Mechanism of resistance to target therapy
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Mechanism of resistance to target therapy

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resistance mechanism to target therapy

resistance mechanism to target therapy

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  • Questi i farmaci ed i loro target. Si suppone che quanto più queste vie siano importanti nel singolo pz e nella singola neoplasia, tanto più il farmaco è efficace. Ma evidentemente ci sono pts la cui neoplasia non è dipendente (o almeno non è strettamente dipendente da questi path ways) tant’è che non rispondono affatto (R 1°) o progrediscono più o meno rapidamente
  • Ensues: si manifesta
  • R. 2°: o adattativa o evasiva: dopo un periodo di sensibilità al farmaco, il T si ADATTA e mette in atto meccanismi di escape -Netta contrazione della angiogenesi; poche mitosi; molte cell in apoptosi In seguito ripresa della NEOANGIOGENESI ma sempre meno dipendenza dalla N. B.:Resistenza 1a Modificazione del Pattern cellulare (molte cell. Tumorali a svantaggio di quelle non t.; molte mitosi) processo di NEOANGIOVENESI è inesorabile e inarrestabile
  • NB: i “poor risk” sono circa il 20-25%!!! Gli Early progressors calcolati ARBITRARIAMENTE fino a < di 6 mesi di PFS
  • Ma sono gli stessi pts della prima linea??? Non dati disponibili. NB: In everolimus solo 40 pts su 274 del braccio Ever. Erano poor risk
  • Ma sono gli stessi pts della prima linea??? Non dati disponibili. NB: In everolimus solo 40 pts su 274 del braccio Ever. Erano poor risk
  • Ensues: si manifesta
  • Ma sono gli stessi pts della prima linea??? Non dati disponibili. NB: In everolimus solo 40 pts su 274 del braccio Ever. Erano poor risk
  • Ensues: si manifesta
  • Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Pàez-Ribes M , Allen E , Hudock J , Takeda T , Okuyama H , Viñals F , Inoue M , Bergers G , Hanahan D , Casanovas O . Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, 08907 L'Hospitalet de Llobregat, Spain. Comment in: Abstract Multiple angiogenesis inhibitors have been therapeutically validated in preclinical cancer models, and several in clinical trials. Here we report that angiogenesis inhibitors targeting the VEGF pathway demonstrate antitumor effects in mouse models of pancreatic neuroendocrine carcinoma and glioblastoma but concomitantly elicit tumor adaptation and progression to stages of greater malignancy, with heightened invasiveness and in some cases increased lymphatic and distant metastasis. Increased invasiveness is also seen by genetic ablation of the Vegf-A gene in both models, substantiating the results of the pharmacological inhibitors. The realization that potent angiogenesis inhibition can alter the natural history of tumors by increasing invasion and metastasis warrants clinical investigation, as the prospect has important implications for the development of enduring antiangiogenic therapies.
  • Modello in Breast cancer. VEGF è sempre presente durante il corso vitale del tumore, pertanto una sua inibizione (se pure non sufficiente) avrebbe senso anche quando la malattia non è più responsiva. Tuttavia, man mano che il T. cresce, altri fattori pro-angiogenetici vengono prodotti a sostituzione/integrazione del VEGF. Quindi se nelle fasi iniziali può essere sufficiente bloccare il VEGF, nelle fasi più avanzate ciò non è più sufficiente. Infatti ……
  • FGF, fibroblast growth factor;    HIF, hypoxia-inducible factor; PlGF, placental growth factor; VEGF, vascular endothelial growth factor.   This schematic shows “angiogenic escape” to anti‑VEGF treatment, which may be dependent on cancer cell phenomena or endothelial cell phenomena. It may be that other growth factors, such as basic fibroblast growth factor, are responsible.   Cancer Cell. 2005 Oct;8(4):299-309. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Casanovas O , Hicklin DJ , Bergers G , Hanahan D . Department of Biochemistry and Biophysics, Comprehensive Cancer Center, and Diabetes Center, University of California, San Francisco, San Francisco, California 94143, USA. Abstract Function-blocking antibodies to VEGF receptors R1 and R2 were used to probe their roles in controlling angiogenesis in a mouse model of pancreatic islet carcinogenesis. Inhibition of VEGFR2 but not VEGFR1 markedly disrupted angiogenic switching, persistent angiogenesis, and initial tumor growth. In late-stage tumors, phenotypic resistance to VEGFR2 blockade emerged, as tumors regrew during treatment after an initial period of growth suppression. This resistance to VEGF blockade involves reactivation of tumor angiogenesis, independent of VEGF and associated with hypoxia-mediated induction of other proangiogenic factors, including members of the FGF family . These other proangiogenic signals are functionally implicated in the revascularization and regrowth of tumors in the evasion phase, as FGF blockade impairs progression in the face of VEGF inhibition. FGF2 supports endothelial proliferation and de novo tubule formation in the presence of sunitinib
  • FGF, fibroblast growth factor;    HIF, hypoxia-inducible factor; PlGF, placental growth factor; VEGF, vascular endothelial growth factor.   This schematic shows “angiogenic escape” to anti‑VEGF treatment, which may be dependent on cancer cell phenomena or endothelial cell phenomena. It may be that other growth factors, such as basic fibroblast growth factor, are responsible.   Cancer Cell. 2005 Oct;8(4):299-309. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Casanovas O , Hicklin DJ , Bergers G , Hanahan D . Department of Biochemistry and Biophysics, Comprehensive Cancer Center, and Diabetes Center, University of California, San Francisco, San Francisco, California 94143, USA. Abstract Function-blocking antibodies to VEGF receptors R1 and R2 were used to probe their roles in controlling angiogenesis in a mouse model of pancreatic islet carcinogenesis. Inhibition of VEGFR2 but not VEGFR1 markedly disrupted angiogenic switching, persistent angiogenesis, and initial tumor growth. In late-stage tumors, phenotypic resistance to VEGFR2 blockade emerged, as tumors regrew during treatment after an initial period of growth suppression. This resistance to VEGF blockade involves reactivation of tumor angiogenesis, independent of VEGF and associated with hypoxia-mediated induction of other proangiogenic factors, including members of the FGF family . These other proangiogenic signals are functionally implicated in the revascularization and regrowth of tumors in the evasion phase, as FGF blockade impairs progression in the face of VEGF inhibition. FGF2 supports endothelial proliferation and de novo tubule formation in the presence of sunitinib
  • NB: IL-8 elevata anche in pts resistenti/refrattari
  • : 4 1. Hum Pathol. 2011 Oct 10. [Epub ahead of print] Sarcomatoid conversion of clear cell renal cell carcinoma in relation to epithelial-to-mesenchymal transition. Boström AK , Möller C , Nilsson E , Elfving P, Axelson H, Johansson ME. Source Center for Molecular Pathology, Department of Laboratory Medicine, Lund University, Skåne University Hospital, Malmö, SE-205 02 Malmö, Sweden. Abstract Approximately 8% of clear cell renal cell carcinoma cases contain regions of radically different morphology, demonstrating a mesenchymal appearance histologically resembling sarcomas. These biphasic neoplasms are called sarcomatoid clear cell renal cell carcinoma. Patients diagnosed with sarcomatoid clear cell renal cell carcinoma face a considerably worse prognosis due to an increased propensity for metastasis. In the present study we investigate whether the sarcomatoid conversion of clear cell renal cell carcinoma could be interpreted as linked to the process of epithelial-mesenchymal transition. Using 6 biphasic clear cell renal cell carcinoma cases we show that sarcomatoid clear cell renal cell carcinoma shares characteristic markers associated with loss of von Hippel-Lindau tumor suppressor with conventional clear cell renal cell carcinoma and also exhibits a markedly higher proliferative index. Furthermore the sarcomatoid elements demonstrate an enhanced expression of epithelial-mesenchymal transition related mesenchymal markers as compared with the clear cell renal cell carcinoma counterparts. We further selected a representative case, clinically demonstrating direct overgrowth of the sarcomatoid component into the liver and colon, for extended immunohistochemical characterization, resulting in a further set of positive and negative epithelial-mesenchymal transition markers as well as pronounced transforming growth factor β positivity, indicating that sarcomatoid clear cell renal cell carcinoma may be associated to epithelial-mesenchymal transition. Transforming growth factor β1 exposure of in vitro cultured primary clear cell renal cell carcinoma cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid clear cell renal cell carcinoma. Corresponding changes in RNA levels for key epithelial-mesenchymal transition markers were also seen. We therefore suggest that sarcomatoid clear cell renal cell carcinoma morphologically and immunohistochemically may represent a completed epithelial-mesenchymal transition and that transforming growth factor β1 could be an important driving force during the sarcomatoid transdifferentiation of clear cell renal cell carcinoma. Copyright © 2011 Elsevier Inc. All rights reserved. Bull Cancer. 2011 May;98(5):32-9. Interleukin-15 is a major regulator of the cell-microenvironment interactions in human renal cancer. Giron-Michel J, Azzi S, Khawam K, Caignard A, Devocelle A, Perrier A, Chouaib S, Eid P, Azzarone B. Source Hôpital Paul-Brousse, université de Paris-Sud, Inserm UMR 1014, 14, avenue Paul-Vaillant-Couturier, 94807 Villejuif Cedex, France. Abstract Primary human epithelial renal cells of normal (HRE), paratumoral (pTEC) and tumoral (RCC) origin display important differences, concerning the expression and biological effects of the IL-15/IL-15R system that deeply influences the evolution of the tumour microenvironment. A major distinguishing feature is represented in RCC and pTEC by the loss of the γc chain leading to the assembly of a IL-15Rαβ heterodimer that in response to physiologic concentrations of IL-15 initiates the process of their epithelial-mesenchymal transition (EMT). In contrast, this treatment in HRE cells, which display the IL-15Rαβγc heterotrimer, causes opposite effects inhibiting their drift towards EMT. Thus, IL-15 at physiologic concentrations displays novel functions acting as a major regulator of renal epithelial homeostasis. As second distinguishing feature, RCC and pTEC but not HRE cells express a trans-membrane-bound IL-15 (tmb-IL-15) able to deliver a reverse signal in response to the soluble IL-15Rα chain inducing their EMT. In conclusion, comparison of primary normal (HRE) to primary pathological cells (pTEC and RCC) highlights two major issues: (1) IL-15 is a major regulator of epithelial homeostasis; (2) "apparently normal" pTEC cells, could contribute to organize a generalized "pre-neoplastic" environment committed to favour tumour progression Cancer Res. 2009 Feb 15;69(4):1561-9. Epub 2009 Feb 3. Human renal cancer cells express a novel membrane-bound interleukin-15 that induces, in response to the soluble interleukin-15 receptor alpha chain, epithelial-to-mesenchymal transition. Khawam K, Giron-Michel J, Gu Y, Perier A, Giuliani M, Caignard A, Devocelle A, Ferrini S, Fabbi M, Charpentier B, Ludwig A, Chouaib S, Azzarone B, Eid P. Institut National de la Sante et de la Recherche Medicale UMR 542, Université de Paris-Sud, Hôpital Paul Brousse, Villejuif Cedex, France. Although interleukin-15 (IL-15) is a powerful immunomodulatory factor that has been proposed for cancer immunotherapy, its intratumoral expression may be correlated with tumor progression and/or poor clinical outcome. Therefore, neoplasias potentially sensitive to immunotherapy should be checked for their IL-15 expression and function before choosing immunotherapy protocols. Primary human renal cancer cells (RCC) express a novel form of membrane-bound IL-15 (mb-IL-15), which displays three major original properties: (a) It is expressed as a functional membrane homodimer of 27 kDa, (b) it is shed in the extracellular environment by the metalloproteases ADAM17 and ADAM10, and (c) its stimulation by soluble IL-15 receptor alpha (s-IL-15Ralpha) chain triggers a complex reverse signal (mitogen-activated protein kinases, FAK, pMLC) necessary and sufficient to ~induce epithelial-mesenchymal transdifferentiation (EMT), a crucial process in tumor progression whose induction is unprecedented for IL-15. In these cells, complete EMT is characterized by a dynamic reorganization of the cytoskeleton with the subsequent generation of a mesenchymal/contractile phenotype (alpha-SMA and vimentin networks) and the loss of the epithelial markers E-cadherin and ZO-1. The retrosignaling functions are, however, hindered through an unprecedented cytokine/receptor interaction of mb-IL-15 with membrane-associated IL-15Ralpha subunit that tunes its signaling potential competing with low concentrations of the s-IL-15Ralpha chain. Thus, human RCC express an IL-15/IL-15R system, which displays unique biochemical and functional properties that seem to be directly involved in renal tumoral progression.
  • J Urol. 2011 Jul;186(1):289-94. Epub 2011 May 20. A specific gene expression signature characterizes metastatic potential in clear cell renal cell carcinoma. Sanjmyatav J, Steiner T, Wunderlich H, Diegmann J, Gajda M, Junker K. Source Department of Urology, Jena University Hospital, Jena, Germany. Abstract PURPOSE: The discovery of metastasis markers in clear cell renal cell carcinoma is of critical importance to define individual metastatic risk and select patients for new targeted therapies. We identified potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis. MATERIALS AND METHODS: We performed transcriptional profiling of 16 primary metastatic and 18 nonmetastatic clear cell renal cell carcinomas with PIQOR™ microarrays. Differentially expressed genes were validated by quantitative real-time polymerase chain reaction. RESULTS: the possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even in a localized situation.. The metastatic signature contained 127 transcripts. In metastatic samples a greater than 4-fold decrease in expression was detected for the genes CD151 and IKBA (t/F statistic p <0.0001). Quantitative real-time polymerase chain reaction revealed significant differences in expression among all metastatic tumors, including synchronously and metachronously metastasized tumors, and nonmetastatic tumors for FRA2 (p = 0.032) and CD151 (p = 0.005). In addition, the genes B7-H1 (p = 0.040), FRA2 (p = 0.035), CD151 (p = 0.004) and BCL2L2 (p = 0.035) showed significantly higher expression in early metastasized than in nonmetastatic tumor samples. Different B7-H1 (p = 0.002) and BCL2L2 (p = 0.007) expression levels were found in samples with late metastasis compared to those in synchronously metastasized tumors. CONCLUSIONS: We determined a metastatic signature of clear cell renal cell carcinoma by microarray analysis. Our data provide the possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even in a localized situation.
  • IFN, interferon; IL, interleukin; MMP, matrix metalloproteinase; uPAR, urokinase-type plasminogen activator receptor; TSP, thrombospondin; VEGF, vascular endothelial growth factor.   Multiple factors affect resistance. These include factors that decrease angiogenesis and factors that increase angiogenesis, both in a single patient or a single model. Several of these factors need to be accounted for when developing a comprehensive treatment approach and in understanding why a patient may be resistant to any one approach.
  • IFN, interferon; IL, interleukin; MMP, matrix metalloproteinase; uPAR, urokinase-type plasminogen activator receptor; TSP, thrombospondin; VEGF, vascular endothelial growth factor.   Multiple factors affect resistance. These include factors that decrease angiogenesis and factors that increase angiogenesis, both in a single patient or a single model. Several of these factors need to be accounted for when developing a comprehensive treatment approach and in understanding why a patient may be resistant to any one approach.
  • cell carcinoma based on a select number of genes even in a localized situation.
  • dovitinib lactate  The orally bioavailable lactate salt of a benzimidazole-quinolinone compound with potential antineoplastic activity. Dovitinib strongly binds to fibroblast growth factor receptor 3 (FGFR3) and inhibits its phosphorylation, which may result in the inhibition of tumor cell proliferation and the induction of tumor cell death. In addition, this agent may inhibit other members of the RTK superfamily, including the vascular endothelial growth factor receptor; fibroblast growth factor receptor 1; platelet-derived growth factor receptor type 3; FMS-like tyrosine kinase 3; stem cell factor receptor (c-KIT); and colony-stimulating factor receptor 1; this may result in an additional reduction in cellular proliferation and angiogenesis, and the induction of tumor cell apoptosis. The activation of FGFR3 is associated with cell proliferation and survival in certain cancer cell types. FGF/FGFR signaling may also serve as an escape pathway in tumors that are being treated with inhibitors of other cellular signaling components, such as vascular endothelial growth factor receptor (VEGFR). receptor tyrosine kinase inhibitor TKI258 RTK inhibitor TKI258
  • Activating mutations or overexpression of fibroblast growth factor receptors (FGFRs) or their ligands have been associated with neoplastic progression and tumor vascularization in multiple cancer types, including breast cancer, bladder cancer, multiple myeloma, hepatocellular, and renal cell carcinoma.17–21 Aberrant activation of FGFR signaling has been shown to result in poor patient prognosis. In a recent analysis of 880 unselected breast carcinomas, amplification of FGFR1 was the strongest independent predictor of poor outcome.17 Inhibition of FGFR may have clinical utility in cancers that over express FGFRs, such as breast cancer,17 or display a prevalence of FGFR mutations, such as bladder cancer.22 FGF/FGFR signaling may also serve as an escape pathway in tumors that are being treated with inhibitors of other cellular signaling components, such as vascular endothelial growth factor receptor (VEGFR). Dovitinib, orally bioavailable, has demonstrated inhibition of VEGFR and FGFRs in clinical trials.23 BGJ398 is an orally bioavailable, selective inhibitor of the FGFRs at nanomolar concentrations in enzymatic assays and proliferative assays and in in vivo models.24 Dovitinib is in phase II development in renal cell carcinoma, advanced breast cancer, and relapsed multiple myeloma. A Phase I study with BGJ398 is ongoing. 23. Shi M, Kim KB, Chesney J, et al. Effect of TKI258 in plasma biomarkers and pharmacokinetics in patients with advanced melanoma. J Clin Oncol . 2009;27(suppl.) Abstract 9020.
  • I target dei diversi farmaci TKI NON SONO esattamente gli srtessi
  • NB: Anche l’affinità per i singoli TARGET e’ DIVERSA Pur appartenendo alla stessa categoria di farmaci, la potenza dell’attività anti VEGF-R è molto diversa a seconda delle molecole, così come quella antiPDGFR
  • Thoroughly: interamente
  • Display Settings: Format Send to: Choose Destination Cancer. 2010 Jun 14. [Epub ahead of print] Phase 3 trial of everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Kay A, Ravaud A; for the RECORD‐1 Study Group. Department of Medicine, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York. Abstract BACKGROUND:: A phase 3 trial demonstrated superiority at interim analysis for everolimus over placebo in patients with metastatic renal cell carcinoma (mRCC) progressing on vascular endothelial growth factor receptor-tyrosine kinase inhibitors. Final results and analysis of prognostic factors are reported. METHODS:: Patients with mRCC (N = 416) were randomized (2:1) to everolimus 10 mg/d (n = 277) or placebo (n = 139) plus best supportive care. Progression-free survival (PFS) and safety were assessed to the end of double-blind treatment. Mature overall survival (OS) data were analyzed, and prognostic factors for survival were investigated by multivariate analyses. A rank-preserving structural failure time model estimated the effect on OS, correcting for crossover from placebo to everolimus. RESULTS:: The median PFS was 4.9 months (everolimus) versus 1.9 months (placebo) (hazard ratio [HR], 0.33; P < .001) by independent central review and 5.5 months (everolimus) versus 1.9 months (placebo) (HR, 0.32; P < .001) by investigators. Serious adverse events with everolimus, independent of causality, in >/=5% of patients included infections (all types, 10%), dyspnea (7%), and fatigue (5%). The median OS was 14.8 months (everolimus) versus 14.4 months (placebo) (HR, 0.87; P = .162), with 80% of patients in the placebo arm crossed over to everolimus. By the rank-preserving structural failure time model, the survival corrected for crossover was 1.9-fold longer (95% confidence interval, 0.5-8.5) with everolimus compared with placebo only. Independent prognostic factors for shorter OS in the study included low performance status, high corrected calcium, low hemoglobin, and prior sunitinib (P < .01). CONCLUSIONS:: These results established the efficacy and safety of everolimus in patients with mRCC after progression on sunitinib and/or sorafenib. Cancer 2010. (c) 2010 American Cancer Society.
  • dovitinib lactate  The orally bioavailable lactate salt of a benzimidazole-quinolinone compound with potential antineoplastic activity. Dovitinib strongly binds to fibroblast growth factor receptor 3 (FGFR3) and inhibits its phosphorylation, which may result in the inhibition of tumor cell proliferation and the induction of tumor cell death. In addition, this agent may inhibit other members of the RTK superfamily, including the vascular endothelial growth factor receptor; fibroblast growth factor receptor 1; platelet-derived growth factor receptor type 3; FMS-like tyrosine kinase 3; stem cell factor receptor (c-KIT); and colony-stimulating factor receptor 1; this may result in an additional reduction in cellular proliferation and angiogenesis, and the induction of tumor cell apoptosis. The activation of FGFR3 is associated with cell proliferation and survival in certain cancer cell types. FGF/FGFR signaling may also serve as an escape pathway in tumors that are being treated with inhibitors of other cellular signaling components, such as vascular endothelial growth factor receptor (VEGFR). receptor tyrosine kinase inhibitor TKI258 RTK inhibitor TKI258
  • Activating mutations or overexpression of fibroblast growth factor receptors (FGFRs) or their ligands have been associated with neoplastic progression and tumor vascularization in multiple cancer types, including breast cancer, bladder cancer, multiple myeloma, hepatocellular, and renal cell carcinoma.17–21 Aberrant activation of FGFR signaling has been shown to result in poor patient prognosis. In a recent analysis of 880 unselected breast carcinomas, amplification of FGFR1 was the strongest independent predictor of poor outcome.17 Inhibition of FGFR may have clinical utility in cancers that over express FGFRs, such as breast cancer,17 or display a prevalence of FGFR mutations, such as bladder cancer.22 FGF/FGFR signaling may also serve as an escape pathway in tumors that are being treated with inhibitors of other cellular signaling components, such as vascular endothelial growth factor receptor (VEGFR). Dovitinib, orally bioavailable, has demonstrated inhibition of VEGFR and FGFRs in clinical trials.23 BGJ398 is an orally bioavailable, selective inhibitor of the FGFRs at nanomolar concentrations in enzymatic assays and proliferative assays and in in vivo models.24 Dovitinib is in phase II development in renal cell carcinoma, advanced breast cancer, and relapsed multiple myeloma. A Phase I study with BGJ398 is ongoing. 23. Shi M, Kim KB, Chesney J, et al. Effect of TKI258 in plasma biomarkers and pharmacokinetics in patients with advanced melanoma. J Clin Oncol . 2009;27(suppl.) Abstract 9020.
  • PHASE I J Clin Oncol 27:15s, 2009 (suppl; abstr 3563) Author(s): E. Angevin, J. A. Lopez, A. Pande, C. Moldovan, M. Shi, J. C. Soria, X. Wang, A. Harzstark, J. Saro, B. Escudier; Institut Gustave Roussy, Villejuif, France; Hospital 12 de Octubre, Madrid, Spain; Novartis Oncology, East Hannover, NJ; University of California, San Francisco, CA Abstract: Background: TKI258 is a potent receptor tyrosine kinase inhibitor (TKI) that selectively targets VEGFR, PDGFR, FGFR, CSF1R, c-KIT, RET, TrKA, and FLT3. Compared to other TKI agents, TKI258 additionally targets FGFR. FGF has been reported as an important escape mechanism of anti-VEGFR therapies. Methods: The primary objective of this phase I was to determine the maximum tolerated dose (MTD) of TKI258, administered orally on a 5 days on / 2 days off schedule in repeated 28 day cycles, in mRCC pts refractory to standard therapies. A two-parameter Bayesian logistic regression model and safety data for at least 21 pts will be used to determine MTD. Results: A phase I study is ongoing. As of December 2008, 11 pts (9 m, 2 f), median age: 55 (29-66 yrs) have been enrolled. Four pts have been treated at 500 mg/day (start dose): 2 are ongoing at cycle (C) 7; 1 pt discontinued due to PD and 1 due to sinus bradycardia. Five pts received 600 mg/day: 2 DLTs (G4 hypertension and G3 fatigue - pts discontinued) leading to dose reduction of all patients to 500mg/day; 2 pts in C5 and C4, 1 pt discontinued for PD. Two pts just entered the extension cohort at 500 mg. Other toxicities ≥G2 included fatigue, nausea, vomiting, diarrhea, neutropenia, folliculitis and dizziness. PK data showed CMax range (180-487 ng/mL, n = 8), and AUC range (2200-8251 ng/mL*h). Preliminary biomarker data indicated pts had high baseline VEGF (506 ± 203 pg/ml, n=6) and bFGF (220 ± 185 pg/ml, n = 6) levels, which may reflect failure of previous anti-VEGF agents. Induction of plasma FGF23 levels, a pharmacodynamic biomarker of FGFR1 inhibition, was observed in pts from the first 500 mg/day dosing cohort. Preliminary evidence of efficacy is observed with one minor response (-17% at C4), 4 stable disease and 1 dramatic shrinkage/necrosis of some target lesions (lymph node & suprarenal mass). Conclusions: TKI258 500mg/day seems a feasible schedule in heavily pre-treated mRCC patients with some indications of clinical benefit. These preliminary findings will be confirmed in the extension cohort.
  • OR/TS, objective response/tumor shrinkage; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.   5. ClinicalTrials.gov. NCT00474786. 6. ClinicalTrials.gov. NCT00678392. This table shows a summary of selected trials of second‑line agents in metastatic kidney cancer. The first 4 rows have been discussed, with the 3 phase II studies and 1 phase III trial showing variable response in degrees of tumor burden shrinkage and a progression‑free survival time averaging approximately 4-7 months. The bottom 2 rows show prospective ongoing trials that are studying metastatic kidney cancer patients who failed previous therapy. The first is examining temsirolimus vs sorafenib in patients previously treated with sunitinib; in essence, comparing switching to an mTOR‑directed approach vs continuing with a VEGF‑targeted approach. The AXIS trial is comparing more- vs less-potent VEGF inhibition by comparing axitinib vs sorafenib in patients who have failed frontline therapy for metastatic RCC. These important and large trials will help shape the landscape of sequenced therapy in kidney cancer. NB: non ci sono studi di confronto tra mTOR in. e nuove molecole anti VEGF (es. Axitinib)  
  • NB: in trials quindi in seconda linea arrivano circa il 50% dei pts; ma fuori trials sono circa il 30%!!!
  • NB: non ci sono studio di confronto tra mTOR in. e nuove molecole (es. Axitinib) Prospective ongoing trials that are studying metastatic kidney cancer patients who failed previous therapy. The first is examining temsirolimus vs sorafenib in patients previously treated with sunitinib; in essence, comparing switching to an mTOR‑directed approach vs continuing with a VEGF‑targeted approach. The AXIS trial is comparing more- vs less-potent VEGF inhibition by comparing axitinib vs sorafenib in patients who have failed frontline therapy for metastatic RCC. These important and large trials will help shape the landscape of sequenced therapy in kidney cancer. RECORD III Sub-category:Kidney Cancer Category:Genitourinary Cancer Meeting:2010 ASCO Annual Meeting Session Type and Session Title:Trials in Progress Poster Session, Trials in Progress Poster Session Abstract No:TPS232 Citation:J Clin Oncol 28:15s, 2010 (suppl; abstr TPS232) Author(s):J. J. Knox, A. C. Kay, E. Schiff, N. Hollaender, N. Rouyrre, A. Ravaud, R. J. Motzer; Princess Margaret Hospital, Toronto, ON, Canada; Novartis Oncology, Florham Park, NJ; Novartis Pharmaceuticals Corporation, Florham Park, NJ; Novartis Pharma AG, Basel, Switzerland; Oncology, Hospital Saint Andre CHU, Bordeaux, France; Memorial Sloan-Kettering Cancer Center, New York, NY Abstract: Background: Targeted therapies for advanced renal cell carcinoma (RCC) have changed treatment paradigms. Currently, sequential monotherapy with targeted agents is the standard of care. Sunitinib is a multikinase inhibitor approved for first-line use in advanced RCC; everolimus, an oral inhibitor of mTOR, is approved for use following sunitinib. Currently, these 2 agents have level 1 recommendations for use in the first and second line settings, respectively. However, the most appropriate sequence for everolimus and sunitinib has not been established in a prospective clinical trial. The RECORD-3 (Renal Cell Cancer Treatment with Oral RAD001 Given Daily) trial will assess progression-free survival (PFS) for everolimus- sunitinib versus sunitinib-everolimus in treatment naïve patients with mRCC. RECORD-3 is the first trial to evaluate everolimus as second-line therapy after treatment solely with sunitinib. Methods: RECORD-3 is a randomized, open-label, multicenter phase II trial currently recruiting participants. Up to 390 patients with mRCC (clear-cell or non-clear-cell), with or without nephrectomy, ≥1 measurable baseline lesion (per RECIST criteria), Karnofsky performance status ≥70%, adequate liver, renal, and bone marrow function, and left ventricular ejection fraction ≥ lower limit of normal will be enrolled. The primary objective is to determine whether everolimus is noninferior to sunitinib, as assessed by PFS, for first-line treatment of mRCC. Patients are randomized 1:1 to receive everolimus 10 mg/d PO once daily or sunitinib 50 mg/d PO for 4 wk followed by 2 wk off therapy until disease progression; upon progression, patients will cross over to second-line treatment with the opposite drug until the second occurrence of progression. The primary endpoint will assess PFS after first-line treatment. Overall efficacy of the 2 sequences will be compared based on the time from start of the sequence to progression after second-line therapy, or death. Overall survival, objective response rate, patient-reported outcomes, and safety also will be assessed. The first patient visit was October 22, 2009; 11 patients have entered the study to date.
  • EGFR, epidermal growth factor receptor; IFN, interferon; mTOR, mammalian target of rapamycin; VEGF, vascular endothelial growth factor.   In other oncology settings, combining multiple active agents, if tolerated, can increase the cure rate. This schematic shows where different inhibitors may act upon the tumor pathway, that is, through angiogenesis or directly on the tumor cells. The VEGF and mTOR inhibitors are most prominent in the setting of kidney cancer. Epidermal growth factor receptor inhibitors have not shown significant clinical activity in RCC. Angiogenesis inhibitors, including inhibitors of Tie‑2    , which is a receptor on endothelial cells, and integrin inhibitors are in clinical development.  
  • GI, gastrointestinal.   This table shows the different major toxicities of available agents, including where they overlap. In early studies, bevacizumab and temsirolimus appear to be the most combinable agents, perhaps because of the nonoverlapping nature of their toxicity profiles.
  • EGFR, epidermal growth factor receptor; IFN, interferon; mTOR, mammalian target of rapamycin; VEGF, vascular endothelial growth factor.   In other oncology settings, combining multiple active agents, if tolerated, can increase the cure rate. This schematic shows where different inhibitors may act upon the tumor pathway, that is, through angiogenesis or directly on the tumor cells. The VEGF and mTOR inhibitors are most prominent in the setting of kidney cancer. Epidermal growth factor receptor inhibitors have not shown significant clinical activity in RCC. Angiogenesis inhibitors, including inhibitors of Tie‑2    , which is a receptor on endothelial cells, and integrin inhibitors are in clinical development.  
  • EGFR, epidermal growth factor receptor; IFN, interferon; mTOR, mammalian target of rapamycin; VEGF, vascular endothelial growth factor.   In other oncology settings, combining multiple active agents, if tolerated, can increase the cure rate. This schematic shows where different inhibitors may act upon the tumor pathway, that is, through angiogenesis or directly on the tumor cells. The VEGF and mTOR inhibitors are most prominent in the setting of kidney cancer. Epidermal growth factor receptor inhibitors have not shown significant clinical activity in RCC. Angiogenesis inhibitors, including inhibitors of Tie‑2    , which is a receptor on endothelial cells, and integrin inhibitors are in clinical development.  
  • Memorial Sloan-Kettering Cancer Center, New York, NY. Fox Chase Cancer Center, Philadelphia, PA; Pfizer Oncology, La Jolla, CA; Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI Sunitinib is an oral, multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors with proven clinical benefit in patients with metastatic renal cell carcinoma (RCC). This phase I/II study investigated sunitinib in combination with an epidermal growth factor receptor inhibitor, gefitinib, in patients with metastatic RCC. In phase I, patients received sunitinib 37.5 or 50 mg in 6-week cycles (4 weeks on treatment, 2 off) plus gefitinib 250 mg, both once daily, to determine the sunitinib maximum tolerated dose (MTD). Pharmacokinetics was assessed for both drugs. In phase II, patients received sunitinib MTD plus gefitinib to evaluate the safety and antitumor activity of this combination. Forty-two patients were enrolled: 11 in phase I, and 31 in phase II. In phase I, 2 dose-limiting toxicities were observed with sunitinib 50 mg ( grade 2 left ventricular ejection fraction decline and grade 3 fatigue), and 37.5 mg was declared the MTD. Thirteen patients treated at the MTD achieved a partial response (objective response rate: 37%; 95% confidence interval, 22-55) and 12 (34%) had stable disease. Median progression-free survival was 11 months (95% confidence interval, 6-17). The most commonly reported grade 3/4 treatment-related adverse event was diarrhea (14%), the only grade 3/4 adverse event to occur in >2 patients. Pharmacokinetic analyses did not indicate any drug-drug interactions. In metastatic RCC, sunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapy with an acceptable safety profile. Dosing, pharmacokinetic profile, and safety support study of sunitinib plus an epidermal growth factor receptor inhibitor in other tumor types.
  • EGFR, epidermal growth factor receptor; IFN, interferon; mTOR, mammalian target of rapamycin; VEGF, vascular endothelial growth factor.   In other oncology settings, combining multiple active agents, if tolerated, can increase the cure rate. This schematic shows where different inhibitors may act upon the tumor pathway, that is, through angiogenesis or directly on the tumor cells. The VEGF and mTOR inhibitors are most prominent in the setting of kidney cancer. Epidermal growth factor receptor inhibitors have not shown significant clinical activity in RCC. Angiogenesis inhibitors, including inhibitors of Tie‑2    , which is a receptor on endothelial cells, and integrin inhibitors are in clinical development.  
  • DUBBIA
  • Dati preliminari ad ASCO 2008 SONO le PFS più lunghe mai ottenute
  • CALG:
  • NB: primo endpoint NON RAGGIUNTO. PFS per Sunitinib molto breve. Perche?
  • Most common events included gastrointestinal fistula/rectal hemorrhage, general physical health deterioration, Fatigue/asthenia/malaise and renal failure
  • Most common events included gastrointestinal fistula/rectal hemorrhage, general physical health deterioration, Fatigue/asthenia/malaise and renal failure
  • Nashville, Florida Center, USA
  • Beva 10 mg/kg evary 2 ww ev; Eve 10 mg/die os.
  • Beva 10 mg/kg evary 2 ww ev; Eve 10 mg/die os.
  • Journal of Clinical Oncology , Vol 25, No 22 (August 1), 2007: pp. 3288-3295 Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First- or Second-Line Therapy in Patients With Metastatic Renal Cell Cancer Jared A. Gollob, W. Kimryn Rathmell, Tina M. Richmond, Christine B. Marino, Elizabeth K. Miller, Gayle Grigson, Catharine Watkins, Lin Gu, Bercedis L. Peterson, John J. Wright From the Division of Medical Oncology, Department of Medicine, and Departments of Biostatistics and Bioinformatics, Duke University Medical Center, Durham; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC; and Investigational Drug Branch, National Cancer Institute, Bethesda, MD Address reprint requests to Jared A. Gollob, MD, Duke University Medical Center, DUMC 3441, Durham, NC 27710; e-mail: jared.gollob@duke.edu Purpose We undertook this study to determine the activity and tolerability of sorafenib administered with interferon alfa-2b (IFN- -2b) as first- or second-line therapy in metastatic renal cell cancer (RCC). Patients and Methods Between November 2004 and October 2006, 40 patients at two sites were enrolled onto a phase II trial of sorafenib plus IFN- -2b. Treatment consisted of 8-week cycles of sorafenib 400 mg orally bid plus IFN- -2b 10 million U subcutaneously three times a week followed by a 2-week break. Patients were eligible to receive additional cycles of therapy until disease progression. Dose reduction of both drugs by 50% was permitted once for toxicity. Results The response rate was 33% (95% CI, 19% to 49%; 13 of 40 patients), including 28% partial responses (n = 11) and 5% complete responses (n = 2). Responses were seen in treatment-naïve and interleukin-2 (IL-2) –treated patients within the first two cycles. The median duration of response was 12 months. With a median follow-up time of 14 months, median progression-free survival time was 10 months (95% CI, 8 to 18 months), and median overall survival time has not yet been reached. Fatigue, anorexia, anemia, diarrhea, hypophosphatemia, rash, nausea, and weight loss were the most common toxicities. Grade 3 toxicities were uncommon but included hypophosphatemia, neutropenia, rash, fatigue, and anemia. Dose reductions were required in 65% of patients. Conclusion The combination of sorafenib and IFN- -2b has substantial activity in treatment-naïve and IL-2–treated patients with RCC. The toxicity exceeded that of either drug alone, but dose reductions and breaks between cycles allowed for chronic therapy. A larger, randomized trial would determine whether there is any advantage to this regimen compared with sorafenib alone.
  • NB: PFS di solo Sora in II linea: 7 mesi. Auspicato dall’Autore uno studio di fase III (Sora vs Sora + IFN) mai fatto.

Mechanism of resistance to target therapy Mechanism of resistance to target therapy Presentation Transcript

  • Otranto 27 gennaio 2012MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC Michele Guida Dipartimento di Oncologia Medica Istituto dei Tumori Bari
  • Drugs Resistance in mRCC1. Definition of resistance2. The resistance mechanisms3. How can we overcome the resistance mechanisms?
  • Drugs Resistance in mRCC1. Definition of resistance2. The resistance mechanisms3. How can we overcome the resistance mechanisms?
  • Drugs Resistance: DefinitionPRIMARY(also “refractoriness” or “intrinsic responsiveness”):Lack of efficacy to TKI from the start of therapySECONDARY(also “acquired” or “adaptive” or “evasive” or“angiogenesis escape”):Arises upon the initial response to TKI lastingfor a period of time of variable length
  • Primary and Secondary Resistance Adaptive (evasive) resistance Intrinsic non-responsiveness 2008
  • Pattern of Response to Available Therapy in mRCC about 6 months about 12 months 30% of pts 10-15% of pts 50-60% of pts Rini, Urologic Oncology 2008 Rini, Lancet Oncol 2009
  • Drugs Resistence in mRCC: Influence of patient risk score and prior therapy % primarySetting Author Drug resistance Motzer, 2007 Ranpura, 2010 Sunitinib 22.41a linePts with good-intermediate prognosis Su, 2010 Sorafenib 22.61a linePts with poor Hudes, 2007 Temsirolimus 33prognosis Everolimus after Motzer, 2008 20 TKI2a line Sunitinib after Su, 2010 52.2 Sorafenib
  • Percentage of pts who receives a 2d line therapy Predictive First line Second line factors N. PtsDrug/Author N. Pts Terapia (%)Sunitinib 375 Anti-VEGF/ 182Motzer et al, -JCO 2009 (sunitinib arm) anti-mTOR (56)Beva + IFN 325 180Escudier et al, JCO TKI -2010 (beva-IFN arm) (55)TKI (vari studi) Anti-VEGF/ 216Vikers et al, 645 Basal PSUrology 2010 anti-mTOR (30)
  • Drugs Resistance in mRCC Conclusive ConsiderationsAbout 30% of mRCC has an innate resistance to all availabletreatmentsResistance to TKi seems to be independent from the type ofTKi usedPrior treatment with Sunitinib significantly increased the riskof resistance to SorafenibResistance is present also in mTORi treated ptsResistance is correlated to the pts characteristics (histology,risk score) and to the type of prior therapy
  • Resistance to TKI in mRCC1. Definition of resistance2. The resistance mechanisms3. How can we overcome the resistance mechanisms?
  • Resistance Mechanisms in mRCC General considerations1. The “angiogenic escape” to anti‑VEGF treatment is dependent both on cancer cell phenomena or endothelial cell phenomena ?2. Hypoxia is a known inducer of angiogenic response in a wide variety of tumors3. Nevertheless, it is strongly believed that hypoxia is also the key mechanism of angiogenic escape4. When angiogenesis is inhibited, tumors are in a hypoxic state and develop new alternative pathways to guarantee their further growth
  • Drugs Resistance: MechanismsPRIMARY(also “refractoriness” or “intrinsic responsiveness”):Lack of efficacy to TKI from the start of therapySECONDARY(also “acquired” or “adaptive” or “evasive” or“angiogenesis escape”):Arises upon the initial response to TKI lastingfor a period of time of variable length
  • Which mechanisms?Primary Resistance to TKI in mRCC1. These cases have already activated one or more mechanisms of resistance not in response to therapy but in response to the selective pressure of their microenvironment2. Probably these cases of mRCC are not sustained (not only) by angiogenesis mechanisms 2008
  • Drugs Resistence in mRCC: Which mechanisms? Primary Resistance • Upregulation of alternate proangiogenic pathways (FGFR, IL-8, insulin-like GFR, ephrins, and angiopoietins) • Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) • Hypovascularity and indifference toward angiogenesis inhibitors (desmoplastic stroma) • Co-option of normal vessels without requisite angiogenesis Sleijfer et al. Oncologist. 2007 Blanke et al. J Clin Oncol. 2008 Huang et al. Cancer Res 2010
  • Drugs Resistance: MechanismsPRIMARY(also “refractoriness” or “intrinsic responsiveness”):Lack of efficacy to TKI from the start of therapySECONDARY(also “acquired” or “adaptive” or “evasive” or“angiogenesis escape”):Arises upon the initial response to TKI lastingfor a period of time of variable length
  • Secondary resistance to anti-angiogenic therapies Hypoxia: the key of the escape Casanovas et al, Cancer Cell 2005;8:299-309
  • Angiogenic Escape (II)Experimental “Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis” Ebos et al, Cancer Cell 2009 “Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis” Paez-Ribes et al, Cancer Cell 2009
  • Neoplastic Evolution and Mechanisms of Angiogenic Escape
  • Angiogenic Escape in mRCCIt has been reported that the endothelial cell inhibitionmediated by TKi can be rescued by 19 pro-angiogenic factorssecreted by the tumoral vasculatureIn particular, FGF2 and IL-8 support endothelial proliferationand de novo tubule formation in the presence of sunitinib Faivre et al, Nat Rev Drug Discov. 2007; 6(9):734-745. Review.
  • Development of Resistance: Angiogenic Escape (I) Early Phase: Response to Anti-VEGF Treatment Late Phase: Escape to Anti-VEGF Treatment Cancer cells Cancer cellsVEGF inhibitors VEGF inhibitors VEGF VEGF PIGF PIGF FGF/IL-8 and other HIF factors No angiogenesis HIF Second wave of angiogenesis Hypoxia Endothelial Cell Endothelial Cell FGF, fibroblast growth factor; HIF, hypoxia-inducible factor; PlGF, placental growth factor; VEGF, vascular endothelial growth factor Adapted from Casanovas et al, Cancer Cell 2005;8:299-309.
  • Development of Resistance: Angiogenic Escape (I) Early Phase: Response to Anti-VEGF Treatment Late Phase: Escape to Anti-VEGF Treatment Cancer cells Cancer cellsVEGF inhibitors VEGF inhibitors VEGF VEGF PIGF PIGF FGF/IL-8 and other HIF factors No angiogenesis HIF Second wave of angiogenesis Hypoxia Endothelial Cell Endothelial Cell FGF, fibroblast growth factor; HIF, hypoxia-inducible factor; PlGF, placental growth factor; VEGF, vascular endothelial growth factor Adapted from Casanovas et al, Cancer Cell 2005;8:299-309.
  • In hu ma n• FGFR is highly expressed in RCC (80% of pts)• High levels of bFGF are reported in patients with disease progression• Increased expression of FGFR1 is associated with a shorter progression free survival Welti et al. Oncogene 2011; 30(10):1183-1193. Tsimafeyeu Iet al. J Clin Oncol 28:15s, 2010 (suppl; abstr 4621). Ho Th et al. ASCO meeting 2011. J Clin Oncol 29: 2011 (suppl; abstr e15015).
  • Angiogenic Escape IL-8 mediates resistance to SunitinibIn Xenograft modelsThe resistance to sunitinib is associated to a higher microvesseldensity, indicating an escape from antiangiogenesis, and IL-8 levelsSunitinib IL-8resistent/refractory + Ac anti IL-8 Resensitized tumor IL-8Sunitinibresponsive Conclusions: IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib Huang et al, Cancer Res 2010
  • In hu ma n• Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib Huang et al, Cancer Res 2010.• Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib Liu et al, ASCO 2011.
  • Secondary resistance to anti-angiogenic therapiesThe epithelial-to-mesenchymal transition process
  • The epithelial-to-mesenchymal transition process
  • The epithelial-to-mesenchymal transition process Mechanisms of Disease: epithelial–mesenchymal transition—does cellular plasticity fuel neoplastic progression? Eva A Turley, Mandana Veiseh, Derek C Radisky and Mina J Bissell Nature Clinical Practice Oncology 2008
  • Secondary resistance to anti-angiogenic therapies The epithelial to mesenchymal transition process: What significance? • Sarcomatoid phenotype is observed across all histological subtypes, and associated with a poorer prognosis • It is a potentially transient/reversible phenotype of epithelial cancers • Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma Hugo H, Ackland ML, Blick T, et al: Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression. J Cell Physiol 2007; 213:374–383. Hammers HJ, Verheul HM, Salumbides B, et al: Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma: evidence from a xenograft study. Mol Cancer Ther 2010; 9:1525-1535. Klymkowsky MW, Savagner P: Epithelial-mesenchymal transition: A cancer researchers conceptual friend and foe. Am J Pathol 2009; 174:1588–1593.
  • Secondary resistance to anti-angiogenic therapies The epithelial to mesenchymal transition process: Main characteristics • Higher proliferative index • Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype • IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer • Loss of the epithelial markers E-cadherin and ZO-1 Bostrom et al, Hum Pat 2011 Giron-Michel et al, Bull Cancer 2011 Khawam et al, Cancer Res 2009
  • Secondary resistance to anti-angiogenic therapiesThe intratumoral heterogeneity and gene mutations
  • A specific gene expression signature characterizes metastatic potential in ccRCC • Transcriptional profiling of 16 primary metastatic and 18 non- metastatic clear cell renal cell carcinomas with microarrays • Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even • Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis Sanimyatav et al, J Urol 2011
  • Secondary resistance to anti-angiogenic therapies The intratumoral heterogeneity and gene mutations • Due to this genomic instability, it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure, hypoxia pressure, etc) and during the tumor growth • Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase, calvasculin, chemokine receptor 4 (CXCR4), NNP1, arginase II, hypoxia-inducible protein-2 (HIG2) and VEGF) • Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma, in particular IP10 (CXCL10) and Mig (CXCL9)) Lee AJ, Endesfelder D, Rowan AJ, Walther A, et al: Chromosomal instability confers intrinsic multidrug resistance. Cancer Res. 2011; 71(5):1858-70. Navin N, Kendall J, Troge J, et al: Tumour evolution inferred by single-cell sequencing. Nature 2011; 472(7341):90-94.
  • Working Model: Factors Associated With Resistance -VEGF -Ang2 -IL8 -MMP1 -uPAR -Calvasculin -IL10 -Arginase -IFNγ -?TSPAntiangiogenic Proangiogenic Progrowth Atkins M, et al. ASCO GU Symposium 2008. Abstract.
  • Factors Associated With Resistance in mRCCClinical: - Poor risk pts - Histology non clear - Prior TKi Laboratory: - levels of IL-8; IL-15 (proangiogenic) - level of HIF - Level of FGF - level of CA IX (?) Bio-molecular: - Specific mutation? - Gene profiling? - …??? Huang et al, Cancer Res 2010
  • Main mechanisms of primary and secondary resistance in mRCC - Alternative pro-angiogenic pathways mediated by FGFR, interleukin-8 (IL-8), insulin-like GFR, ephrins, and angiopoietins; - Non angiogenic mechanisms - Pre-existing inflammatory cell-mediated vascular protection (myeloid cell);Primary resistance - Hypovascularity status with consequent indifference toward angiogenesis inhibitors (desmoplastic stroma); - Co-option of normal vessels without requisite angiogenesis - Non clear cell histology - New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs - Epithelial to mesenchymal transition - Intra-tumoral heterogeneity - Gene instability and gene iperexpression - Secondary mutations in tyrosine kinase receptorsSecondary resistance - Bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling; - Increasing of pericyte coverage of the tumour vasculature, serving to support its integrity and attenuate the necessity for VEGF-mediated survival; - Access to normal tissue vasculature without obligate neovascularisation
  • Resistance to TKI in mRCC1. Definition of resistance2. The resistance mechanisms3. How can we overcome the resistance mechanisms?
  • How can we overcome the resistance to TKI? • Using non cross-resistant drugs • New drugs (denosumab, …) • Re-challenge with TKi/Sequential therapies • Integrating the current treatment – Combined therapies (?)
  • Resistance to anti-angiogenic therapies in mRCC •Re-challenge with anti-angiogenic agents could be a valid option for some pts •It is thought that a “holiday” period from anti-VEGF therapies is able to determine a reacquired drug- sensitivity by clones become resistant to TKi drugs Zama IN, Hutson TE, Elson P, et al: Sunitinib rechallenge in metastatic renal cell carcinoma patients. Cancer 2010; 116(23):5400-5406. Rini BI, Hutson HE, Elson P et al: Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma. GU ASCO 2010, J Clin Oncol 2010, Abst 396.
  • Michele Guida and Giuseppe Colucci
  • Adaptive mechanisms of secondary resistance to anti-angiogenic therapies 1.Activation/upregulation of alternative pro-angiogenic signalling pathways 2.Recruitment of bone marrow-derived pro- angiogenic cells, which can obviate the necessity of VEGF signalling, thereby effecting re-initiaton and continuance of tumour angiogenesis 3. Incrising pericyte coverage of the tumour vasculature, serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling 4.Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
  • Adaptive mechanisms of secondary resistance to anti-angiogenic therapies 1.Activation/upregulation of alternative pro-angiogenic signalling pathways 2.Recruitment of bone marrow-derived pro- angiogenic cells, which can obviate the necessity of VEGF signalling (circulating endotelial cells; myeloid cell) 3. Incrising pericyte coverage of the tumour vasculature, serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling 4.Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
  • Potential Mechanisms of Treatment Resistance In mRCC Rini and Atkins 2010
  • Potential mechanisms of VEGFR TKI Resistance
  • How can we overcome the resistance to TKI? • Using non cross-resistant drugs • Re-challenge with TKI/Sequential therapies • Integrating the current treatment – Combined therapies • Using revertant drugs (IFN, …)
  • Everolimus vs Placebo After Progression on a VEGFR-TKI in mRCC (RECORD-1 study) Phase III Study Design Prim Endpt:  PFS RAD001 (everolimus) 10 mg/d + BSC Sec Endpts: S Randomize C  Response R N = 362 Upon Disease Progression  Response E 2:1 E RAD001 : Placebo duration N Placebo + BSC  Survival Stratification  Safety  Previous VEGFR-TKI:  QoL 1 or 2  MSKCC risk group – Favorable (29%) – Intermediate (56%) – Poor (15%) (N = 410) Motzer et al, The Lancet 2008
  • Everolimus in mRCC (RECORD 1 study)Final results and analysis of prognostic factors • OR: 2% • SD: 67% • PFS: 4.9 vs 1.9 • OS: 14.4 vs 14.4 (cross-over 80% of pts) Independent prognostic factors for shorter OS – low performance status – high corrected calcium – low hemoglobin – prior sunitinib (P < .01) Motzer, Escudier, et al, Cancer 2010
  • Benefit of everolimus after multiple lines of treatment Escudier B et al. ESMO 2008; abstr 720
  • mRCC: about mTOR inhibitionWhat is the optimal time to use mTOR inhibitors in the treatment sequence?
  • Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy Late Phase: Escape to Anti-VEGF Treatment Cancer cells VEGF inhibitors VEGF PIGF FGF and other factors Second wave of HIF angiogenesis Endothelial Cell FGF/FGFR has been reported as one of the most important escape pathway of anti-VEGFR therapies
  • Dofitinib: a new multitarget agentA phase I dose finding and biomarker study of TKI258 (dovitinib lactate) inpatients with advanced melanomaK. B. Kim, J. Saro, S. S. Moschos, P. Hwu, A. A. Tarhini, W. Hwu, G. Jones, Y. Wang, H. Rupaniand J. M. Kirkwood (ASCO 2008)TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC)patients refractory to approved targeted therapies: A phase I/II dose findingand biomarker studyE. Angevin, J. A. Lopez, A. Pande, C. Moldovan, M. Shi, J. C. Soria, X. Wang, A. Harzstark, J.Saro, B. Escudier ASCO 2009 Abst 3563Study CTKI258A2202: A multicenter, open-label phase II trial of dovitinib(TKI258) in FGFR1-amplified and nonamplified HER2-negative metastaticbreast cancerF. Andre, J. Baselga, M. J. Ellis, S. A. Hurvitz, H. S. Rugo, N. C. Turner, E. Argonza-Aviles, S.Lake, M. M. Shi and O. Anak (ASCO 2009)
  • TKI 258 (Dovitinib) in mRCC Phase III Study Designthird line therapy S C Dovitinib + BSC R E Randomize E N Sorafenib + BSC
  • How can we overcome the resistance to TKI? • Using non cross-resistant drugs • Re-challenge with TKI/Sequential therapies • Integrating the current treatment – Combined therapies
  • Selected Trials of Second-Line Agents After TKI/BevaAgent Study N % PFS OS PopulationAuthor phase pts OR/SD (Mo) (Mo)Everolimus 4.9 416 14vs placebo TKI refractory III (2:1) 2/67 vs vs 14*Motzer et al Lancet ‘08 1.8Axitinib Sorafenib II 62 23/55 7.4 naRini et al, JCO ‘09 refractorySunitinib Bev II 62 23/75 7.1 10.2Rini et al, JCO ‘08 refractorySorafenib Bev/sunitinib 26 refractory II each 3/38 3.8Shepard et al, ASCO ‘08 *cross-over 80% of pts
  • Second line therapy in mRCC: For how many pts? First line Second lineTherapy/Authors N. Pts Therapy N. Pts (%)Sunitinib 375 Anti-VEGF/anti- mTOR 182 (56)Motzer et al, JCO 2009 (sunitinib arm)Beva + IFN (AVOREN study) 325 TKI 180 (55)Escudier et al, JCO 2010 (beva-IFN arm)TKI (various studies; 7 centers) Anti-VEGF/anti- 645 mTOR 216 (30)Vikers et al, Urology 2010
  • Estimated PFS of pts receiving sequential therapies 30-50% of pts 10% of pts 5%pts 2a line 3a line 4a line Escudier et al, Cancer 2009
  • Optimal Sequence May Depend on Response to First Line Therapy
  • Sequential therapy: ongoing studies Pts NAgent Sponsor phase population ptsSunitinib - sorafenibvs Sequential Bayer III 540Sorafenib - sunitinib (I and II line)(SWITCH trial)Pazopanib - Sunitinib Sequentialvs GSK III 160 (I and II line)Sunitinib - PazopanibSunitinib - Everolimusvs Sequential Novartis II 390Everolimus - Sunitinib (I and II line)(RECORD III trial)
  • How can we overcome the resistance to TKI? • Using non cross-resistant drugs • Re-challenge with TKI/Sequential therapies • Integrating the current treatment – Combined therapies
  • Is Combination Therapy Better?VEGF inhibitors: EGFR inhibitors:-sunitinib - erlotinib-sorafenib - gefitinib-axitinib - lapatinib-pazopanib - cetuximab-bevacizumab IFN Angiogenesis Tumor cell proliferationInhibitors ofangiogenic escape mTOR/akt inhibitors:mechanisms: - temsirolimus-dovitinib - everolimus-AMG 386 - perifosine-M200
  • Combination Drug Therapy: Selected Adverse Events Rash or GI orAgent Hand-Foot Hypertension Cytopenia Proteinuria Mucosal ReactionSunitinib Yes Yes Yes Yes YesSorafenib Yes Yes Yes YesBevacizumab Yes YesTemsirolimus/ Yes Yes YesEverolimus
  • Combined therapies in mRCC: the future? •Beva + TK inhibitors •TK inhibitors + mTOR inhibitors •Beva + mTOR inhibitors
  • Is Combination Therapy Better?VEGF inhibitors: EGFR inhibitors:-sunitinib - erlotinib-sorafenib - gefitinib-axitinib - lapatinib-pazopanib - cetuximab-bevacizumab IFN Angiogenesis Tumor cell proliferationInhibitors ofangiogenic escape mTOR/akt inhibitors:mechanisms: - temsirolimus-dovitinib - everolimus-AMG 386 - perifosine-M200
  • Bevacizumab + TKI in mRCC:Drug Study/ PFS OR Toxicity Commentscombinations Pts (Mo) AnBeva +Sunitinib* ega Phase I 31 - 3/7 RCC 1/3 Mela Mild (?) Good tiveGarcia et al, ASCO ‘08 (various) 1 adrenal activity expBeva + erie High (hypertension, nceSunitinib 16 microangiop.Feldman,. Motzer, TransientAsco ‘08 ischemic CNS) HighBeva + 0 CR (hypertension, No Phase I-IISorafenib** 48 14 25 PR stomatitis, full dosesSosman et al, ASCO ‘08 18 SD hand-foot skin together reaction)* Escalating doses** Full dose Sorafenib + 50% Beva and reverse
  • Is Combination Therapy Better?VEGF inhibitors: EGFR inhibitors: - erlotinib-sunitinib-sorafenib - gefitinib-axitinib - lapatinib-pazopanib - cetuximab-bevacizumab IFN Angiogenesis Tumor cell proliferationInhibitors ofangiogenic escape mTOR/akt inhibitors:mechanisms: - temsirolimus-dovitinib - everolimus-AMG 386 - perifosine-M200
  • EGFR EXPRESSION IN SELECTED HUMAN TUMORSTumor Type Percentage of Tumors References Expressing EGFRColorectal 25-77% Salomon (1995); Messa (1998)Advanced Colorectal 75% Goldstein (2001)Head and Neck 80-100% Salomon (1995); Grandis (1996)Pancreatic 30-95% Salomon (1995); Uegaki (1997)Advanced Stage 95% Abbruzzese (2001) Fujino (1996); Rusch (1997);NSCLC 40-80% Fontanini (1998)Renal Carcinoma 50-90% Salomon (1995); Yoshida (1997) Klijn (1992); Beckman (1996);Breast 14-91% Bucci (1997); Walker (1999) Bartlett (1996);Ovarian 35-70% Fischer-Colbrie (1997) Salomon (1995); Watanabe (1996);Glioma 40-63% Rieske (1998)Bladder 31-48% Salomon (1995); Chow (1997)
  • Phase I/II trial of sunitinib plus gefitinib in patients with mRCC (first line) A 42 pts d isa- Sunitinib 37.5 or 50 mg/d oral (4 weeks on, 2 off) pp- Gefitinib 250 mg/d oral oin Results tin - OR: 37% ge - SD: 34% xp - Median PFS: 11 moths eri en - Accettable toxicity (diarrea G3-4 in 14%) ce - No pharmacokinetic drug-drug interactionConclusions: “Sunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapy” Motzer RJ, et al, Am J Clin Oncol 2010
  • Is Combination Therapy Better?VEGF inhibitors: EGFR inhibitors:-sunitinib - erlotinib-sorafenib - gefitinib-axitinib - lapatinib-pazopanib - cetuximab-bevacizumab IFN Angiogenesis Tumor cell proliferationInhibitors ofangiogenic escape mTOR/akt inhibitors:mechanisms: - temsirolimus-dovitinib - everolimus-AMG 386 - perifosine-M200
  • Bevacizumab + mTOR inhibitor A questionable experience
  • Bevacizumab + mTORI in mRCC A questionable experienceFirst and Second lineDrug Study/ PFS OS OR Toxicitycombinations Pts (Mo) (Mo) Phase IIBeva + Everolimus 11 12 23% PRWhorf et al, ASCO ‘08 (in 29 pretr. 53% SD - mild 59 with TKI) (first line)Beva + TemsirolimusMerchan et al, JCO ’09 45 5.3 18 14.5 - acceptable
  • Bevacizumab + mTOR inhibitor Phase III randomized first-line study Temsirolimus + Bevacizumab 1° Endpoint:Screen R 1:1  PFS Interferon alfa-2a + Bevacizumab 822 pts RECORD-2: randomized phase II first-line study Everolimus + Bevacizumab 1° Endpoint:Screen R 1:1  PFS Interferon alfa-2a + Bevacizumab Randomized phase III second line study (CALG study) Everolimus + BevacizumabScreen 1° Endpoint: R 1:1  PFS Placebo
  • Bevacizumab + mTOR inhibitor First line therapyCan the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC? Results of the randomized TORAVA phase II trial Escudier BJ, Negrier S, Gravis G, et al. ASCO 2010. Abstract 4516 .
  • TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC • Primary endpoint: non-progression rate at week 48 > 50% (42% to 46% previous studies) • 160 patients required for 2:1:1 randomization
  • TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS Temsirolimus/Beva Sunitinib Beva/Interferon Outcome (n = 88) (n = 42) (n = 41) 48 ww 30.7 40.5 65.9 non PD>50% PFS (Mo) 8.2 8.2 16.8 Best OR /%) 27.3 23.8 39 SD (%) 47.7 50 34.1
  • TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC ToxicitySerious Adverse Temsirolimus/Beva Sunitinib Beva/InterferonEvents, % (n = 88) (n = 42) (n = 40)Grade 3 26.1 11.9 20.0Grade 4 12.5 2.4 7.5Death 3.4 0 0Note:50% of pts in temsirolimus/beva arm ceased therapy before Week 48 for reasons notrelated to progressive disease, primarily toxicity (41%)
  • Conclusions of the Authors:TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC Escudier BJ, Negrier S, Gravis G, et al. ASCO 2010. Abstract 4516.
  • Bevacizumab + EverolimusFirst an second line therapy Phase II trial of Bevacizumab + Everolimus in pts with advanced RCC J.D. Hainsworth,…. Whorf, J Clin Oncol 2010
  • Bevacizumab + mTOR inhibitor Bevacizumab + Everolimus phase II study Naïve pts Pre-treated pts*Outcomes (N = 50) (N = 30)OR (%) 30 23SD 50 64N. with tumor shrinkage 78 73PFS (mo) 9.1 7.1Survival (mo) 21.3 14.5 *Sunitinib or Sorafenib Hainsworth et al, JCO 2010
  • Bevacizumab + Everolimus Bernard Escudier, Editorial JCO 2010• The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 9,1 for untreated and 11 vs 7.1 for pre-treated pts)• PFS has became the same that of control arm (8.5-12.2 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)• The rationale for the two large randomized studies is much weaker and questionable• Usefulness of phase II non randomized small study
  • How can we overcome the resistance to TKI? Using old and new drugs (IFN, …) “Redefining the role of Interferon in the treatment of malignant diseases” Bracarda, Eggermont, Samuelsson Eur J Cancer 2010
  • Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First- or Second-Line* Therapy in mRCC Gollob et al, JCO 2007 •Sorafenib 400 mg orally bid for 8 weeks •IFN alpha-2b: 10 mil. IU subcutaneously three times a week followed by a 2-week break *IL-2 pre-treated pts
  • Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First- or Second-Line Therapy in mRCC All pts First line Second line (40 pts) (20 pts) (20 pts) Response, n (%) 13 (33) 10 3 CR 2 (5) PR 11 (28) SD 12 (29) PFS (mo) 10 Dose reduction (% of pts*) 65 *Fatigue, anorexia, anemia, diarrhea, hypophosphatemia, rash, nausea, and weight loss Gollob et al, JCO 2007
  • CARCINOMA RENALE METASTATICOTERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO Studio G.O.I.M. 2901 PIANO DI TRATTAMENTO •Braccio A Everolimus 10 mg/die per via orale •Braccio B Everolimus stesse dosi + Interferone alpha-2a, basse dosi s.c. (3 Mil U.I. x 3 volte/settimana)