Criteri di risposta durante terapie con TKI: criteri clinici o molecolari? - Aiom

 
Criteri di risposta durante terapie con TKI: criteri clinici o molecolari? - Aiom
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
Criteri di risposta durante terapie con TKI: criteri clinici o molecolari? - Aiom
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? - Aiom
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? - Aiom
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? - Aiom
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? - Aiom
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? - Aiom
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? - Aiom
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? - Aiom
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? - Aiom
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 2013
Criteri 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 2014
Criteri 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 2016
Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?

TKIs Generation according to EGFR-binding and selectivity

        GEFITINIB                     AFATINIB                            OSIMERTINIB
        ERLOTINIB                    DACOMITINIB
Criteri 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 2014
Criteri 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 2018
Criteri 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 2018
Criteri 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 2018
Criteri 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 Clearance
Criteri 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 2018
Criteri 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 2018
Criteri 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 2018
Criteri 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 2018
Criteri 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 2018
Criteri 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 Clearance
Criteri 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 2018
Criteri 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 2018
Criteri 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 2017
Criteri 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 2017
Criteri 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 2017
Criteri 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 2017
Criteri 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 2017
Criteri 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 2018
Criteri 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 2015
Criteri 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 2015
Criteri di risposta durante terapie con TKI: criteri clinici o molecolari?

Dynamic monitoring of EGFR mutations in ctDNA

                                                                                   Ni JJ et al, Oncol Lett 2017
Criteri 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 2017
Criteri 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 2014
Criteri 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 2018
Criteri 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 2018
Criteri 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 2018
Criteri 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. Pilotto
Criteri 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, 2019
Criteri 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 disease
You can also read
Next slide ... Cancel