Qu avons-nous appris du développement des anti-her2? Ahmad Awada MD, PhD Medical Oncology Clinic Institut Jules Bordet Université Libre de Bruxelles

Transcription

1 Qu avons-nous appris du développement des anti-her2? Ahmad Awada MD, PhD Medical Oncology Clinic Institut Jules Bordet Université Libre de Bruxelles FOM Lille

2 Her2 breast cancer expression = Poor Prognostic but good predictive marker! HER2overexpresion (3+) HER2amplific = IHC FIS

3 Cancer du sein: oncogène HER-2 Amplification de l oncogène HER-2 Survie plus courte HER2 surexprimée HER2 normal 3 ans 6-7 ans Surexpression du récepteur HER-2

4 Biology: Heterogeneity Within Primary Breast Tumor

5 Significant Rate of Discordancy Between Primary and Metastases of Breast Cancer Studies ER+ primary with loss in recurrence ER- primary with gain in recurrence #1007 Amir et al. N=271 #CRA 1008 Locatelli et al. N=255 #1009 Karlsson et al. N=477 prospective retrospective (liver) retrospective 21/174 (12%) 22/197 (11%) 123/336 (36%) 8/57 (14%) 15/58 (25%) 32/141 (22%) Overall ER discordance rate 12% 14.5% 32% Overall PR discordance rate 34% 48% 43% HER2- primary with gain in recurrence HER2+ primary with loss in recurrence Change in management from results of recurrence biopsy 9/197 (4.6%) 7/118 (5.9%) n.d. 3/24 (12.5%) 17/54 (31.5%) n.d. 15% 12% n.d. Discussion ASCO 2010: Richardson AL

6 Understanding The Receptor expression (HR, HER2) Changes within the primary and between primary and metastatic sites Inaccurate testing Low volume of tumor in some metastatic biopsies True shift over time as a result of genetic/epigenetic changes Emergence of dominant clone

7 HER-2 OVEREXPRESSING METASTATIC BREAST CANCER: TOWARDS A CURE OF THIS DISEASE? HER 2 HER 2 OVEREXPRESSION AMPLIFICATION = IHC FISH NEW TREATMENT APPROACHES Early use of trastuzumab Alone in selected women (ORR %) in combination with cytotoxics (ORR > 50%!) or hormonal agents (PFS gain: 2-5mo.) Docetaxel + trastuzumab + bevacizumab (No therapeutic breakthrough) New HER-2 drugs (lapatinib, neratinib, afatinib, trastuzumab-dm1, pertuzumab) Dual HER-2 inhibition + cytotoxics or endocrine agents

8 Lapatinib Mechanism of Action Binds to intracellular ATP binding site of EGFR (ErbB-1) and HER2 (ErbB-2) preventing phosphorylation and activation Dual blockade of TKs signaling may be more effective than the single-target inhibition provided by agents such as trastuzumab Lapatinib Downstream signaling cascade Rusnak et al. Mol Cancer Ther 2001;1:85-94; Xia et al. Oncogene 2002;21: ; Konecny et al. Cancer Res. 2006;66:

9 Gomez et al. JCO2008 FIRST-LINE LAPATINIB IN HER2 BREAST CANCER Efficacy by Dose Schedule Response N= mg BID (n=69) 1500 mg QD (n=69) CR 0 0 PR 18 (26%) 15 (22%) SD 31 (45%) 40 (58%) PD 16 (23%) 8 (12%) Unknown 4 (6%)* 6 (7%) Overall RR : 24%; AE = diarrhea, rash, nausea Lapatinib+Capecitabine > Capecitabine (Taxane + trastuzumab pretreated)

10

11

12 The Increasing Challenge Of Brain Metastases

13 CAPECITABINE + LAPATINIB STUDY IN HER2 BRAIN METASTASES Key Inclusion Criteria HER2+ MBC Newly diagnosed brain metastases, at least 1 cm in diameter (T1 gado. MRI) Not candidate for brain surgery Any previous treatment except WBR, lapatinib or capecitabine ECOG PS status 0-2 Treatment (q3 weeks): L: 1,250 mg/d, PO, continuous C: 2,000 mg/m²/d, PO, d1 14 Clinical assessment (including NSS) every 3 weeks Cerebral and systemic imaging every 6 weeks NSS : Neurologic signs and symptoms Bachelot et al. ASCO 2011

14 Primary Endpoint: CNS volumetric response CNS-OR : 29/43 = 67.4% (95% CI: 52-81) CNS Volumetric change n = 43 (%) 80% Reduction 9 (20.9) 50- <80% Reduction 20 (46.5) 20- <50% Reduction 6 (14) > 0- <20% Reduction 2 (4.7) Progression* 6 (14) *2 patients had extra-cns disease progression NSS improvement : 14/24 = 58.3% (95% CI: ) Bachelot et al. ASCO 2011

15 HER-2 Therapy in breast cancer: Lessons Learnt and Perspectives (1) HER-2 expression is a poor prognostic marker HER-2 expression (IHC 3+; FISH+) is a good predictive marker to HER-2 therapy Discordance in HER2 expression was observed within primary and between primary and metastatic sites HER-2 therapies are efficacious as single agent but significant synergy with cytotoxics and endocrine agents No therapeutic breakthrough reported by combining docetaxel with trastuzumab and bevacizumab A challenging increased incidence of brain metastases in treated HER2+ patients

16 Relative Risk 1.0 THE GROUND-BREAKING ADJUVANT TRASTUZUMAB TRIALS N = 10,720 women Chemo alone D.F.S. Chemo + trast 33 to 58% 0.86 O.S. Chemo + trast 33 to 59% Severe CHF: 0% - 3.6% Systolic dysfunction: 3.5%-19% Absolute gains of 5 to 12% at 2 to 4 y (except PACS01)

17 Dual Blockade of HER-2 with Taxanes in the Neoadjuvant Setting NeoAltto and NeoSphere: Studies Design R A N D O M I Z E Lapatinib Paclitaxel Trastuzumab Paclitaxel Lapatinib Trastuzumab Paclitaxel S u r g e r y R A N D O M I Z E Trastuzumab Docetaxel Pertuzumab Docetaxel Trastuzumab Pertuzumab Docetaxel Trastuzumab Pertuzumab S u r g e r y 18 weeks 12 weeks Neo-Altto Neo-Sphere

18 Pathologic CR Rates in NeoSphere: Three main messages 63%

19

20 (10% of pts received adjuvant trastuzumab!!)

21 Anatomy of Trastuzumab-DM1 Trastuzumab

22 EMILIA Study Design HER2+ (central) LABC or MBC (N=980) T-DM1 3.6 mg/kg q3w IV PD Prior taxane and trastuzumab Progression on metastatic tx or within 6 mos of adjuvant tx 1:1 Capecitabine 1000 mg/m 2 orally bid, days 1 14, q3w + Lapatinib 1250 mg/day orally qd PD Stratification factors: World region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral disease Primary end points: PFS by independent review, OS, and safety Key secondary end points: PFS by investigator, ORR, duration of response, time to symptom progression 22

23 Proportion progression-free EMILIA Study : Progression-Free Survival by Independent Review Median (mos) No. events Cap + Lap T-DM Stratified HR=0.650 (95% CI, 0.55, 0.77) P< Time (mos) No. at risk by independent review: Cap + Lap T-DM Unstratified HR=0.66 (P<0.0001). 23

24 Proportion surviving Overall Survival: Interim Analysis % 77.0% 65.4% Median (mos) No. events Cap + Lap T-DM1 NR 94 Stratified HR=0.621 (95% CI, 0.48, 0.81) P= Efficacy stopping boundary P= or HR= % Time (mos) No. at risk: Cap + Lap T-DM Unstratified HR=0.63 (P=0.0005). NR=not reached. 24

25 Evolving

26 Courtesy Sherene LOI LYMPHOCYTIC INFILTRATION PREDICTS FOR TRASTUZUMAB RESPONSE IN THE FINHER TRIAL LPBC Non-LPBC HR 0.16 ( ) P=0.013 HR 1.0 ( ) P=0.99 LPBC Significant interaction p value p=0.032 Interaction p value for Stromal-Ly as a continuous variable (10%) p=0.02

27

28 The rationale to investigate THP+MoAb targeting PD-L1 or CTLA4

29 Getting familiar with circus plots in the era of NGS Genomic «landscape» of the tumor PRESENTED BY: Martine J. Piccart

30 HER2 Somatic Mutations identified by Breast Cancer Genome Sequencing in HER2 Non Amplified Tumors (Bose R et al SABCS 2012)

31

32

33

34 Molecular/Functional imaging : To map HER2 expression To monitor the efficacy of HER2

35 Zirconium-89-trastuzumab localizes to HER-2 expressing tumors (and heart) : Mapping HER-2 heterogeneity? Bone & liver metastases Bone metastases Heart uptake Massive bone metastases S.M Knowles, JCO, 2012

36 FDG PET/CT and 89 Zr-Trastuzumab PET/CT in a patient (ER+/HER-2+) with bone metastases responding to therapy (Response after 2 months of exemestane+trastuzumab)

37 Anti HER2 therapy for 2 weeks : a dramatic early response in the neoaltto trial Primary Tumor + 2 Lymph Node Mets Baseline After 2 weeks FDG PET-CT images

38 HER2 therapy: Lessons Learnt and Pespective(2) Adjuvant trastuzumab (1 year) improved significantly the outcome of HER2 patients Dual inhibition of HER2 in the metastatic and neoadjuvant settings is an interesting therapeutic approach Trastuzumab is used as a driver for toxic cytotoxic agent to cancer cells harboring HER-2 with an excellent therapeutic index (T-DM1) Immune system seems important for tumor response to monoclonal antibodies targeting HER2 Radiolabelled (Zirconium) trastuzumab is under investigation to map HER2 expression in metastases

39 HER-2 and Gastric Cancer HER-2 oncogene found in 12 to 20% of gastric cancers HER-2 expression is mainly linked to the intestinal type histology HER-2 + gastric cancer is characterized by a more aggressive phenotype with lower survival rates David et al 1992 Barros-Silva JD: Br J Cancer 2009; 100:

40 Trastuzumab + Chemotherapy in Advanced HER2+ Gastric Cancer: ToGA Trial Stratified by ECOG PS, advanced vs metastatic, gastric vs GEJ, measurable disease, capecitabine vs 5-FU Patients with advanced gastric cancer screened for HER2 status (N = 3803) Patients with HER2+ advanced gastric cancer (n = 810; 22% of successful screenings) Primary endpoint: OS R (n = 584) 5-FU or Capecitabine* + Cisplatin 80 mg/m 2 q3w x 6 + Trastuzumab 6 mg/kg q3w until PD (8 mg/kg loading dose) (n = 294) 5-FU or Capecitabine* + Cisplatin 80 mg/m 2 q3w x 6 (n = 290) *Selected at investigator s discretion: 5-FU 800 mg/m 2 /day infusional on Days 1-5 q3w x 6; capecitabine 1000 mg/m 2 BID on Days 1-14 q3w x 6. Bang YJ, et al. Lancet. 2010;376:

41 ToGA: OS in IHC 2+/FISH+ or IHC 3+ (Exploratory Analysis) Survival Probability Pts at Risk, n Mos FC + T FC Events Median OS HR % CI The Lancet, 376(9742), Bang YJ, et al., Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial , Copyright

42 LOGiC: Phase III Trial of Lapatinib + CapeOx in HER2+ Gastric/ GEJ Cancers Patients with HER2-amplified locally advanced, unresectable, or metastatic gastric, esophageal, or GEJ cancer (Planned N = 535) CapeOx + Lapatinib CapeOx + Placebo Primary endpoint: OS Data expected mid-2012 ClinicalTrials.gov. NCT

43 THANK YOU