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I FARMACI MULTITARGETED NEL CANCRO DELLA MAMMELLA

I FARMACI MULTITARGETED NEL CANCRO DELLA MAMMELLA. Giampaolo Tortora. Cattedra di Oncologia Medica e Laboratori di Terapia Molecolare Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica Università di Napoli “Federico II”. Farmaci con bersagli multipli.

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I FARMACI MULTITARGETED NEL CANCRO DELLA MAMMELLA

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  1. I FARMACI MULTITARGETED NEL CANCRO DELLA MAMMELLA Giampaolo Tortora Cattedra di Oncologia Medica e Laboratori di Terapia Molecolare Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica Università di Napoli “Federico II”

  2. Farmaci con bersagli multipli • Farmaci che bloccano più recettori della stessa famiglia, per aumentare l’efficienza del “targeting” selettivo. • Farmaci che bloccano recettori e proteine di segnale di classi e funzioni diverse, per bloccare a più livelli la trasmisione di segnali.

  3. SIGNALLING PATHWAYS IN CANCER CELLS PDGFR, c-KITR HER/erbB P P p21 ras GRB2 SOS Raf P PKAI P PI3K PLCg VEGF MEK MAPK PTEN PKC AKT Angiogenesis Bcl-2 Cyclin D1 Invasion metastasis mdm2 E2F mTOR CDK p53 Rb Cell Proliferation Apoptosis

  4. I recettori della famiglia ErbB/HER funzionano in coppia, formando omo- o eterodimeri P EGFR EGFR/ErbB2 EGFR/ErbB3 Tortora et al., 2007

  5. Co-expression of EGFR and ErbB-2 • Co-expression of EGFR and ErbB-2 has been observed in 10-30% primary human breast carcinomas. • Overexpression of both ErbB-2 and EGFR is associated with a poorer prognosis than overexpression of either receptor alone in breast cancer patients. • A recent study has demonstrated an adverse prognostic independent role of ErbB-2 and EGFR coexpression in a subset of radically resected early breast cancers. (Di Giovanna et al., JCO, 23: 1152-1160, 2005).

  6. Phase I study of Erlotinib plus Trastuzumab and Taxol • Escalating doses of Erlotinib (25 to 150 mg); Taxol 80 or 90 mg/m2; Trastuzumab 2 mg/kg. Weekly administration with different schedules. • Selected the 1, 8, 15, 28 schedule and the recommended doses of Erlotinib 150 mg, Taxol 90 mg/m2, Trastuzumab 2 mg/kg. • 14/16 patients had MBC, HER2+ (8 pre-treated with Tastuzumab). • Mild toxicity and PKA interaction. • 1 CR and 2 PR in patients HER2+, taxane-resistant. In 2 cases also Trastuzumab-resistant. • Important the role of Taxanes ? Major activity of Erlotinib ? A. Patnaik, ASCO 2005

  7. Doppi inibitori di EGFR e HER-2Pertuzumab e Lapatinib

  8. Omnitarg Riconosce Epitopi diversi da Trastuzumab su HER2 e impedisce la etero-dimerizzazione EGFR-HER2 HER2 Ligand-binding domain (inactive) Omnitarg Trastuzumab Cell membrane Tyrosine kinase domain

  9. Lapatinib inhibits EGFR and HER-2 Erlotinib Gefitinib GW572016 Lapatinib Small head group quinazolines Large head group quinazoline

  10. EGF20009: A Phase II, Randomized trial using Lapatinib as a first-line treatment in patients with FISH Positive Advanced or Metastatic Breast Cancer *Two subjects considered to have a PR by investigator had <28 day confirmation scans. ** One subject not evaluated due to death from multiple injuries prior to tumor assessment. † 1 subject by the investigator review and 4 subjects by independent review had only one timepoint and that timepoint did not meet the criteria for SD per the protocol (8 weeks). Sledge group updated from ASCO 2005 and SABCS

  11. Randomized Phase III Study EGF100151 • Progressive, HER2+ MBC or LABC • Previously treated with anthracycline, taxane and trastuzumab* • No prior capecitabine R A N D O M I Z E Lapatinib 1250 mg po qd continuously + Capecitabine 2000 mg/m2/d po days 1-14 q 3 wk Capecitabine 2500 mg/m2/d podays 1-14 q 3 wk • Stratification: • Disease sites • Stage of disease Patients on treatment until progression or unacceptable toxicity, then followed for survival N=528 *Trastuzumab must have been administered for metastatic disease

  12. Prior Therapy

  13. Lapatinib + Capecitabine Capecitabine No. of pts 160 161 Progressed or died* 45 (28%) 69 (43%) 90 Median TTP, wk 19.7 36.9 80 Hazard ratio (95% CI) 0.51 (0.35, 0.74) 70 P-value (log-rank, 1-sided) 0.00016 60 50 40 30 20 10 0 10 20 50 0 30 60 40 Time (weeks) Time to Progession – ITT Population % of patients free from progression* 100 70 * Censors 4 patients who died due to causes other than breast cancer

  14. Progression-Free Survival - ITT Population Lapatinib + capecitabine 100 Capecitabine Cumulative Progression-Free Survival, % No. of pts 160 161 90 Progressed or died 45 (28%) 73 (45%) 80 Median PFS, wk 36.9 17.9 70 Hazard ratio (95% CI) 0.48 (0.33, 0.70) P-value (log-rank, 1-sided) 0.000045 60 50 40 30 20 10 0 10 20 0 30 70 50 40 60 Time (weeks)

  15. Overall Survival - ITT Population 100 Cumulative Survival % 90 80 70 60 50 Lapatinib + Capecitabine Capecitabine 40 No. of pts 160 161 30 Deaths 29 (18%) 29 (18%) Median OS NR NR 20 Hazard ratio (95% CI) 0.93 (0.55, 1.59) 10 P value (log-rank, 2-sided) 0.800 0 0 10 20 30 40 50 60 70 80 90 Time (weeks)

  16. Brain Metastases as Site of Progression *P-value (Fisher’s exact, 2-sided)= 0.110

  17. Mean LVEF at Scheduled Assessments 80 Lapatinib + Capecitabine Capecitabine 75 70 65 Mean LVEF (%) 60 55 n=108n=92 n=84 n=67 n=160n=160 n=37 n=26 n=63 n=37 n=15 n=9 n=7 n=1 50 Week 24 Screening Week 6 Week 12 Week 18 Week 36 Week 48 Assessment

  18. A Phase II Trial of Lapatinib (Tykerb) Monotherapy in Patients With Relapsed/Refractory Inflammatory Breast Cancer (IBC): Clinical Activity and Biologic Predictors of Response EGF103009 Spector N, K Blackwell, J Hurley, J Harris, D Lombardi, S Bacus, SB Ahmed, H Boussen, M Frikha, FB Ayed Cohort A ErbB2+ Cohort B ErbB1+/ErbB2-

  19. ErbB2 (IHC 3+/FISH+) p-ErbB2 positive 17% PD 17% pending PTEN deficient 58% PD 100% 69% 17% SD 8.3% Preliminary Results: Treatment Response 100% 21% SD 50% 62% clinical responders 62% PR 0% Cohort A ErbB2+ 24 patients Cohort B ErbB1+/ErbB2- 12 patients 5 enrolled patients were not evaluable (did not express target or died prior to Day 28)

  20. EGF10023: Phase I, open-label study of the Safety, Tolerability and Pharmacokinetics of Lapatinib in combination with Trastuzumab • The proposed phase II and III dose for this combination is 1000 mg/day lapatinib and standard weekly trastuzumab • The most frequent AEs with this combination were diarrhea, fatigue, nausea, and anorexia • The combination of lapatinib and trastuzumab was very active (6/27 CR+PR and 2/27 PR in the PK groups = 8% total) in this heavily pretreated population, all of whom had progressed on prior trastuzumab • Additional randomized studies are planned with lapatinib and trastuzumab Storniolo et al., ASCO 2005 and SABCS

  21. STUDI IN CORSO : ADIUVANTE, METASTATICO E NEOADIUVANTE

  22. P EGFR EGFR/ERbB2 HER3/erbB3 HER2/HER3 Heterodimers formation • The prevalence of certain ErbB heterodimers may cause an alternative driving force for the growth of cancer cells bypassing the blackade by specific inhibitors. • For instance the heterodimer HER2-HER3 is an “odd couple” with a powerful kinase activity. Tortora et al., 2007

  23. Ras/Raf, Abl, ER PI3-K TSC2 TSC1 Akt/PKB • CCI-779 (temsirolimus) • RAD-001 (everolimus) • AP23573 S6K1 X X X mTOR Pathway islinked to EGFR and VEGF Growth factors IGF-1, VEGF, ErbB, etc PTEN Oxygen, energy, and nutrients VEGF HIF-1 Ras/Raf pathway kinases mTOR 4E-BP1 elF-4E S6 Protein production Cell growth Angiogenesis Cell division

  24. Randomized Phase II Trial with Temsirolimus/CCI-779 in advanced breast cancer • 109 patients randomized to receive 75 mg or 250 mg i.v weekly. • Toxicity profile favored 75mg dose: Anaemia, hyperglycemia, hypophostatemia & hypertrigliceridemia as grade 3/4 events • Overall response: 9% (10 PRs), 26% MR • mTTP: 3 m, mOS: 15m • Phase III development ongoing in combination with letrozole Chan, S. et al. J Clin Oncol; 23:5314-5322 2005

  25. Progression of pro-Angiogenic activity in Breast cancer VEGF bFGF TGFb PLGF PD-ECGF Etc…. VEGF bFGF VEGF VEGF bFGF TGFb PLGF VEGF bFGF TGFb VEGF bFGF TGFb PLGF PD-ECGF Modified by Tortora, 2003 from Relf et al., Cancer Res. 1997

  26. Endothelial cells Cross-talk tra diverse vie di segnale : base Per l’ acquisizione di resistenza a terapie selettive Tortora et al., 2006 PDGFR, IGF-R1 HER/erbB c-KITR P P p21 ras GRB2 SOS Raf P PKAI P PI3K VEGF PLCg MEK MAPK PTEN PKC AKT VEGFR1 VEGFR2 Bcl-2 Cyclin D1 mdm2 E2F mTOR CDK Angiogenesis p53 Rb Cell Proliferation Apoptosis Invasion metastasis

  27. Angiogenesis • Serine/threonine kinases Novel Paradigm :“Multi-targeted therapy” • Multiple targeted cells • Cancer cells • Endothelial cells • Pericytes • Fibroblasts • Multiple molecular targets • HER • VEGF/VEGFR • PDGF/PDGFR • KIT/MET/RET • Others kinases Receptor tyrosine kinases Faivre et al. Sem Oncol, 2006

  28. I recettori del VEGF VEGFR-3/Flt-4 VEGFR-1/Flt-1 VEGFR-2/KDR LYMPHANGIOGENESIS ANGIOGENESIS

  29. Multitargeted agents affecting VEGF-Rs and EGFR, PDGF-Rs, Kit etc. • ZD6474/Vandetanib (VEGFR2 + EGFR + RET) • AE778 (VEGF-R2 + EGFR) • Sunitinib (VEGFRs + PDGFRs+ c-Kit) • Sorafenib (VEGFRs + PDGFRs + raf1 + MAPK + Erk + c-Kit) • PTK787/Vatalanib (VEGFRs + PDGF-Rs) • GW786024 (Pazopanib) (VEGFRs + PDGF-Rs+ c-Kit) • AG013736 (VEGFRs + PDGF-Rs

  30. ZD6474 inhibits KDR and EGFR TGF ZD6474 EGFR KDR Endothelial cells RET Cancer cells VEGF Angiogenesis Tortora & Ciardiello 2003 Carlomagno et al, Cancer Res. 2002 Ciardiello et al., Clin Cancer Res. 2003 Ciardiello et al., Clin Cancer Res. 2005 Damiano et al., Clin Cancer Res 2005 Cell Proliferation

  31. A Multicenter Phase II Trial of ZD6474, a VEGFR-2 and EGFR TKI, in Patients with Previously Treated Metastatic Breast Cancer Kathy D.Miller, JoseManuelTrigo, Catherine Wheeler, Alan Barge, Jacqui Rowbottom, George Sledge, and Jose Baselga 100mg/d n=22 300mg/d n=24 The median time to progression was similar in both groups: 45 days in the 300mg group; 44 days in the 100mg/d group. There were no responses (only 1patient, in 300 mg/d group, had a SD for >24 weeks) Miller KD, Clin Cancer Res 2005;11(9)May 1, 2005

  32. The endothelial cell-pericyte network of signals • Pericytes protects endothelial cells from apoptosis • and overexpress PDGF-R • PDGF-R is overexpressed in many tumors • PDGF-R and VEGF cooperate Nature Review Cancer

  33. Vehicle control SU11248 40 mg/kg per day PO Docetaxel 15 mg/kg IV once per week x 3 SU11248 40 mg/kg per day + docetaxel 15 mg/kg once per week x 3 SU11248 increased activity in combination with Docetaxel in a breast cancer model 1,500 1,000 Average Tumor Volume, mm3 500 Complete regression in 33% of mice, with no regrowth 3 months after dosing stopped on day 72 0 0 10 20 30 40 50 60 70 Days After Dosing Began Docetaxel SU11248 Abrams et al. Mol Cancer Ther. 2003;2:1011-1021, with permission.

  34. Phase II study of Sunitinib in MBC KD Miller, HJ Burstein, AD Elias, HS Rugo, MA Cobleigh, AC Wolff, PD Eisenberg, MD Pegram, M Collier, BJ Adams, CM Baum • 6 weeks cycle (50 mg/day for 28 d. and 2 weeks rest). • 64 pts enrolled (84% HER-2 negative/unknown; 56% ER pos). • 82% with (multiple) visceral sites. Heavily pretreated (several previous CT regimens in adjuvant setting and in metastatic setting). • Asthenia and diarrhea major grade 2 toxicities. 40% grade 3 neutropenia. • 51 evaluable for responses. PR: 7 (14%);SD > 6 mo: 1 (2%). • No clear correlation between response and ER or HER-2 status. Miller et al., ASCO 2005 e SABC

  35. Ongoing studies with Sunitinib Phase III randomized study of Sunitinib + capecitabine vs capecitabine in pretreated advanced breast cancer patients 430 pts. Primary endpoint: PFS Phase III randomized study of Sunitinib vs capecitabine in advanced breast cancer patients who failed both taxane and anthracycline (or failed a taxane and anthracycline therapy is not indicated). 700 pts. Primary endpoint: PFS Phase 2 randomized, double blind study of Sunitinib in combination with Trastuzumab in 1st line for MBC. Primary endpoint: Response Rate 2 Phase I studies of Sunitinib in combination with Paclitaxel (or with Docetaxel) in 1st line for MBC. 20 pts. each Primary endpoint: Safety

  36. Ongoing studies with Sunitinib Phase 1-2 study of Sunitinib in combination with Exemestane in 1st line for MBC. 70 pts. Primary endpoint: PFS, Safety Phase 2 randomized study of Sunitinib vs Standard of care in previously treated Triple receptor negative (ER, PR, HER2) BC. 200 pts. Primary endpoint: PFS

  37. Cl O O N F C N H N H 3 C H 3 O N H BAY 43-9006 (Sorafenib) • Bisaryl urea, multiple targeted inhibitor. • Inhibits B-Raf-1 kinase (including the mutated form) with IC50 of 6 nM, MAPK, ERK. • Inhibits also endothelial cells and VEGFR2, VEGFR-3,FLT-3, PDGFR, c-Kit. • Raf is probably important in endothelial cells and double targeting (Raf and VEGFR-2) may be critical.

  38. Sorafenib Phase II trial in metastatic breast cancer patients failing anthracycline and/or taxane Limited single-agent activity. Only 1/23 patients responding to therapy.Moreno-Aspitia A et al., JCO 24:18S, 2006 (abstract #577) A phase I trial combining sorafenib with bevacizumab Dose escalation trial in 34 patients with multiple tumor types. Both toxicity and efficacy are increased compared with single-agent therapy.Azad N et al., ASCO 2006, abstract # 3004

  39. PTK787/ZK 222584 (Vatalanib) • Complete inhibitor of the VEGF receptor tyrosine kinasesVEGFR1(FLT-1), VEGFR2 (KDR) and VEGFR3 (FLT-4). It also inhibits PDGF-R. • Well tolerated up to 1250 mg/day (phase III dose, used up to 15 mo) A phase I/II study of vatalanib in combination with trastuzumab in HER-2-overexpressing MBC

  40. International Phase I/II trial with AG-013736 plus docetaxel vs. docetaxel plus placebo in first-line MBC. • Analysis of the phase I study showed good tolerability and activity. • The Phase II is ongoing and has currently enrolled over 60 patients. (Rugo et l., 2006).

  41. Anti-VEGFRs, c-Kit and PDGFRs GW786034 (Pazopanib)

  42. Horizontal and Vertical blockade • Combinations of targeted agents to block signaling with: • an horizontal blockade : EGFR, VEGF and PDGFR. • a vertical blockade : at two levels of the same pathways: HIF + VEGF or VEGF+VEGFR

  43. GW786034 (Pazopanib) in combination with Lapatinib in breast cancer xenografts

  44. Phase III Randomized double blind study with Pazopanib in combination with Lapatinib in MBC Lapatinib 1500 mg/day + placebo PD* relapsed or refractory inflammatory breast cancer overexpressing ErbB2 (n=320) Lapatinib 1500 mg/day + Pazopanib 800 mg/day PD • Primary endpoint: PFS • Secondary endpoint: overall Response Rate, time-to-response, response duration, quality of life, overall survival (OS), safety and tolerability, biomarkers, pharmacokinetics and pharmacogenomics • Patients in the bevacizumab plus CP arm may receive single-agent bevacizumab until disease progression

  45. CONCLUSIONI • I farmaci multitargeted sono agli esordi nella terapia dei tumori della mammella. • Molti studi sono in corso e prevedono analisi genomiche e farmacodinamiche che ptrebbero aiutare a interpretare I risultati e a selezionare I pazienti.

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