Choice of Chemotherapy Combination with Targeted Agent in Metastatic Breast Cancer

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1 Choice of Chemotherapy Combination with Targeted Agent in Metastatic Breast Cancer Department of Oncology National Taiwan University Hospital Yen-Shen Lu MD., PhD.

2 Targeted Therapy for Breast Cancer Anti-HER Trastuzumab Lapatinib Neratinib Pertuzumab Trastuzumab-MCC-DM1 Anti-angiogenesis Bevacizumab Sorafenib Sunitinib PI3K/Akt/mTor inhibitor Everolimus Tensirolimus PARP inhibitor BSI-201 AZD-2281 Others HDACi Src inhibitor Farnesyltransferase inhibitor

3 Promising Single Agent Activity Anti-HER Trastuzumab Lapatinib Neratinib Pertuzumab Trastuzumab-MCC-DM1 Anti-angiogenesis Bevacizumab Sorafenib Sunitinib PI3K/Akt/mTor inhibitor Everolimus Tensirolimus PARP inhibitor BSI-201 AZD-2281 Others HDACi Src inhibitor Farnesyltransferase inhibitor

4 Positive Randomized Study Result for Combination Therapy Anti-HER Trastuzumab Lapatinib Neratinib Pertuzumab Trastuzumab-MCC-DM1 Anti-angiogenesis Bevacizumab Sorafenib Sunitinib PI3K/Akt/mTor inhibitor Everolimus Tensirolimus PARP inhibitor BSI-201 AZD-2281 Others HDACi Src inhibitor Farnesyltransferase inhibitor

5 Available and Approved in Breast Cnacer Anti-HER Trastuzumab Lapatinib Neratinib Pertuzumab Trastuzumab-MCC-DM1 Anti-angiogenesis Bevacizumab Sorafenib Sunitinib PI3K/Akt/mTor inhibitor Everolimus Tensirolimus PARP inhibitor BSI-201 AZD-2281 Others HDACi Src inhibitor Farnesyltransferase inhibitor

6 IHC HER2/neu expression and amplification FISH Pos

7 Trastuzumab improve overall survival of HER2 positive metastatic breast cancer Dowood S et al ASCO abstract 2008 # 1018

8 Choices of First Line Treatment in MBC

9 Choices of First Line Treatment in MBC HER2-Targeted agent monotherapy in MBC Trastuzumab 1 Trastuzumab 2 Lapatinib 4 mg/kg 8 mg/kg 8 mg/kg 1500 mg QD or 2 mg/kg 4 mg/kg 6 mg/kg 500 mg BID weekly weekly q3wk daily n=58 n=53 n=105 n=138 Objective Response (CR/PR), ITT 14 (24%) 15 (28%) 20 (19%) 39 (24%) Clinical Benefit Rate, ITT 20 (34%) 22 (42%) 35 (33%) 43 (31%) Median TTP, ITT, months Median TTF, ITT, weeks Vogel et al (2002) J Clin Oncol 20: Baselga at al (2005) J Clin Oncol 23:

10 Trastuzumab with Chemotherapy as First-line Therapy for Metastatic Disease Agent(s) Administered with Trastuzumab Response Rate (%) Median Response Duration (months) Median TTF (months) Median Survival (months) Doxorubucin Cyclophosphamide Paclitaxel Docetaxel Vinorelbine 3,4 68 N/P 5.6 /8.5 N/P N/P= Not Provided 1 Slamon DJ, Leyland-Jones B, Shak S, et al. N Engl J Med 2001;344: Marty M, Cognetti F, Maraninchi D, et al. J Clin Oncol 2005;23: Burstein HJ, Harris LN, Marcom PK, te al. J Clin Oncol 2003;21: Burstein Cancer 2007

11 Contradictive data about weekly paclitaxel vs 3-weekly paclitaxel Comparison Response % OR p All patients (combined) 3-weekly weekly HER2 negative 3-weekly weekly HER2 negative No trastuzumab trastuzumab HER2 positive 3-weekly weekly Abbreviations: OR, odds ratio; 3-weekly, every 3 weeks; HER-2, human epidermal growth factor receptor 2. *Unadjusted OR; the ratio of the odds of tumor response in the second group to the first group (eg, weekly v 3-weekly). Data from CALGB 9840 Adrew D et al JCO 2008

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13 NAVELBINE + HERCEPTIN vs TAXANE + HERCEPTIN IN 1 st LINE HER2+ MBC (TRAVIOTA STUDY) Phase III study Efficacy Schedule* NVB 25 mg/m²/week (39 pts) PTX 80 mg/mg/m²/week (24 pts); DTX 35 mg/m²/week (14 pts); PTX 175 mg/m² D1 = D21 + CBDCA AUC 6 (2 pts) Median n n of cycles Evaluable pts OR (%) CR (%) 12 5 PR (%) TTP (mo) First study comparing the best available chemotherapy regimens for HER2 + patients * Plus Herceptin: 4 mg/kg as a loading dose, 2 mg/kg/week thereafter Burstein, Cancer 2007

14 PFS of Chemotherapy Vs. Herceptin + chemotherapy AC (Slamon 2002) Herceptin + AC (Slamon 2002) Paclitaxel (Slamon 2002) Herceptin + Paclitaxel (Slamon 2002) Docetaxel (Marty 2005) 3.0 m 6.1 m 7.8 m 6.9 m 6.1 m Herceptin + docetaxel (Marty 2005) (n=41) Herceptin + vinorelbine (n=40) Herceptin + Taxane (n=98) Herceptin + paclitaxel (Q3W) =98) Herceptin + Paclitaxel + Carboplatin (n=131) Herceptin + Docetaxel 131) Herceptin + Docetaxel + Carboplatin 6 m 7.0 m 11.7 m 9 m 12.0 m 10 m 11 m Time (months)

15 Paclitaxel 175 mg/m2 q3w ± lapatinib 1500 mg (EGF30001 ) HER2-positive P + L P n = 52 n = 39 HER2-negative P + L n = 199 P n = 202 Odds ratio = 2.9 (1.1, 7.9) p = Odds ratio = 1.5 (0.9, 2.3) p = (45-73) Response rate,% 36 (21-53) Response rate,% 31 (24-38) 24 (18-30) Median duration of response* Median duration of response*

16 Time to Progression by HER2 Status HER2-positive HER2-negative Cumulative progression-free, % P + L (n = 52) P (n = 39) Median, mos HR (95% CI) 0.57 (0.34, 0.93) P value P + L (n = 199) Interaction test p = (Cox s proportional hazards model) P (n = 202) Median, mos HR (95% CI) 1.04 (0.83, 1.30) P value Total 75 events (83%) Total 299 events (75%) P + Lapatinib P + placebo Time, months P + Lapatinib P + placebo Time, months

17 Phase III study of taxane based chemotherapy with lapatinib or trastuzumab as 1 st line therapy for ErbB2+ MBC (EGF NCICTG MA31) Eligibility criteria: ErbB-2 + MBC Newly diagnosed or after failure of adjuvant therapy No CNS mets confirmed by MRI/CT Primary endpoint: PFS R A N D O M I Z E (n = 536) Secondary endpoints: ORR, OS, time to CNS met Arm 1: 24weeks TYKERB 1250 mg/day p.o. Taxane based therapy (Paclitaxel 80 mg/m 2 /week I.V. 3 of 4 weeks or Docetaxel 75mg/m 2 /3week I.V.) Arm 2: 24weeks Trastuzumab 4mg/m 2 then 2mg/m 2 /week and Paclitaxel 80 mg/m 2 /week I.V. 3 of 4 weeks OR Trastuzumab 8mg/m 2 then 6mg/m 2 /3week and Docetaxel 75mg/m 2 /3week I.V. Arm 1 TYKERB 1500 mg/day p.o. until PD Arm 2 Trastuzu mab 6mg/m 2 / 3week until PD

18 What about the sequence?

19 HERTAX study design (phase II study) R Trastuzumab qw Trastuzumab qw + docetaxel 100 mg/m² PD docetaxel 100 mg/m² Until PD HER2 +, 1 st line M+ Primary objective: PFS Secondary objectives: RR & OS Patient number : 99 M. Bontenbal et al. ASCO Abstract 1014

20 RR (%) T followed by D 50 T + D 73 p 0.02

21 M77001: overall survival patients who received who crossed over to receive trastuzumab after progressing on docetaxel alone has similar OS as those patients who receive trastuzumab and docetaxel first-line treatment M Marty, J Clin Oncol 2005

22 ~ T Chemo T/Chemo T T/Chemo ~ Chemo T/Chemo

23 Choices Beyond Progression After 1 st Trastuzumab Treatment

24 French Hermine retrospective cohort study of trastuzumab beyond progression continuing treatment with multiple lines of trastuzumab offered significant survival benefit Extra JM et al, SABCS 2006

25 Capecitabine ± trastuzumab in patients with HER2+ MBC progression after trastuzumab treatment (GBG 26/BIG 3-05 ) Trastuzumab + Capecitabine Capecitabine alone Response 48.0% 27.0% p=0.011 Clinical Benefit 75.3% 54.0% p=0.007 Median TTP 8.2 m 5.6 m Median OS 25.5 m 20.4 m p=0.034 HR=0.69 p=0.26 HR=0.76 Cardiac Toxicity (Grade 3/4) 5.2% 2.7% NS von Minckwitz SABC 2007

26 Phase III trial of capecitabine ± lapatinib in trastuzumab refractory & taxane/anthracycline pretreated MBC (EGF100151) Lapatinib + capecitabine Capecitabine % of patients free from progression* TTP (n=324) No. of pts CR+PR (%) Progressed or died Median TTP, mo Hazard ratio (95% CI) 0.49 (0.34, 0.71) P-value < Time (weeks) Geyer C, et al. NEJM 2006;355:

27 Change title on Master-Arial 14-Unbold Purple (R191 G126 B204) Total Blockade of HER2 May Provide Greater Anti-tumor Activity and Overcome Resistance MUC4 HER1 - HER1 HER1 - HER2 p95 HER1 - HER3 HER2 - HER2 PTEN PTEN HER1 - HER4 HER2 - HER3 HER2 - HER4 PI3K SOS Akt RAS RAF MAPK MEK Cell proliferation Cell survival Cell mobility and invasiveness Transcription O Shaughnessy J, et al. ASCO Abstract clinicaloptions.com/oncology

28 Lapatinib + trastuzumab significantly prolonged PFS compared with lapatinib alone in trastuzumab refractory breast cancer (EGF104900) Cumulative progression-free (%) month PFS 28% 13% Lapatinib Lapatinib + trastuzumab n=145 n=146 Progressed or died, n Median, wks HR (95% CI) 0.73 (0.57, 0.93) p value Subjects at risk: Time from randomisation (weeks) Lapatinib Lapatinib + trastuzumab O Shaughnessy J, et al. J Clin Oncol ASCO Annual Meeting Proceedings 2008; 26(Suppl.): Abstract 1015 and oral presentatio

29 EGF103892: Phase I, dose escalation study of lapatinib plus carboplatin and paclitaxel, with and without trastuzumab, in MBC patients Lapatinib, paclitaxel and carboplatin plus trastuzumab (n=11) PD 1 CR 1 Diarrhoea is a frequent drugrelated AE in both the threedrug and four-drug combinations PR 8 One patient in each group is awaiting anti-tumour assessment Storniolo et al. Breast Cancer Res Treat 2008;112(Suppl.):Abstract 3121 and poster

30 The angiogenic switch in tumour development Small tumour (1 2mm diameter) avascular dormant Larger tumour vascular metastatic potential Angiogenic switch

31 Avastin has both early and continued effects on tumour vasculature EARLY EFFECTS CONTINUED EFFECTS Regression of some tumour vasculature 1 2 Normalisation of surviving tumour vasculature 1,4,5 3 new and Inhibition of recurrent vessel growth Willet, et al. Nat Med 2004; 2. Baluck, et al. Curr Opin Genet Dev 2005; 3. Inai, et al. Am J Pathol 2004; 4. Gerber, et al. Cancer Res 2005; 5. Jain. Science 2005

32 Single-agent Avastin in breast cancer 3mg/kg* 10mg/kg* 20mg/kg* Response (n=75) (n=18) (n=41) (n=16) Complete response, n (%) 0 1 (2.4) 0 Partial response, n (%) 1 (5.6) 4 (9.8) 1 (6.3) Clinical benefit at 22 weeks, n (%) 2 (11) 7 (17) 3 (19) Median response duration (months) *Every 2 weeks Based on the observed efficacy and safety in this phase I/II trial, Avastin 10mg/kg every 2 weeks or 15mg/kg every 3 weeks was selected for further testing in combination with chemotherapy in mbc mbc = metastatic breast cancer Cobleigh, et al. Semin Oncol 2003

33 Anti-VEGF antibody normalises the tumour vasculature Anti-VEGF 0 1 mm Hg 5 mm Hg 15 mm Hg Reduces IFP & MVD & Increases drug delivery 0 1 mm Hg 2 mm Hg 10 mm Hg Jain R. Nature Med 2001;7:987 9; Willett CG, et al. Nat Med 2004;10:145 7; Wildiers H, et al. Br J Cancer 2003;88: Jain 1988, 1990

34 The addition of Avastin more than doubles overall response rate ECOG 2100 Complete response 40 Partial response 36.2 Overall response rate (%) % p< Paclitaxel (n=268) Avastin + paclitaxel (n=246) Roche data on file submitted to regulatory authority in 2006

35 The addition of Avastin doubles median progression-free survival, the primary trial endpoint Progression-free survival estimate Avastin + paclitaxel (n=368) Paclitaxel (n=354) HR=0.48; p< Median progression-free survival (months) 99% increase in median progression-free survival Time (months) Paclitaxel 13.3 Avastin + paclitaxel HR = hazard ratio Avastin Summary of Product Characteristics (SmPC)

36 Bevacizumab Reported Trials: Efficacy E2100 AVADO RIBBON-1: Cape RIBBON-1: A/T P P+B D+PI D+B C+PI C+B A/T+PI AT+B ORR, % / PFS, mo / (7.5 mg) HR 0.60 p< p= (15 mg) 0.69 p= p< p= OS, mo HR 0.88 p= p= p= p=0.83

37 E2100: most frequent grade 3 adverse events ( 5% incidence) NCI-CTCAE term Paclitaxel (n = 348) (%) Paclitaxel + Avastin (n = 363) (%) Difference (%) Patients with 1 event Neuropathy Hypertension Fatigue Infection without neutropenia Neutropenia (grade 4) Vomiting # Includes NCI AdEERS mandatory collection in the Avastin + paclitaxel arm only, which does not allow valid comparison between the two arms Data on file submitted to CHMP Nov 07

38 Avastin s safety profile in combination with chemotherapy Commonly reported events hypertension proteinuria bleeding Less frequently reported events congestive heart failure (CHF)/ cardiomyopathy arterial/venous thromboembolism (ATE/VTE) wound-healing complications gastrointestinal (GI) perforations Typical chemotherapy-associated side effects neuropathy neutropenia fatigue

39 Overall Survival of Avastin + Paclitaxel Overall survival estimate 100 Avastin + paclitaxel (n=368): median overall survival 25.7 months Paclitaxel (n=354): 80 median overall survival 23.8 months year survival*: 82.3% vs 73.8%; p=0.007 HR=0.82; p= Months *Exploratory analysis Roche data on file submitted to regulatory authority in 2006

40 AVADO: Overall Survival (15 mg/kg q3w a ) 1.0 Crossover, % Overall survival estimate Placebo + docetaxel Avastin b + docetaxel Events, n (%) 108 (44.8) 116 (47.0) Median, months HR (95% CI) 1.03 ( ) p= year rate, % p= Number at risk Avastin 15 + doc Placebo + doc Months a ITT population Avastin SmPC 2009; Roche data on file

41 Addition of Avastin to capecitabine in a highly pretreated population Overall response rate (%) Capecitabine alone (n=230) Avastin + capecitabine (n=232) p value Investigators Independent review facility Median progression-free survival (months) NS Median overall survival (months) NS The addition of Avastin to capecitabine more than doubled the response rate in this phase III trial according to an independent review facility NS = not significant Miller, et al. JCO 2005

42 Redundancy of pro-angiogenic factors --VEGF, FGF, PDGF, PLGF, TGFβ1, pleitrophin1.. Evasion of antiangiogenic targeting of VEGF by inducing other pro-angiogenic factors Lack of biomarker to guide the therapy Casanovas & Hanahan, cancer cell 2005

43 Median PFS/TTP/TTF and PPS x median OS Median PPS has a stronger correlation with median OS than do median PFS/TTP/TTF This is partly explained by the fact that PPS is longer (median=12 months) than PFS/TTP/TTF (median=6 months) Subsequent lines of therapy seem to play a major role in determining 43 OS

44 Issues regarding the future of antiangiogenesis therapy How to evaluate the effect How to predict the effect When to start treatment When to stop treatment Which salvage treatment

45 Factors to consider when choosing regimens for metastatic breast cancer? 1. Overall survival (OS) 2. Progression free survival (PFS) 3. Response rate (RR) 4. Clinical benefit (CR/PR/SD) 5. Toxicity 6. Quality of life

46 Objective response rates with common taxane-containing regimens Single agent paclitaxel Single agent docetaxel Paclitaxel + gemcitabine Docetaxel + capecitabine Docetaxel + gemcitabine Paclitaxel + bevacizumab Docetaxel + bevacizumab * * * * * * * * 10 AVADO 2008 (15mg/kg q3w) AVADO 2008 (7.5mg/kg q3w) E Chan et al Melemed et al O Shaughnessy et al O Shaughnessy et al Jones et al E Chan et al AVADO 2008 Jones et al Melemed et al RiBBON-1 (15mg q3w) *Includes patients with measurable disease only Objective response rate (%)

47 Monotherapy Combination chemotherapy Avastin + Docetaxel (AVADO) 1st line MBC treatment : PFS/TTP Avastin + chemotherapy (E2100) Docetaxel Chan 1999 Doxorubicin Chan 1999 Paclitaxel Seidman 2004 Vinorelbine Muñoz 2006 Doxorubicin + paclitaxel Jassem 2001 Xeloda + docetaxel O Shaughnessy 2002 Gemcitabine + paclitaxel Albain 2004 FEC Zielinski 2005 Epirubicin + docetaxel Pacilio 2006 Gemcitabine + docetaxel Patrizia 2009 Avastin 15mg/q3w + docetaxel Pivot 2009 Avastin 7.5mg/q3w + docetaxel Pivot 2009 Docetaxel Pivot 2009 Avastin + paclitaxel E Paclitaxel E Median PFS / TTP 7 months Avastin + Xeloda (RiBBON-1) Avastin + Capecitabine RiBBON Capecitabine RiBBON Time (months)

48 Thank You Very Much!