Criteri di risposta durante terapie con TKI:
criteri clinici o molecolari?
Roma, 20 Maggio 2019
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
• 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
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
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
ONCOGENE Addiction [‘Stupid’ Disease]
NON-ONCOGENE ADDICTION [‘Smart’ Disease]
• Single Dominant Driver • Multiple Drivers & Passengers
• Small Mutational Load (LOW Tumor Mutation Burden)
• Large Mutational load (HIGH Tumor Mutation Burden)
• Targeted TKIs COULD work
• Immunotherapy MAY NOT
• (Un)Targeted TKIs are NOT effective
• Immunotherapy MAY effective
• Low Early Resistance Rate
• Always Late Acquired Resistance (same/other pathways)
• High Early Resistance Rate (common/frequent)
• Few Late Acquired Resistance (long-term survivors, cured patients?)
• Traditional Intermediate End-points MAY work as surrogate (in absence of cross-over)
• Traditional Intermediate End-points does NOT correlate with efficacy
Adapted from G. Sledge, ASCO 2011
Molecular Biology Behind is crucial for the overall understanding of the clinical behavior of tumors
‘Operative’ Classification according to Molecular Biology
ONCOGENE Addiction [‘Stupid’ Disease]
NON-ONCOGENE ADDICTION [‘Smart’ Disease]
• Single Dominant Driver • Multiple Drivers & Passengers
• Small Mutational Load (LOW Tumor Mutation Burden)
• Large Mutational load (HIGH Tumor Mutation Burden)
• Targeted TKIs COULD work
• Immunotherapy MAY NOT
• (Un)Targeted TKIs are NOT effective
• Immunotherapy MAY effective
• Low Early Resistance Rate
• Always Late Acquired Resistance (same/other pathways)
• High Early Resistance Rate (common/frequent)
• Few Late Acquired Resistance (long-term survivors, cured patients?)
• Traditional Intermediate End-points MAY work as surrogate
• Traditional Intermediate End-points does NOT correlate with efficacy
Adapted from G. Sledge, ASCO 2011
‘Operative’ Classification according to Molecular Biology
Barlesi F et al, Lancet 2016
IFCT (France) [N=13,425 pts]
Response Criteria: EGFR De-addiction
Overall Activity
(Overall Response Rate (ORR), RECIST) RCTs of TKIs vs. Firs-Line Chemo
Pilotto S et al, Crit Rev Oncol Hem 2014
Example: EURTAC (Erlotinib vs.
Chemo) Watefall Plot
Rosell R et al, Lancet Oncol 2012 Lynch T et al, NEJM 2005
70,2 70,2 75,6
44,5
38,3
53,9
0 10 20 30 40 50 60 70 80
Total FACT-L TOI LCS
p<0.0001 p<0.0001 p=0.0003
% patients with significant improvement
Gefitinib (n=131) Carboplatin / paclitaxel (n=128)
Evaluable for QoL population; logistic regression model with covariates
a6-point improvement (FACT-L and TOI); 2-point improvement (LCS), maintained ≥21 days
HRQoL Enhances Understanding of Treatment Benefits
Gefitinib vs. Chemotherapy: Quality of Life (IPASS) for Pts with EGFR Mutation
(Clinical) Response: Symptoms and QoL
Mok T et al, NEJM 2009 Perol M, WCLC 2018
LUX-Lung 3: Afatinib vs. Cisplatin-Pemetrexed in Pts with EGFR Mutation
Dyspnea
(Clinical) Response: Symptoms and QoL
Yang J et al, JCO 2013 Perol M, WCLC 2018
Response Criteria: Symptoms and QoL
Shaw A et al, NEJM 2013
Coherent Results Between
Symptoms Improvement and (Radiological) Response
Response Criteria: Symptoms and QoL
Solomon B et al, NEJM 2014
Coherent Results Between
Symptoms Improvement and (Radiological) Response
Caccese M et al, Exp Opinion Pharm 2016
Phase 1 Phase 2 Phase 3 Phase 3 Phase 3
Consistent Activity of Crizotinib (ORR) Across
Developmental Phases (from Phase 1 to 3)
TKIs Generation according to EGFR-binding and selectivity
GEFITINIB ERLOTINIB
AFATINIB DACOMITINIB
OSIMERTINIB
Janne P, ESMO-ASIA 2015
Do newer EGFR TKIs hit the target harder?
Activity Profiles of EGFR Inhibitors
0 10 20 30 40 50 60 70 80 90 100
2 hours 3 days 2 hours 3 days 2 hours 3 days
Osimertinib Dacomitinib Afatinib Erlotinib Gefiinib
H1975 (T790M/L858R)
PC-9 VanR (ex19del/T790M)
PC-9 (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
IC50 [EGFR phosphorylation in vitro]
Cross DAE et al, Cancer Disc 2014
Ramalingam S et al, ESMO 2017; Ohe Y et al, ESMO-ASIA 2017 Soria JC et al, NEJM 2017; Ekman S, ELCC 2018
FLAURA: Response and Symptoms
Changes in key patient-reported symptom scores over time from baseline until randomized treatment discontinuation (MMRM analysis)
HRQoL Enhances Understanding of Treatment Risk-Benefit Balance Archer 1050 Trial: Dacomitinib vs. Gefitinib
OS
ARCHER: Response and Symptoms
Wu et al., Lancet Oncol 2017; Mok, JCO 2018 Perol M, WCLC 2018
HRQoL Enhances Understanding of Treatment Toxicity ALEX Trial: Alectinib vs. Crizotinib
Change from baseline in tolerability outcomes
ARCHER: Response and Symptoms
Peters S et al, NEJM 2017 Pérol M et al, ELCC 2018 Perol M, WCLC 2018
ORR Crizotinib
(N=151)
Alectinib
(N=152)
Resp. Pts, ORR (%) 114 (76) 126 (83)
Median DOR (mo.) 11.1 NR
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 Clearance
Zhong W et al, ESMO 2018
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 2018
Neoadjuvant Erlotinib vs. Chemotherapy [CTONG1103]
• No pCR;
• Lower PR than advanced disease; too few courses? Different disease?
Expected %
Zhong W et al, ESMO 2018
Neoadjuvant Erlotinib vs. Chemotherapy [CTONG1103]
• No significant difference in Nodal Clearance and Resection
Zhong W et al, ESMO 2018
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
Neoadjuvant Erlotinib vs. Chemotherapy [CTONG1103]
Patient’ Case (receiving Erlotinib), pathological evaluation revealed:
• Much higher proportion of TILs
• Significantly less tumor cells
• Patient disease-free for 27 months
Pathological Regression (%)
Zhong W et al, ESMO 2018
Neoadjuvant Erlotinib vs. Chemotherapy [CTONG1103]
Secondary Endpoint: PFS （ITT population） PFS according to Subgroups
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 Clearance
Detection of MRD Using ctDNA in Lung Cancer
Chae YK et al, J Thor Oncol 2018
Proposed design for clinical trial evaluating tailored treatment based on circulating tumor DNA–
based detection of minimal residual disease (MRD).
Detection of MRD Using ctDNA in Lung Cancer
Chae YK et al, J Thor Oncol 2018
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.
Summary of Clinical Data Supporting Use of ctDNA in Detecting Minimal Residual Disease
Chaudhuri AA et al, Cancer Disc 2017
Early Detection of Molecular Residual Disease by ctDNA Profiling
Early Detection of Molecular Residual Disease by ctDNA Profiling
Chaudhuri AA et al, Cancer Disc 2017
Correlation between ctDNA concentration with
pretreatment metabolic tumor volume (MTV) by PET-CT in patients with detectable ctDNA (n = 37)
Pretreatment ctDNA concentration in stage I (n = 7)
and stage II–III (n = 30) patients with lung cancer
Outcome according to ctDNA during POST-TREATMENT SURVEILLANCE
Chaudhuri AA et al, Cancer Disc 2017
PFS - Ever positive (n=20) vs. never positive (n=17).
[Landmark analysis from the 1st post-treatment blood draw]
DFS - Ever positive (n=20) vs. never positive (n=17).
[Landmark analysis from the 1st post-treatment blood draw]
Next Wave of Adjuvant trials focusing on MRD
Chaudhuri AA et al, Cancer Disc 2017
Time to ctDNA detection and Time to Imaging PD from the end of treatment
[for all patients with PD by RECIST 1.1 (n=18); HR = 2.4]
Example of patient with stage IIIB NSCLC with equivocal surveillance imaging and undetectable posttreatment ctDNA
who achieves long-term survival
• 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.
ctDNA Detection at the MRD landmark (1st F.U.)
Chaudhuri AA et al, Cancer Disc 2017
PFS DFS
Do NSCLC with MSAF <1% live longer? See ICIs…..
Wan CJM et al, Nat Rev Cancer 2017 Bettegowda C et al, Science Transl Med 2014
ctDNA (mutant fragm./mm) and 2-year survival [Cox regression modeled]
Leveraging multiple mutations to detect Low-
Burden Disease & overcome sampling noise
Questions with the Next Wave of Adjuvant trials focusing on MRD
Ng TL, Camidge DR, Lancet Oncology 2018
Normanno N et al, Cancer Treatment Rev 2018 Alizadeh et al, Nat Med 2015
Current Research Strategies on Liquid Biopsy: Identifyng
Resistance Mechanism (and Heterogeneity) First
Early Prediction of Response to TKI by EGFR Mutations in Plasma
Marchetti A et al, J Thor Oncol 2015
Quantification of mutated EGFR DNA from plasma [PCR test] after TKI start
Correlation between Mutated Plasma EGFR Response and Percentage Tumor Shrinkage
Quantification of mutated
EGFR DNA from plasma of two slow responders with T790M mutation by
the PCR test.
Rapid responders
Slow responders
Dynamic monitoring of EGFR mutations in ctDNA
Ni JJ et al, Oncol Lett 2017
Dynamics of EGFR mutations in plasma recapitulates the clinical response to EGFR-TKIs in NSCLC patients
Xiong L et al, Oncotarget 2017
Timing of Metabolic Response Monitoring During Erlotinib
Van Gool MH et al, J Nucl Med 2014
Relative change in SUVmax data for individual patients with DECREASE in SUVmax
on early scan.
Relative change in SUVmax data for individual patients with
INCREASE in SUVmax on early scan
Relative change in SUVmax according to histopathologic response. pCR 5 more than 90%
tumor necrosis; pPR 5 50%–90%
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.
Longitudinal ctDNA analysis for predicting Response to Osimertinib and Progression
Kim C et al, WCLC 2018
Longitudinal ctDNA analysis for predicting Response to Osimertinib and Progression
Kim C et al, WCLC 2018
Chen & Oxnard, Clin Cancer Res 2018
TP53 and TMB status are Predictors of Efficacy to
TKIs in EGFR-addicted NSCLC
Protocol no.
ESR-18-13811 Sponsor:
Fondazione Policlinico Universitario ‘A. Gemelli’
IRCCS, Università
Cattolica del Sacro Cuore, Roma
P.I.: E. Bria
Trial Coord. : S. Pilotto
Screening Phase Treatment Phase Follow-up Phase
EGFR mutant 88 pts
44 TP53 wild-type
44 TP53 mutant
Osimertinib until progression or unacceptable toxicity
Baseline 8 weeks Progression
Primary endpoint: PFS
[Staging CT/MRI every 8 weeks until PD]
Translational research study sub-proposal (DNA and RNA analysis)
Rebiopsies at disease progression are highly
recommended
NGS NGS NGS
tissue blood
* If clinically feasibile tissue* blood blood
