Resistance to anti-her2 therapies Pr David Khayat Service d Oncologie Médicale Groupe Hospitalier Pitié Salpêtrière -Paris
Disclosure statment
Trastuzumab in HER2+ MBC A major impact but resistance will unfortunately occur during disease course Dawood et coll. JCO 2010 28(1)
How can resistance to trastuzumab occur? Alteration of the target HER2 mutation HER2 ECD overexpression MUC4 overexpression Other oncogenic event(s) cross-talk: IGF1R, MET downstream pathways: PTEN deletion, AKT activation ADCC modulation
How can resistance to trastuzumab occur? Alteration of the target HER2 mutation HER2 ECD overexpression MUC4 overexpression Interesting concepts but a lack of clinical data! Other oncogenic event(s) cross-talk: IGF1R, MET downstream pathways: PTEN deletion, AKT activation ADCC modulation
How can we overcome resistance to trastuzumab? 1. Is progression under trastuzumab a resistance to trastuzumab? 2. Is progression under trastuzumab a resistance to anti HER2 therapies? 3. Can sensitivity to trastuzumab t be restored?
How can we overcome resistance to trastuzumab? 1. Is progression under trastuzumab a resistance to trastuzumab? 2. Is progression under trastuzumab a resistance to anti HER2 therapies? 3. Can sensitivity to trastuzumab t be restored?
Progression under trastuzumab may be a resistance to the associated cytotoxic Extra JM. et al. The Oncologist 2010
French study Hermine: Trastuzumab beyond progression Cohort study Metastatic Breast Cancer 18 years Initiation of trastuzumab in 2002 623 patients Objectives : evaluation of trastuzumab in real life setting Efficacy Cardiac safety evaluation of the impact of trastuzumab beyond progression Extra JM. et al. The Oncologist 2010
French study Hermine: Trastuzumab beyond progression MBC HER2+ Patients (n = 623) First line Trastuzumab (n = 221) Trastuzumab en 2 ème ligne (n = 138) Progression or death during follow up a (n = 185) Progression or death during follow up b (n = 121) Trastuzumab at No Trastuzumab Trastuzumab at No Trastuzumab progression at progression progression at progression (n = (n = 107) (n = 70) (n = 87) 30) a Missing data for 8 ptes b Missing data for 4 pts Extra JM. et al. The Oncologist 2010
French study Hermine: Overall Survival after progression (1st Line) 1.0 0.8 median OS months 21.3 4.6 p < 0.0001 0.6 n = 107 0.4 0.2 4.6 n = 70 21.3 months months 00 0.0 0 5 10 15 20 25 Months 30 Trastuzumab after progression Trastuzumab stopped at progression Extra JM. et al. The Oncologist 2010
French study Hermine: Overall Survival after progression (2nd Line) 1.0 median OS months 0.8 95 % IC 15.55 13.4-18.0 11.0 2.3-20.7 p 0.02 0.6 0.4 0.2 0.0 11.0 months 15.5 months 0 5 10 15 20 25 30 35 40 Mois Trastuzumab after progression Trastuzumab stopped at progression Extra JM. et al. The Oncologist 2010
N=156
Median PFS X : 5.6 months XH : 8.2 months HR : 0.69
Median OS X : 20.4 months XH : 25.55 months NS Higher response rate p=0.011 Better clinical benefit (ORR + PR/CR) p= 0.0068 SD PR CR SD PR CR
How can we overcome resistance to trastuzumab? 1. Is progression under trastuzumab a resistance to trastuzumab? 2. Is progression under trastuzumab a resistance to anti HER2 therapies? 3. Can sensitivity to trastuzumab t be restored?
Trastuzumab + Pertuzumab : xenograft Tumor vol (mm 3 ) 650 600 550 500 450 400 350 300 250 200 150 100 50 0 Control Pertuzumab (30/15 mg/kg/wk ip) Trastuzumab (30/15 mg/kg/wk ip) Pertuzumab + Herceptin BT 474 cell line 0 10 20 30 40 50 60 70 80 Time (days) Friess et al. ESMO 2006
Dual HER2 inhibition can do better than single shot (1st line) Baselga J. et al. N Eng J Med 2012
Even in advanced disease: HER2 inhibition is still important MBC HER2-positif (FISH) progression on prior trastuzumab-containing regimens R Lapatinib 1 000 mg/d + Trastuzumab 2 mg/kg/wk (n = 148) Lapatinib 1 500 mg/d (n = 148) Cross over allowed (73 ptes) Blackwell KL. et coll J Clin Oncol 2010
HER2 remains a driver event => the goal is to optimize its inhibition Blackwell KL. et coll J Clin Oncol 2010
How can we overcome resistance to trastuzumab? 1. Is progression under trastuzumab a resistance to trastuzumab? 2. Is progression under trastuzumab a resistance to anti HER2 therapies? 3. Can sensitivity to trastuzumab t be restored?
HER2 Signaling and mtor Activation HER Receptor dimerization HER2 Cancer Cell BETWEEN THE HAMMER P P P P Ras/Raf MAPK PTEN PI3K AKT/PKB mtor ps6 kinase Proliferation and Angiogenesis AND THE ANVIL
Multicenter Phase I Trial of Daily and Weekly Everolimus plus Weekly Paclitaxel and Trastuzumab in Pts with HER2- Overexpressing mbc with Prior Resistance to Trastuzumab Background: PTEN loss or PI3K mutations induces mtor activation and Trastuzumab resistance Hypothesis: Everolimus could potentially ti reverse Trastuzumab resistance by inhibiting mtor signaling Study: Phase I studies combining everolimus + Trastuzumab ± chemotherapy in patients with HER2-overexpressing breast cancer who progressed during or after trastuzumab F. André et al. ASCO annual meeting 2008
Study Design (Phase I) Open-label, multicenter, Phase I, dose-escalation study of Everolimus in combination with Trastuzumab and Paclitaxel Paclitaxel: 80 mg/m 2 (Days 1, 8, and 15, q28 days) Trastuzumab: 2 mg/kg/week (Day 1: 4mg/kg) ARM 1: Daily Everolimus 5 mg (starting dose) 10 mg/day ARM 2: Weekly Everolimus 30 mg (starting dose) 50 mg and 70 mg/week Treatment until progression or unacceptable toxicity Paclitaxel continuation after 6 cycles: optional
Patient Characteristics Characteristic Total (n=19) Everolimus Everolimus Everolimus 5 mg daily 10 mg daily 30 mg weekly (n=6) (n=3) (n=10) Median Age (Range) 58 (42-75) 56 (42-61) 68 (68-70) 58 (52-75) WHO Performance Status: 0:1 9:10 4:2 1:2 4:6 No. of Previous Regimens Median (Range) 6 (4-26) 4.5 (4-10) 6 (4-8) 7 (1-26) Pretreated With Trastuzumab 19 (100%) 6 3 10 Trastuzumab Resistant 19 (100%) 6 3 10 Pretreated With Taxane 17 (89%) 6 2 9 Taxane Resistant 12 (63%) 6 1 5 F. André et al. ASCO annual meeting 2008
Efficacy in Patients with Trastuzumabresistant Tumors Best Overall Overall 5 mg Daily 10 mg Daily 30 mg Weekly Response (N=13) (N=5) (N=1) (N=7) Partial Response 6 /13 (46%) Stable Disease Disease Control (PR / SD>16 Weeks) (83%) 4 0 2 6 1 1 (7+) 4 10/12 5 NA 5 Progressive Disease 1 0 0 1 F. André et al. ASCO annual meeting 2008
Regression of a Lung Metastasis in a Patient with Taxane- / Trastuzumab-refractory Tumor Baseline Day 50 (1 st Evaluation) F. André et al. ASCO annual meeting 2008
Regression of Skin Lesions in a Patient with Taxane- / Trastuzumab-refractory Tumor Baseline (sept 07) Cycle 3 (nov 07) F. André et al. ASCO annual meeting 2008
Regression of a Brain Metastasis in a Patient with Taxane- / Trastuzumab-refractory Tumor Baseline Month 1 Month 5 F. André et al. ASCO annual meeting 2008
In conclusion: does resistance to anti- HER2 agents really exist? HER2 is a driver event for HER2+ breast cancer and its inhibition appears to remain important along disease course. The key is to find the good partner(s): cytotoxic, other anti-her2 agents, other MTT
Inefficacy of trastuzumab can be linked to two additional mechanisms 1. We always consider tumor profile but we should also consider patient's profile
Part of trastuzumab activity is linked to ADCC Hudis C. N Engl J Med Do immunoglobulin G Fragment C Receptor polymorphisms impact trastuzumab activity?
2. If resistance to anti-her2 disease, consider a non HER2-disease! Vignot et al. CROH 2012
Resistance to anti-her2 therapies Pr David Khayat Service d Oncologie Médicale Groupe Hospitalier Pitié Salpêtrière -Paris