RESEARCH IN ONCOLOGY Geraldine Gebhart 1 Outline Part 1: HER2 - PowerPoint PPT Presentation

The contribution of molecular imaging to investigate tumor heterogeneity and early evaluation of response to anti- HER2 agents in Breast Cancer 4th International conference « TRANSLATIONAL RESEARCH IN ONCOLOGY » Geraldine Gebhart 1

Outline • Part 1: HER2 receptor, Anti-HER2 therapies and molecular imaging in breast cancer • Part 2: Response prediction to neoadjuvant anti-HER2 therapies using FDG PET/CT: the Neo-ALTTO trial • Part 3: Heterogeneity of HER2 imaging across metastatic lesions and prediction of response to T-DM1 using FDG and/or 89 Zr-trastuzumab PET/CT: the ZEPHIR trial • Conclusions and perspectives 2

Epidermal growth factor receptor family Extracellular domain Intracellular domain 3 Adapted from Tzahar and Yarden. Biochim Biophys Acta. 1998;1377:M25.

HER2 + Breast Cancer Normal HER2 gene Amplified HER2 gene (15-20 0 % of of breast st cancer) er) 1984 – HER2 gene discovery (Weinberg and associates) 1987 – Aggressive Biology ( Slamon ) 1992 – Humanized anti HER2 mAb (Carter) Start of clinical development in breast cancer 4

Anti-HER2 therapies used in the clinic LAPATINIB T-DM1 TRASTUZUMAB PERTUZUMAB 5 Baselga et al., Nat Rev Cancer 2009

The medical treatment of HER2 positive Breast Cancer 2016 1999 2005 2010 Dual HER2 blockade Single HER2 blockade superior to single HER2 blockade with a MAb TDM1- prolongs with TKi survival and improves quality of life Mab: monoclonal antibody Tki: Tyrosine kinase inhibitor 6

The context of trastuzumab resistance: early disease HERA Trial DFS (%) 100 CHEMOTHERAPY + 80 TRASTUZUMAB 60 CHEMOTHERAPY 3-year 40 DFS Events HR 95% CI p value 218 80.6 0.63 0.53, 0.75 <0.0001 20 316 74.0 0 0 6 12 18 24 30 36 Months from randomisation No. 1703 1591 1434 1127 742 383 140 at risk 1698 1533 1301 930 606 322 114 7 Smith IE et al., Lancet 2007

Predictive factors in HER2 positive breast cancer HER2 8

PET: Positron-Emitting Tomography TARGET PROBE

Molecular imaging in HER2 positive BC Monoclonal antibodies Nanobodies Affibodies FDG PET/CT HER2 PET/CT or SPECT/CT 10 *Dijkers et al. Clin Pharmacol Ther 2010 *Keyaerts et al. JNM 2016

Molecular imaging in HER2 positive BC clinical trials The literature Our Experience - 6 trials* (1 multicentric) Molecular imaging could contribute to E - Neoadjuvant chemotherapy + better treatment individualization A trastuzumab R - FDG PET/CT repeated after one or 2 L cycles Neo-ALTTO Y - FDG PET correlated with pCR in 5/6 trials - Variable SUVmax criteria (absolute value versus Δ SUVmax) A D V A ZEPHIR N C E D 11 *Groheux, Zucchini, Humbert, Koolen, Coudert

Part 2 FDG-PET/CT for Early Prediction of pathological complete Response to Neoadjuvant Lapatinib, Trastuzumab, and their Combination in HER2 Positive Breast Cancer Patients: The Neo-ALTTO PET Study Results 12 Gebhart et al. JNM 2013

Neo-ALTTO Study (N = 455 women 86 sites in 23 countries in Europe, Asia, North and South America, and South Africa) Primary pCR Lapatinib R endpoint C Paclitaxel A S 25% N U Trastuzumab D R C Paclitaxel O G 29% M E Lapatinib I R C Trastuzumab Z Y 51% Paclitaxel Biological Window E 6 weeks + 12 weeks B w2 w6 Sub-study in 86 patients 30 centers in 14 countries 13 FDG-PET/CT J. Baselga, Lancet 2012

Objectives of the Neo-ALTTO PET sub-study 1. To evaluate early metabolic changes in primary tumor during anti-HER2 therapies (at week 2 and 6) 2. To test whether FDG-PET metabolic response with anti- HER2 therapies alone predicts pathological Complete Response (pCR) at the time of surgery 14

Methods • Standardized PET/CT acquisition protocol • PET/CT analysis based on SUV max of the primary tumor (EORTC criteria) • Central imaging analysis performed by 2 independent nuclear medicine experts blinded to the assigned therapies (Bellvitge-Barcelona & Bordet- Brussels) 15

EORTC criteria +25% Baseline SUVmax -15% or -25% Normal FDG uptake + + Metabolic Responder: Metabolic Non-responder: mPR mCR mSD mPD 16 Young et al. Eur J Cancer 1999; 35 1773-1782

Neo-ALTTO STUDY : RESULTS 17

Comparison Neo-ALTTO and PET sub-study cohort Candidates for Tumor Size Clinical Node Status breast conservation % % ≤ 5 cm % BCS candidate N2+ 100 100 100 39,8 54,5 71,4 71,4 84,2 85,7 50 50 50 60,2 45,5 28,6 28,6 14,3 15,8 0 0 0 PET NEO-ALTTO PET NEO-ALTTO PET NEO-ALTTO pCR at Surgery Hormone Receptor Status Treatment Allocation % Positive Negative pCR No pCR 100 L T L + T 44,2 49 NO NO 33.7% 33.8% 64.9% 64.8% 50 33,8% 32,7% 55,8 51 YES YES 32.5% 33.4% 35.2% 35.1% 0 PET NEO-ALTTO PET NEO-ALTTO PET NEO-ALTTO

Description of the metabolic changes observed during the biological window R²=0.81 Δ SUVmax 15% 19

Description of the metabolic changes observed during the biological window Δ SUVmax 25% 20

Description of the metabolic changes observed during the biological window PPV: 79% (33/42) NPV: 90% (18/20) 21

Metabolic responder… BASELINE WEEK 2 WEEK 6 … and metabolic non -responder BASELINE WEEK 2 WEEK 6 22

Correlation between metabolic response & pCR Mean SUVmax reduction as a pCR rate as a function of function of pCR status metabolic response 100% pCR Week 2 pCR Non-pCR 33% Week 2 50% 54% p=0.12 42% 21% 0% PET NON-RESPONDER PET RESPONDER (n =19) (n =48) 100% pCR Non-pCR pCR Week 6 34% Week 6 50% 62% 44% p=0.05 19% 0% PET NON- PET RESPONDER RESPONDER (n =39) 23 (n =26)

PART 3 M OLECULAR IMAGING AS A TOOL TO INVESTIGATE HETEROGENEITY OF ADVANCED HER2- POSITIVE BREAST CANCER AND TO PREDICT PATIENT OUTCOME UNDER TRASTUZUMAB EMTANSINE (T-DM1) THE ZEPHIR TRIAL 24 Gebhart et al. Annals of oncology 2015

T-DM1: 1st-in-class HER2 antibody-drug T-DM1 selectively delivers a highly toxic payload to conjugate (ADC) HER2-positive tumour cells Target expression: HER2 T-DM1 binds to the HER2 protein on cancer cells Monoclonal antibody: trastuzumab Cytotoxic agent: DM1 Receptor-T-DM1 complex is Highly potent chemotherapy Potent antimicrotubule internalised into HER2-positive agent is released once inside (maytansine derivative) cancer cell the HER2-positive tumour cell T-DM1 Linker Systemically stable Breaks down in target cancer cell 25

Zephir trial design Main eligibility criteria • HER2 + primary tumor or HER2 + 89 Zr-trastuzumab 89 Zr-trastuzumab metastatic lesion injection PET/CT • Progressive metastatic disease • Any metastatic line of treatment accepted Screening • 2 measurable lesions on CT (RECIST) and FDG-PET (PERCIST) D 4 D 0 Baseline FDG PET/CT T-DM1 T-DM1 T-DM1 Diagnostic CT FU until PD D 15 D 1 D 22 J 43 D 57 D 64 Early FDG PET/CT Diagnostic CT 26

ZEPHIR trial Groningen Amsterdam Nijmegen Antwerpen Brussels Boellaard et al. EJNM 2015 27 Makris et al. JNM 2014

Prediction of morphological response 89 Zr-Trastuzumab T T T D D D PET/CT Diagnostic Diagnostic M M M 1 1 1 CT CT Early 18 FDG-PET/CT 28

Methodology HER2 PET/CT FDG PET/CT 29

ZEPHIR: two different ways to image the disease 30 FDG HER2

FDG HER2 FDG HER2 B A HER2 PET Classification FDG HER2 FDG HER2 D C 31

NR 1 2 Response FDG PET response classification Non Response R 4 3 32

ZEPHIR STUDY : RESULTS 33

Patterns of HER2 expression revealed by HER2 PET/CT imaging B A 34% 38% C D 12% 16% All or most of the tumor load is seen on 89 Zr-Trastuzumab PET/CT Minority of tumor load or no lesions are seen on 89 Zr-Trastuzumab PET/CT 34

Correlation between molecular imaging and morphological Response RECIST 1.1 PPV: R NR Total 72% + 28 11 39 HER2 NPV: PET - 2 14 16 88% RECIST 1.1 PPV: R NR Total 96% R 26 1 27 Early NPV: FDG NR 5 24 29 83% 35

Suboptimal NPV of early FDG PET/CT: potential explanation T T T D D D 2 nd Baseline Baseline Early Late M M M 18 FDG PET/CT 18 FDG PET/CT 18 FDG PET/CT 18 FDG PET/CT 1 1 1 16 days Significant increase in metabolism 36

Suboptimal NPV of early FDG PET/CT: potential explanation 89 Zr-trastuzumab 89 Zr-trastuzumab injection PET scan Screening D 4 T-DM1 T-DM1 T-DM1 D 0 Baseline FDG PET/CT D 1 D 15 D 22 J 43 D 57 D 64 Early FDG PET/CT Late FDG PET/CT • 16 days • Tumoral marker CA15-3: 36->64 • Liver enzyme: • GOT: 37-> 73 • GPT: 37-> 74

Combined imaging modalities predicting morphological response RECIST 1.1 R NR Total PPV: eR 24 0 24 100% HER2 PET + eNR 4 11 15 ! eR 2 1 3 HER2 PET - NPV: eNR 0 13 13 100% 38

Time to treatment failure TTF: Time from start of T-DM1 until its discontinuation 89 Zr-trastuzumab PET/CT Early FDG PET/CT 11.2 13.3 months months 3.5 4.2 months months HR 4.5 95% CI 2.1-9.4 p < 0.0001 HR 3.8 95% CI 2-7.4 p < 0.0001 39