-points MAY work as • Traditional Intermediate End-points does NOT
surrogate (in absence of cross-over) correlate with efficacy
Molecular Biology Behind is crucial for the overall understanding of the
clinical behavior of tumors
Adapted from G. Sledge, ASCO 2011
Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
‘Operative’ Classification according to Molecular Biology
ONCOGENE Addiction NON-ONCOGENE ADDICTION
IFCT (France) [N=13,425 pts]
[‘Stupid’ Disease] [‘Smart’ Disease]
• Single Dominant Driver • Multiple Drivers & Passengers
• Small Mutational Load (LOW Tumor Mutation • Large Mutational load (HIGH Tumor Mutation
Burden) Burden)
• Targeted TKIs COULD work • (Un)Targeted TKIs are NOT effective
• Immunotherapy MAY NOT • Immunotherapy MAY effective
• Low Early Resistance Rate • High Early Resistance Rate (common/frequent)
• Always Late Acquired Resistance (same/other • Few Late Acquired Resistance (long-term
pathways) survivors, cured patients?)
• Traditional Intermediate End-points MAY work as • Traditional Intermediate End-points does NOT
surrogate correlate with efficacy
Barlesi F et al, Lancet 2016
Adapted from G. Sledge, ASCO 2011
Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Response Criteria: EGFR De-addiction
Overall Activity Lynch T et al,
(Overall Response Rate (ORR), RECIST) NEJM 2005
RCTs of TKIs vs. Firs-Line Chemo
Example: EURTAC (Erlotinib vs.
Chemo) Watefall Plot
Pilotto S et al, Crit Rev Oncol Hem 2014 Rosell R et al, Lancet Oncol 2012
Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
(Clinical) Response: Symptoms and QoL
HRQoL Enhances Understanding of Treatment Benefits
Gefitinib vs. Chemotherapy: Quality of Life (IPASS) for Pts with EGFR Mutation
Gefitinib (n=131) Carboplatin / paclitaxel (n=128)
p
Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
(Clinical) Response: Symptoms and QoL
LUX-Lung 3: Afatinib vs. Cisplatin-Pemetrexed in Pts with EGFR Mutation
Dyspnea
Yang J et al, JCO 2013
Perol M, WCLC 2018
Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Response Criteria: Symptoms and QoL
Coherent Results Between
Symptoms Improvement and (Radiological) Response
Shaw A et al, NEJM 2013Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Response Criteria: Symptoms and QoL
Coherent Results Between
Symptoms Improvement and (Radiological) Response
Solomon B et al, NEJM 2014Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Consistent Activity of Crizotinib (ORR) Across
Developmental Phases (from Phase 1 to 3)
Phase 1 Phase 2 Phase 3 Phase 3 Phase 3
Caccese M et al, Exp Opinion Pharm 2016Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
TKIs Generation according to EGFR-binding and selectivity
GEFITINIB AFATINIB OSIMERTINIB
ERLOTINIB DACOMITINIBCriteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Do newer EGFR TKIs hit the target harder?
Activity Profiles of EGFR Inhibitors IC50 [EGFR phosphorylation in vitro]
H1975 PC-9 VanR PC-9
(T790M/L858R) (ex19del/T790M) (ex19del)
2 hours 3 days 2 hours 3 days 2 hours 3 days
Osimertinib 15 11 6 40 17 8
Dacomitinib 40 335 6 531 0,7 0,4
Afatinib 22 483 3 679 0,6 0,8
Erlotinib 3102 6962 741 4232 7 23
Gefiinib 6073 6165 1262 5778 6 28
100 Osimertinib
90
Dacomitinib
80
70 Afatinib
60 Erlotinib
50
Gefiinib
40
30
20
10
0
2 hours 3 days 2 hours 3 days 2 hours 3 days
Janne P, ESMO-ASIA 2015 Cross DAE et al, Cancer Disc 2014Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
FLAURA: Response and Symptoms
Changes in key patient-reported symptom scores over time from
baseline until randomized treatment discontinuation (MMRM analysis)
Ramalingam S et al, ESMO 2017; Ohe Y et al, ESMO-ASIA 2017
Soria JC et al, NEJM 2017; Ekman S, ELCC 2018Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
ARCHER: Response and Symptoms
HRQoL Enhances Understanding of Treatment Risk-Benefit Balance
Archer 1050 Trial: Dacomitinib vs. Gefitinib
OS
Wu et al., Lancet Oncol 2017; Mok, JCO 2018
Perol M, WCLC 2018Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
ARCHER: Response and Symptoms
HRQoL Enhances Understanding of Treatment Toxicity
ALEX Trial: Alectinib vs. Crizotinib
ORR Crizotinib Alectinib
(N=151) (N=152)
Change from baseline in tolerability outcomes
Resp. Pts, ORR (%) 114 (76) 126 (83)
Median DOR (mo.) 11.1 NR
Peters S et al, NEJM 2017
Pérol M et al, ELCC 2018
Perol M, WCLC 2018Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Presentation Outline: Response Criteria
• Clininical Response Criteria:
– Objective Response Rate (ORR)
– Symptoms Improvement
• Pathological
– pCR (for neoadjuvant approach)
– MPR (Major Pathological
Response)
• Molecular
– ctDNA
– Driver Gene ClearanceCriteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Neoadjuvant Erlotinib vs. Chemotherapy [CTONG1103]
Randomized, Phase II Study
Improvement in ORR was determined as follows:
• ORR: from 36% (‘Chest’ trial) to 70%, alpha 5%, power 80%
Zhong W et al, ESMO 2018Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Neoadjuvant Erlotinib vs. Chemotherapy [CTONG1103]
Expected %
• No pCR;
• Lower PR than advanced disease; too few courses? Different disease? Zhong W et al, ESMO 2018Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Neoadjuvant Erlotinib vs. Chemotherapy [CTONG1103]
• No significant difference in Nodal Clearance and Resection
Zhong W et al, ESMO 2018Criteri di risposta durante terapie con TKI: criteri clinici o molecolari? Neoadjuvant Erlotinib vs. Chemotherapy [CTONG1103] Pataer A, et al. J Thorac Oncol 2012 Hellmann MD et al, Lancet Oncology 2014 Zhong W et al, ESMO 2018
Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Neoadjuvant Erlotinib vs. Chemotherapy [CTONG1103]
Pathological Regression (%) Patient’ Case (receiving Erlotinib), pathological
evaluation revealed:
• Much higher proportion of TILs
• Significantly less tumor cells
• Patient disease-free for 27 months
Zhong W et al, ESMO 2018Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Neoadjuvant Erlotinib vs. Chemotherapy [CTONG1103]
Secondary Endpoint: PFS （ITT population） PFS according to Subgroups
Zhong W et al, ESMO 2018Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Presentation Outline: Response Criteria
• Clininical Response Criteria:
– Objective Response Rate (ORR)
– Symptoms Improvement
• Pathological
– pCR (for neoadjuvant approach)
– MPR (Major Pathological
Response)
• Molecular
– ctDNA
– Driver Gene ClearanceCriteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Detection of MRD Using ctDNA in Lung Cancer
Proposed design for clinical trial evaluating tailored treatment based on circulating tumor DNA–
based detection of minimal residual disease (MRD).
Chae YK et al, J Thor Oncol 2018Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Detection of MRD Using ctDNA in Lung Cancer
Summary of Clinical Data Supporting Use of ctDNA in Detecting Minimal Residual Disease
ctDNA, circulating tumor DNA; Ref., reference; CAPP-Seq, cancer personalized profiling by deep sequencing; SCC, squamous cell
carcinoma; AC, adenocarcinoma; SNV, single-nucleotide variation; NGS, nextgeneration sequencing; BEAMing, a term formed
from the words beads, emulsion, amplification, and magnetics technique.
Chae YK et al, J Thor Oncol 2018Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Early Detection of Molecular Residual Disease by ctDNA Profiling
Chaudhuri AA et al, Cancer Disc 2017Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Early Detection of Molecular Residual Disease by ctDNA Profiling
Correlation between ctDNA concentration with Pretreatment ctDNA concentration in stage I (n = 7)
pretreatment metabolic tumor volume (MTV) by PET-CT in and stage II–III (n = 30) patients with lung cancer
patients with detectable ctDNA (n = 37)
Chaudhuri AA et al, Cancer Disc 2017Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Outcome according to ctDNA during POST-TREATMENT
SURVEILLANCE
PFS - Ever positive (n=20) vs. never positive (n=17). DFS - Ever positive (n=20) vs. never positive (n=17).
[Landmark analysis from the 1st post-treatment blood draw] [Landmark analysis from the 1st post-treatment blood draw]
Chaudhuri AA et al, Cancer Disc 2017Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Next Wave of Adjuvant trials focusing on MRD
Time to ctDNA detection and Time to Imaging Example of patient with stage IIIB NSCLC with equivocal
surveillance imaging and undetectable posttreatment ctDNA
PD from the end of treatment who achieves long-term survival
[for all patients with PD by RECIST 1.1 (n=18); HR = 2.4]
Chaudhuri AA et al, Cancer Disc 2017Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
ctDNA Detection at the MRD landmark (1st F.U.)
PFS DFS
• ctDNA analysis can robustly identify post-treatment MRD in patients with localized lung
cancer, identifying residual/recurrent disease earlier than standard-of-care radiologic imaging,
and thus could facilitate personalized adjuvant treatment at early time points when disease
burden is lowest.
Chaudhuri AA et al, Cancer Disc 2017Criteri di risposta durante terapie con TKI: criteri clinici o molecolari? Do NSCLC with MSAF
Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Questions with the Next Wave of Adjuvant trials
focusing on MRD
Ng TL, Camidge DR, Lancet Oncology 2018Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Current Research Strategies on Liquid Biopsy: Identifyng
Resistance Mechanism (and Heterogeneity) First
Normanno N et al, Cancer Treatment Rev 2018 Alizadeh et al, Nat Med 2015Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Early Prediction of Response to TKI by EGFR Mutations in Plasma
Quantification of mutated Correlation between Mutated Quantification of mutated
EGFR DNA from plasma of two slow
EGFR DNA from plasma Plasma EGFR Response and
responders with T790M mutation by
[PCR test] after TKI start Percentage Tumor Shrinkage the PCR test.
Rapid responders
Slow responders
Marchetti A et al, J Thor Oncol 2015Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Dynamic monitoring of EGFR mutations in ctDNA
Ni JJ et al, Oncol Lett 2017Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Dynamics of EGFR mutations in plasma recapitulates the
clinical response to EGFR-TKIs in NSCLC patients
Xiong L et al, Oncotarget 2017Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Timing of Metabolic Response Monitoring During Erlotinib
Relative change in SUVmax Relative change in SUVmax Relative change in SUVmax
according to histopathologic
data for individual patients data for individual patients with
response. pCR 5 more than 90%
with DECREASE in SUVmax INCREASE in SUVmax on early tumor necrosis; pPR 5 50%–90%
on early scan. scan necrosis; pSD 5 less than 50%
necrosis
• Response monitoring with 18F-FDG PET/CT scans within 1 wk after the start of erlotinib treatment
identified most histopathologic responders.
• A decrease in metabolic activity within 1 wk is likely to continue after 3 wk of therapy.
• Therefore, an additional 18F-FDG PET/CT scan after 3 wk of treatment seems to have less value.
Van Gool MH et al, J Nucl Med 2014Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Longitudinal ctDNA analysis for predicting Response to
Osimertinib and Progression
Kim C et al, WCLC 2018Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Longitudinal ctDNA analysis for predicting Response to
Osimertinib and Progression
Kim C et al, WCLC 2018Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
TP53 and TMB status are Predictors of Efficacy to
TKIs in EGFR-addicted NSCLC
Chen & Oxnard, Clin Cancer Res 2018Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
TEMPLE-2: TP53 in EGFR Mutant NSCLC Patients: a Look towards the Efficacy of Osimertinib
Screening Phase Treatment Phase Follow-up Phase
Efficacy study of
Rebiopsies at disease Osimertinib in
EGFRmutant Osimertinib until progression or
88 pts unacceptable toxicity
progression are highly treatment-naïve patients
recommended
with EGFR mutant
44 TP53 44 TP53 NSCLC according to
wild-type mutant Primary endpoint: PFS TP53 mutational status
[Staging CT/MRI every 8 weeks until PD]
Protocol no.
ESR-18-13811
Sponsor:
Baseline 8 weeks Progression Fondazione Policlinico
Universitario ‘A. Gemelli’
IRCCS, Università
NGS NGS NGS Cattolica del Sacro Cuore,
Roma
tissue blood tissue* blood
blood
Translational research study sub-proposal P.I.: E. Bria
(DNA and RNA analysis) * If clinically feasibile Trial Coord. : S. PilottoCriteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Apple trial: Feasibility and Activity of AZD9291 (Osimertinib) Treatment on
Positive PLasma T790M in EGFR-mutant NSCLC Patients. EORTC 1613.
Trial’ Design Accrual [Overall N: 115 pts]
Courtesy of Giaj-Levra M
EORTC Meeting
Brussels (BEL), March 14th, 2019Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?
Conclusions
• TKIs exert a dramatic activity (in terms
of response) in Oncogene addicted
disease
Rapidly, ORR and Symptoms Improve
Earlier Driver Gene Clearance in plasma
represent a potential surrogate of benefit for
these featured pts (to be validated)
• The therapeutic window of (neo)
adiuvant treaments might be improved
by addressing to therapy only those
patients with MRD after local therapy
Valid hypothesis for both oncogene- and
non-oncogene addicted diseaseYou can also read
