ADAPT Adjuvant Dynamic marker- Adjusted Personalized Therapy trial optimizing risk assessment and therapy response prediction in early breast cancer
Therapieindikation gesteuert durch prognostische Information 11.10.2011 WSG GmbH 2
Intermediate risk group (~ 30 %) 30% carriers of micromets + one third treated successfully 10% successfully treated 70 % are not carriers of micromets 70 % overtreatment 30% carriers of micromets + two thirds not successfully treated 20% mistreated 11.10.2011 WSG GmbH 3
High risk group (~ 70 %) 70% carriers of micromets + one third treated successfully 23,4 % successfully treated 30 % are not carriers of micromets 30 % overtreatment 70% carriers of micromets + two thirds not successfully treated 46,6 % mistreated! 11.10.2011 WSG GmbH 4
Prognostic tests ADJUVANT ONLINE ST. GALLEN upa/pai1(n0, G 2 ) Mammaprint (N 0-1 ) OncotypeDX (HR+, N 0-1 ) Weitere Signaturen 11.10.2011 WSG GmbH 5
Main problems per subgroup: HR+/HER2-: overtreatment TP: overtreatment/mistreatment HER2+/HR-: mistreatment TN: mistreatment
Prediction HR endocrine therapy Her2 trastuzumab, lapatinib pcr chemotherapy
Adjuvant Dynamic marker Adjusted Personalized Therapy trial optimizing risk assessment and therapy response prediction in early breast cancer
General Inclusion Criteria I Female patients, age at diagnosis 18-75 years Histologically confirmed unilateral primary invasive carcinoma of the breast Clinical T1 - T4 (except inflammatory breast cancer) All clinical N No clinical evidence for distant metastasis (M0) Central pathology available (HR, HER2, G, ki-67, RS) Performance Status ECOG 1 or KI 80 % 11.10.2011 WSG GmbH 9
Trial design Optimal baseline risk assessment Prognosis Estimation B I o P S Y* HR + HER2 + TN RS Proliferation genes Apoptosis genes 11.10.2011 WSG GmbH 10
Trial design 3 week specific induction therapy Prognosis Estimation B I o P S Y* HR + HER2 + TN RS Proliferation genes Apoptosis genes therapy 3 w Tamoxifen premenopausal patients AH postmenopausal patients Cht + antiher2 therapy Cht 11.10.2011 WSG GmbH 11
Trial design Second tissue sample : early response assessment Prognosis Estimation B I o P S Y* HR + HER2 + TN RS Proliferation genes Apoptosis genes Therapy 3 w Efficacy Estimation B I o P S Y* RS Proliferation genes Apoptosis genes 11.10.2011 WSG GmbH 12
Trial design HR+: reduction of chemotherapy HER2+/TN evaluation of early surrogates for pcr Prognosis Estimation B I o P S Y* HR + HER2 + TN RS Proliferation genes Apoptosis genes Therapy 3 w Efficacy Estimation B I o P S Y* RS Proliferation genes Apoptosis genes HR+ HER2+ TN Low risk+ good responders Endocrine therapy only high risk+ low responders Cht Endocrine therapy Evaluation of early surrogates for pcr Evaluation of new targeted therapies 11.10.2011 WSG GmbH 13
ADAPT Umbrella 11.10.2011 WSG GmbH 14
Trial design Prospective, multi-center, controlled, non-blinded, randomized phase III Prognosis Estimation B I o P S Y* HR + HER2 + TN RS Proliferation genes Apoptosis genes Therapy 3 w Efficacy Estimation B I o P S Y* RS Proliferation genes Apoptosis genes HR + approx. 70 % HER2 + approx. 15 % TN approx. 15 % 11.10.2011 WSG GmbH 15
Run-in and main phase Run in Main HR+: 400 3600 HER2+: 150* 320* TN: 150* 320* *Case numbers are to be discussed. Exact numbers will be readily available, when the protocol is amended for activation of the respective sub protocol. 11.10.2011 WSG GmbH 16
Objectives Run-in Phase HR+ Analysis of feasibility/ reproducibility of each biomarker Assessment of drop out rate Assessment of proportions of marker responders vs. nonresponders Central/local pathology Central/local Ki-67 assessment Ki-67 change after inductive endocrine therapy Comparison of changes in RS, Ki-67, quantitative ER and proliferation group within the RS Assessment of percentage of low, intermediate and high-risk patients on RS and the respective rates of responders/low responders in these groups with the aim to allow early adjustment of the statistical plan Identification of other proliferation markers that drop significantly 11.10.2011 WSG GmbH 17
PRIMARY OBJECTIVES Identification of a subpopulation with excellent outcome (like HR+/RS 11) over all subgroups, which in future might be spared (longer) therapy Comparison of dynamic, therapy induced early molecular changes in the different subgroups
Sub-trials: ADAPT HR+ (I+ II) 11.10.2011 WSG GmbH 19
ADAPT HR+ Prognosis Estimation B I o P S Y* HR + HER2 + TN RS Proliferation genes Apoptosis genes therapy 3 w Efficacy Estimation B I o P S Y* RS Proliferation genes Apoptosis genes HR + approx. 70 % HER2 + approx. 15 % TN approx. 15 % Endocrine induction: Tam in premenopausal women Aromatase inhibitors in postmenopausal women 11.10.2011 WSG GmbH 20
HR+: dynamic testing translates into therapeutic consequences Hypothesis: good responders are treated sufficiently by endocrine therapy only Definition of good responder dynamic assessment of Ki-67 under 3 weeks of endocrine therapy
ADAPT I/II: HR+, HER2- N2 R cht cht Prognosis Efficacy RS>25 Ki 67 post >10%** Core biopsy ET 3 weeks Surgery/ Core biopsy N0 N1 RS12 25 *or decrease >30-50% if initial ki-67<15% **or decrease <30-50% if initial ki-67<15% Ki 67 post <10%* Ki 67 RS Ki 67 RS RS<12 ET only 11.10.2011 WSG GmbH 22
HR+/HER2 intermediate risk chemo or no chemo??? intermediate risk (~50%) intermediate risk (~50%)
Statistical endpoints Run-in and whole trial HR+ Primary endpoint: ADAPT HR+/HER2- part I: Comparison of EFS in patients with intermediate risk by RS (12-25)/good response vs. patients with low risk by RS (RS 11; N0-1) both groups receiving endocrine therapy only Secondary endpoint: Evaluation of the association between baseline biomarker/ biomarker changes under induction therapy and EFS in the following groups of HR+/HER2- patients:» Patients with intermediate risk by RS (12-25) with Ki-67 response to neoadjuvant therapy, who are treated without chemotherapy» Patients with intermediate risk by RS (18-25) without Ki- 67 response to neoadjuvant endocrine therapy, who are 11.10.2011 treated with chemotherapy WSG GmbH 24
optimal sequencing?
ADAPT II Randomization for all patients with: pn0-1 + RS > 25 pn0-1+ RS 12-25 + low response pn2 E 90 C 600 E C E C E C Doc 100 Doc Doc Doc E 90 C 600 E C E C E C Pac 80mg q1wx12 R Doc 100 Doc Doc Doc E 90 C 600 E C E C E C Pac 80mg q1wx12 E 90 C 600 E C E C E C 11.10.2011 WSG GmbH 26
Sub-trials: ADAPT HR+/HER2+(TP) 11.10.2011 WSG GmbH 27
ADAPT HER2+ and TN Prognosis Estimation B I o P S Y* HR + HER2 + TN RS Proliferation genes Apoptosis genes Therapy 3 w Endocrine therapy or chemotherapy Efficacy Estimation B I o P S Y* RS Proliferation genes Apoptosis genes HR + approx. 70 % HER2 + approx. 15 % TN approx. 15 % 11.10.2011 WSG GmbH 28
TP breast cancer has substantially better prognosis than HER+/HR- disease is routinely treated with the combination of chemotherapy and anti HER2 therapy has not yet been regarded upon as an separate entity
T DM1
magic bullet : T DM1 Ziel: HER2 Monoklonaler Antikörper: Trastuzumab Zytostatikum: DM1 Hochpotente Chemotherapie (Maytansin-Derivat) Verbindung/Koppler Systemisch stabil - wird erst in der Zielzelle freigesetzt T-DM1
General concept B I O P S Y R T-DM1 B I O P S Y T-DM1 + AH therapy Trastuzumab + AH therapy T-DM1 T-DM1 + AH therapy Trastuzumab + AH therapy S U R G E R Y 4xEC->Taxane* (Trastuzumab as standard for 40 weeks) *at decision of investigator in T- DM1 containing arms Ki 67 Proliferation genes Apoptosis genes MRI RS Ki 67 Proliferation genes Apoptosis genes MRI 3w pcr 12w Trastuzumab alone / EC T) 11.10.2011 WSG GmbH 32
General concept B I O P S Y R T-cht B I O P S Y T-cht + AH Trastuzumab + AH therapy T-cht T-DM1 + AH therapy Trastuzumab + AH therapy S U R G E R Y 4xEC->Taxane* (Trastuzumab as standard for 40 weeks) *at decision of investigator in T- DM1 containing arms Ki 67 Proliferation genes Apoptosis genes MRI RS Ki 67 Proliferation genes Apoptosis genes MRI 3w pcr 12w Trastuzumab alone / EC T) 11.10.2011 WSG GmbH 33
Therapy Neoadjuvant Treatment: T-DM1 (3,6 mg/kg q3w) x4 T-DM1 (3,6 mg/kg q3w) x4 + endocrine therapy trastuzumab (4/2 mg/kg q1w) x12 + endocrine therapy Surgery: Planed after completion of 12 weeks of neoadjuvant treatment for all patients In case of disease progression, treatment will be stopped prematurely and surgery will be performed immediately 11.10.2011 WSG GmbH 34
Therapy Adjuvant Treatment: Patients with no pcr: E 90 C 600 q3w x 4 (T-DM1 containing arms) Pac 80 q1w x 12 -> E 90 C 600 q3w x 4 (trastuzumab + ET) Patients with pcr: further chemotherapy is optional Standard anti-her2 therapy: 52 weeks for all patients (i.e. for further 40 weeks after completition of neoadjuvant treatment). 11.10.2011 WSG GmbH 35
Objectives Pilot Phase Concept Primary objective: Evaluation of dynamic testing (based on proliferation/apoptosis changes in serial biopsy and imaging by MRI) after three weeks of treatment as a surrogate parameter for response (pcr (residual cancer burden (RCB) 0-1) or resistance/low response (RCB II-III or progressive disease) 11.10.2011 WSG GmbH 36
Additional Inclusion criteria for participation in the TP sub-protocol Confirmed ER and/or PR positive and HER2 positive by central pathology Clinical ct1c - T4a-c (participation of patients with tumors >ct2 is strongly recommended) All clinical N (participation of patients with cn+ if ct1c is strongly recommended) Patients must qualify for neoadjuvant treatment. LVEF within normal limits of each institution measured by echocardiography and normal ECG (within 42 days prior to inductive treatment) 11.10.2011 WSG GmbH 37
Thank s!