LAPATINIB-Resistance to small Molecule ErbB2 Tyrosine Kinase Inhibitor (TKI)
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1 LAPATINIB-Resistance to small Molecule ErbB2 Tyrosine Kinase Inhibitor (TKI) Prim Mr Sc Dr Suzana Vasović Institute for oncology and radiology of Serbia UMOS, X Conference, Belgrade
2 How do we translate complex molecular interactions into therapeutic benefit? 1 1. Reprinted from Cell, Volume 100. Hanahan D, Weinberg RA. The hallmarks of cancer. Pages Copyright (2000), with permission from Elsevier.
3 Why the need to understand the biological effects of targeted agents? Identify the target population Evaluate biologically active doses rather than MTD Use in minimal disease settings Chronic therapy Reduce toxicity in combination with other agents Enhance efficacy of second-generation therapies Rationale for combination therapies ( strategies to overcome resistance)
4 Signal transduction - Erb family of receptors
5 Lapatinib is an oral, small molecule, dual targeted agent for the treatment of ErbB2- positive breast cancer that acts intracellularly
6 Lapatinib inhibits both Erk and AKT signalling pathways
7 Additional benefit of intracellular mode of action of lapatinib Lapatinib provides direct inhibition of signalling pathways different to those affected by trastuzumab 1 Lapatinib is active in tumours that express p95 ErbB2, 2 which characterises a particularly aggressive phenotype of breast cancer 3 1. Nagata et al. Cancer Cell 2004;6:117 27; 2. Scaltriti et al. J Natl Cancer Inst 2007;99:628 38; 3. Saez et al. Clin Cancer Res 2006;12:424 31
8 How specific are TKIs? Examples: Lapatinib: binds only 4/113 kinases tested CI-1033 (pan- ErbB): binds ate least 36/113 Staurosporine: binds 104/113 8
9 Clinical experience with lapatinib in ErbB2- positive metastatic breast cancer patients pre-treated with trastuzumab
10 Phase III, randomised, controlled study of lapatinib plus capecitabine versus capecitabine alone (study EGF ) 1 Patients with ErbB2-positive locally advanced or metastatic breast cancer that progressed after prior anthracycline, taxane and trastuzumab (N=399) RANDOMISATION Lapatinib 1250 mg po qd continuously + capecitabine 2000 mg/m 2 /d po days 1 14 q 3 wk Capecitabine 2500 mg/m 2 /day p.o. days 1 14 q 3 wk po = oral; qd = once daily; q 3 wk = once every 3 weeks Treatment continued until progression 1. Cameron et al. Breast Can Res Treat 2008;[Epub ahead of print]; 2. Geyer et al. N Engl J Med 2006;355:
11 1. Cameron et al. Breast Can Res Treat 2008;[Epub ahead of print]. Figure Adapted from Cameron D, Casey M, Press M et al. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat, 2008 Epub ahead of print, with kind permission of Springer Science and Business Media. Lapatinib plus capecitabine: significantly longer time-to-progression in difficult to treat population (study EGF ; independent assessment)* 1 *Primary endpoint was independently assessed time to progression 2 ; HR = hazard ratio; CI = confidence interval
12 1. Cameron et al. Breast Can Res Treat 2008;[Epub ahead of print]. Figure Adapted from Cameron D, Casey M, Press M et al. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat, 2008 Epub ahead of print, with kind permission of Springer Science and Business Media. Lapatinib plus capecitabine: overall survival by independent assessment (study EGF100151) 1 Data presented are from an April 2006 analysis, which was conducted prior to patients being permitted to switch therapy.
13 Observations Clinical response (CR and PR) to lapatinib is generaly transient In BT474 cells: initial massive apoptosis in response to lapatinib followed by outgrowth of ER+ resistant cells The development of resistance tolapatinib in the clinic appears similar to that which occurs in cell culture
14 Non-classical ER Signaling: ER Crosstalk Enhances IGFR/HER2 Signaling * * Stephen Johnston, CCR, 2010 Crosstalk at the membrane to enhance IGFR/HER2 signaling via ER leading to TOR activation London 2012 FASDAT Advisory Board The Sheraton Skyline
15 Proposed mechanisms of acquired resistance: Akt, protein kinase B; HER, human epidermal growth factor receptor; HSP90, heat shock protein 90; IGF1R, insulin-like growth factor receptor 1; MAPK, mitogen-activated protein kinase; MET, mesenchymal epithelial transition factor; mtor, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; VEGFR, vascular endothelial growth factor receptor.
16 LAPATINIB in ErbB2- + /ER- + mbc 1 3 Aromatase inhibitor ErbB heterodimer signal transduction Ligands Androgens Estrogen EGFR (or other ErbB) ErbB2 Non-genomic ER response lapatinib lapatinib lapatinib Estrogen receptor Citoplasm Cross talk PI3K/Akt MAPK pathway Jedro Genomic ER response Gene transcription
17 Hormonal Therapy in HER2+ ABC Regimen ORR, % PFS, mo Anastrozole + trastuzumab (N = 103) Anastrozole (N = 104) Lapatinib + letrozole (N = 642) Letrozole (N = 644) Abbreviations: ORR, overall response rate; PFS, progression-free survival. 1. Mackey JR, et al. SABCS 2006, Abstract Johnston S, et al. J Clin Oncol. 2009;27:
18 EGF30008 study design Front line MBC Postmenopausal ER+ and/or PgR+ (N=1286 including 217 HER2+) Letrozole 2.5 mg QD + Lapatinib 1500 mg QD Stratification: Visceral vs. non-measurable disease Prior hormone therapy Letrozole 2.5 mg QD + Placebo Hierarchical Statistical Analysis 1. Test HER2+ subgroup at α=0.05 (55% increase in median PFS) 2. If significant then test: ITT population at α=0.05 (30% increase in median PFS) 3. HER2- subgroup provided as supportive to determine degree HER2+ influences TTP endpoint
19 EGF30008 study results Clinical efficacy in overall population Clinical efficacy in ITT population Johnston et al. JCO
20 Model for ER/AXLdependent lapatinib resistance and the crosstalk among ER, AXL, and HER family receptors in ER-positive and HER2+ BC cells. Coactivation of AXL with HER2 leads to downstream PI3K/AKT and ERK signaling which are essential to cell growth and survival. ER blockers such as estrogen deprivation or fulvestrant reduce the expression of AXL Inhibiting both HER2and AXL is necessary to reduce the downstream PI3K/AKT and ERK signaling and cell growth. 26
21 MAIN strategy : restoration of trastuzumab/her2 sensitivity by targeting the PI3K/Akt/mTOR pathway The PI3K/Akt/mTOR signal transduction pathway is critical to cell growth, proliferation, metabolism, survival, and angiogenesis and has been implicated in several types of cancers HER2+ BC: - with high levels of phosphorylated Akt, - activating mutations of PI3CKA, - loss of PTEN have worse outcomes after trastuzumab-based therapy Activated PI3K/Akt/mTOR signaling appears to play a role in both acquired and de novo HER2 resistance. 1. Sharial, J Crown and B.T.Hennessy. Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer. Annals of Oncology 2012; 23 (12):
22 Future strategies for overcoming HER2 resistance: inhibitors of the PI3K/Akt/mTOR pathway mtor interacts with ER signaling as well as growth factors including IGF-1, VEGF, and ErbB1,2 RTKs: EGFR, HER2, IGF1-R ER ER PTEN Src CoA Inactivated suppressors PI3K E Aberrations of this pathway are common in multiple cancers, including BC3,4 P Ras TSC2 TSC1 Nonnuclear/ nongenomic AKT S6K1 Activation of transcription factors Proliferation Survival Invasion mtor Cellular metabolism Angiogenesis ER Nuclear/ genomic mtor inhibitor MAPK P P P P ER P ER P CoA EREs P CoA mtor is a central regulator of multiple signaling pathways involved in cancer P CoA AP-1 TFs AP-1/SP-1 TFs-REs Gene expression (GFs, RTKs) Furthermore, hyperactivation of the PI3K/AKT/mTOR pathway has been observed in endocrine-resistant BC cells4 Inhibition of the mtor pathway may enhance endocrine sensitivity by inhibiting ligand-independent activation of the estrogen receptor Dual blockade of the mtor and endocrine pathways via mtor inhibition in combination with endocrine therapy offers clinical benefits for patients progressing on NSAIs 1. Osborne CK, et al. Annu Rev Med. 2011;62: ; 2. Yamnik RL, et al. J Biol Chem. 2009;284(10): ; 3. Samuels Y, et al. Science. 2004;304(5670):554; 4. Miller TW, et al. J Clin Invest. 2010;120(7):
23 Clinical data of everolimus in patients with trast-refractorher2+ BC
24 Current strategies for overcoming resistance: maintaining HER2-targeted therapy switching chemotherapeutic agent switching HER2-targeted therapy combining HER2 inhibitors combining HER2 inhibitors with antiestrogens (AI) combining HER2 inhibitors with m-tor inhibitors 1. Sharial, J Crown and B.T.Hennessy. Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer. Annals of Oncology 2012; 23 (12):
25 EGF104900: Study design HER2 (FISH+/IHC3+) metastatic BC Progression on antracyclins taxanes trastuzumab Progression on trastuzumab in MBC R A N D O M I S A T I O N Lapatinib (oral) 1500 mg daily (n=148) Crossover allowed on lapatinib + trastuzumab arm if progression occured at least 4 weeks on the therapy Lapatinib (oral) 1000 mg daily+ trastuzumab (IV) 4 mg/kg loading dose, after 2 mg/kg weekly (n=148) Primary endpoint: PFS Secondary endpoint: OS ORR CBR Evaluation of response after 4, 8, 12, 16 weeks, afterwards every 8 weeks Evaluation by independent reviewer (po RECIST krit.) FISH = fluorescence in situ hybridisation; IHC = immunohistochemistry; MBC = metastatic breast cancer; RECIST = Response Evaluation Criteria in Solid Tumours. Blackwell et al. J Clin Oncol. 2010;28:
26 Cumulative % alive without progression EFG104900: PFS in ITT patient population Lapatinib (n=145) Lapatinib + trastuzumab (n=146) Progressed or died Median PFS 128 (88%) 8.1 weeks 127 (87%) 12 weeks P-value % Hazard ratio: 0.73 (95% CI: 0.57, 0.93) 6-months PFS L L+T 0 Patients at risk Investigator-assessed. CI = confidence interval; ITT = intent-to-treat; L = lapatinib; PFS = progression-free survival; T = trastuzumab. Blackwell et al. J Clin Oncol. 2010;28: % Time from randomization (weeks)
27 Survival rate (%) EGF104900: OS in the ITT population Died, n (%) Median p-value Lapatinib (n=145) 113 (78%) 9.5 months Lapatinib + trastuzumab (n=146) 105 (72%) 14 months % 6-months OS 80% 56% 41% 12- months OS HR: 0.75 (95% CI 0.57, 0.97) 49% patients crossed-over from the control arm (lapatinib) to receive vertical dual HER2 blockade Patients at risk Time from randomization (months) L L+T ITT = intent-to-treat; L = lapatinib; OS = overall survival; T = trastuzumab. Blackwell et al. J Clin Oncol. 2012;30:
28 Cumulative Proportion Alive EGF104900: OS subgroup analysis by hormone receptor status HR-positive 1.0 HR-negative Lap+Tras Lap Number at Risk Lap+Tras Lap Time from Randomization (Months) Lap+Tras Lap Lap+Tras N=71 Lap N=70 OS HR (95% CI) Lap+Tras N=75 Lap N=75 OS HR (95% CI) Median OS, months ( ) Median OS, months ( ) CI = confidence interval; HR = hormone receptor; Lap = lapatinib; OS = overall survival; Tras = trastuzumab. Tyverb Assessment report EMEA/H/C/000795/II/ Available at: _Assessment_Report_-_Variation/human/000795/WC pdf. Accessed September 2013.
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