1 / 38

A Report from SABCS Up-to-Date Review of the Treatment of Advanced Breast Cancer

A Report from SABCS Up-to-Date Review of the Treatment of Advanced Breast Cancer. William J. Gradishar, MD Director, Breast Medical Oncology Professor of Medicine Robert H. Lurie Comprehensive Cancer Center Northwestern University Feinberg School of Medicine Chicago, IL.

olathe
Download Presentation

A Report from SABCS Up-to-Date Review of the Treatment of Advanced Breast Cancer

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. A Report from SABCSUp-to-Date Review of the Treatment of Advanced Breast Cancer William J. Gradishar, MD Director, Breast Medical Oncology Professor of Medicine Robert H. Lurie Comprehensive Cancer Center Northwestern University Feinberg School of Medicine Chicago, IL

  2. Chemotherapy for MBC

  3. 305 patients randomized GD: Gemcitabine 1000 mg/m2 d1,8 Docetaxel 75 mg/m2 d1 q 3 w CD: Capecitabine 1250 mg/m2 b.i.d. d1-14 Docetaxel 75 mg/m2 d1 q 3 w Gemcitabine/Docetaxel vs. Capecitabine/Docetaxel in Anthracycline-Pretreated MBC (Phase III)Efficacy Results Chan S, et al. SABCS 2007Abstract 1078.

  4. Gemcitabine/Docetaxel vs. Capecitabine/Docetaxel in Anthracycline-Pretreated MBC (Phase III)Toxicities * P < .05 Chan S, et al. SABCS 2007Abstract 1078.

  5. Ixabepilone (40 mg/m2 IV over 3 hr d1 q 3 wk) + Capecitabine (2000 mg/m2/dayPO 2 divided doses d1-d14 q 3 wk) (N = 375) Metastatic or locally advanced breast cancer RESISTANT to anthracyclines and taxanes (N = 752) Capecitabine (2500 mg/m2/day PO 2 divided doses d1-d14 q 3 wk) (N = 377) • Stratification: • Visceral metastases • Prior chemotherapy for MBC • Anthracycline resistance • Study site Study Design: International, Randomized, Open-Label, Phase III TrialTrial Design Vadhat LT, et al, ASCO 2007 Abstract 1006.

  6. Capecitabine ± IxabepiloneProgression-free Survival by Independent Radiologic Review 1.0 0.8 0.6 0.4 0.2 0 HR: 0.75 (0.64–0.88) P = 0.0003 Proportion Progression-Free 0 4 8 12 16 20 24 28 32 36 Months Vadhat LT, et al, ASCO 2007 Abstract 1006.

  7. Investigator IRR Capecitabine (N = 377) Ixabepilone + Capecitabine (N = 375) Capecitabine (N = 377) Ixabepilone + Capecitabine (N = 375) % Response ORR (CR + PR) 42 23 35 14 P < .0001 P < .0001 Stable disease 36 38 41 46 Progressive disease 14 29 15 27 Unable to determine 8 10 9 12 Capecitabine ± IxabepiloneResponse Vadhat LT, et al, ASCO 2007 Abstract 1006.

  8. Capecitabine ± IxabepiloneToxicity • All toxicity-related deaths in combination arm attributable to neutropenia: • Incidence with baseline ≥ grade 2 LFTs was 31% (5/16) • Incidence post amendment with baseline ≤ grade 1 LFTs was 2% (7/353) • Grade 3/4 hematologic: • 4 versus < 1% FN (0.001) • 8 versus 4% thrombocytopenia (0.011); 10 versus 4% anemia (0.005) • Grade 3/4 nonhematologic: • 23% peripheral neuropathy: • Primarily sensory • Cumulative • Reversible: • Median time to resolution 6 weeks Vadhat LT, et al, ASCO 2007 Abstract 1006.

  9. Efficacy of Ixabepilone/Capecitabine in ER/PR/HER2-Negative MBC Resistant to Anthracyclines and Taxanes Rugo H, et al. SABCS 2007, Abstract 6069.

  10. Hormonal Therapy for MBC

  11. Fulvestrant vs. Exemestane Following Prior Nonsteroidal AI Therapy: EFECT, a Phase III Trial in Postmenopausal Women With Advanced Breast Cancer Eligibility Criteria: Postmenopausal women HR+ Measurable disease Prior nonsteroidal AI failure for advanced breast cancer or for adjuvant therapy or within 6 months of its discontinuation (N = 693) Fulvestrant: loading dose 500 mg on d 0, followed by 250 mg on d 14, 28 q 28 ± 3 days thereafter (N = 351) RANDOMIZE Exemestane: 25 mg orally daily + placebo (N = 342) • Primary Endpoint: • Time to disease progression Chia S, et al. SABCS 2007, Abstract 2091.

  12. Fulvestrant vs. Exemestane Following Prior Nonsteroidal AI Therapy: EFECT TrialEfficacy * Odds ratio Gradishar WJ, et al.Breast Cancer Res Treat2006; 100(suppl 1):S8 (abstract 12).

  13. Fulvestrant vs. Exemestane Following Prior Nonsteroidal AI Therapy: EFECT TrialEfficacy • Adverse events (all grades) similar between arms: • Injection site pain (F 9.7%; E 8.8%) • Hot flashes (F 8.8%; E 11.5%) • Fatigue (F 6.3%; E 10%) Chia S, et al. SABCS 2007, Abstract 2091.

  14. HER2-Targeted Therapy for MBC

  15. Eligibility Criteria: Progressive MBC or LABC HER2 overexpression Previous trastuzumab Trastuzumab-free interval < 6 wks LVEF ≥ 50 Trastuzumab Beyond Progression TrialStudy Design Capecitabine 2,500 mg/m2 d1-14 q21 days(N = 78) RANDOMIZE Capecitabine 2,500 mg/m2 d1-14 q21 days + Continuation of Trastuzumab 6 mg/kg every 3 weeks(N = 78) • Primary endpoint: time to progression • Secondary endpoints: OS, ORR, safety *Study closed at 156 patients due to slow accrual following FDA registration of lapatinib for this indication Von Minckwitz G, et al. SABCS 2007. Poster 4056.

  16. Trastuzumab Beyond Progression TrialResults • Severe cardiac events: 2.9% capecitabine; 4.9% capecitabine/trastuzumab Von Minckwitz G, et al. SABCS 2007. Poster 4056.

  17. RegistHER: CNS Metastases in Patients with HER2-Postitive MBC • Multicenter prospective, observational study • 1023 patients enrolled, 768 included in present analysis • 30.7%developed CNS metastases, 6.8% at time of initial diagnosis • Median time to first CNS event:12.1 mos • Median survival following first CNS metastases: 13.9 mos • Characteristics of patients who developed CNS metastases: • Younger(< 50: 45.3% vs. 39.3% others; P = .0347) • HR-negative(53.4% vs. 39.6% others; P = .0044) • Greater tumor burden(2+ metastatic sites 61% vs. 51.6% others; P = .0356) Yardley D, et al. SABCS 2007 Abstract 6049.

  18. Extension Study Parent Study Lapatinib 1,250 mg/day continuously + Capecitabine 2,000 mg/m2/d po d1-14 q 3 wk Lapatinib monotherapy 750 mg BID CNS PD* Lapatinib + Capecitabine for the Treatment of Brain Metastases in Patients With HER2+ Breast Cancer Trial Design and Parent Study Results • Parent Study Results: • (N = 242) • ≥ 50% CNS volumetric tumor reduction 6% • ≥ 20% CNS volumetric tumor reduction 17% • Median PFS: 9.3 weeks Lin NU, et al. SABCS 2007. Poster 6076.

  19. Lapatinib + Capecitabine for the Treatment of Brain Metastases in Patients With HER2+ Breast Cancer Extension Study Results * HR 0.34 (Patients with ≥ 20% tumor volume reduction versus all others); P =.0013 • Most frequent grade 3/4 adverse events: palmoplantar erthrodysesthesia, • diarrhea, nausea, vomiting, and fatigue Lin NU, et al. SABCS 2007. Poster 6076.

  20. EGFR-Targeted Therapy for MBC

  21. SABCS Abstract 307 TBCRC 001: EGFR Inhibition with Cetuximab in Metastatic Triple Negative Breast Cancer Carey LA, Mayer E, Marcom PK, Rugo H, Liu M, Ma C, Rimawi M, Storniolo A, Forero A, Esteva F, Wolff A, Ingle J, Ferraro M, Sawyer L, Davidson N, Perou CM, Winer EP

  22. Rationale for Combination Cetuximab/Carboplatin in Basal-like Breast Cancer • Basal-like breast cancer is characterized by high expression of EGFR (one of the basal gene cluster) • EGFR targeting is effective in basal-like preclinical models. • Basal-like are "triple negative" (ER-, PR-, and HER2-negative) limiting options to chemotherapy. • Association with BRCA1 mutation carriers raises question of platinum sensitivity. Carey LA, et al. SABCS 2007. Abstract 307.

  23. Arm 1 Cetuximab Cetuximab + carboplatin PD Randomized Phase II Cetuximab + carboplatin Arm 2 Tissue, circulating tumor cells Germline DNA TBCRC 001: Cetuximab in Stage IVTriple Negative Breast CancerStudy Design Carey LA, et al. SABCS 2007. Abstract 307.

  24. TBCRC 001: Cetuximab in Stage IVTriple Negative Breast CancerObjectives • Primary Objectives: • ORR single agent cetuximab in triple negative metastatic breast cancer (MBC). • ORR to combination cetuximab/carboplatin in triple negative MBC • Secondary Objectives: • Time to disease progression on single agent cetuximab • Time to disease progression on combination cetuximab/carboplatin. • Correlation of downstream effects of EGFR inhibitor on MAPK, AKT, Ki67 and EGFR-dependent signaling, proliferation, and apoptosis with toxicity and response (serial bx pts) • Changes in biomarkers and gene expression in circulating tumor cell • Overall survival Carey LA, et al. SABCS 2007. Abstract 307.

  25. TBCRC 001: Cetuximab in Stage IVTriple Negative Breast CancerPatient Population and Treatment • Patient population • 100 patients for 93 evaluable • Stage IV, measurable disease • ER, PR, and HER2-negative (HER2 0-1+ IHC or FISH-negative) • 0-3 prior chemotherapy regimens • Otherwise healthy • Available archival tissue • Treatment • Arm 1: • Cetuximab 400 mg/m2 load then 250 mg/m2 iv q wk • Upon progression – add carboplatin AUC 2 iv q wk (3 of 4 wks) • Arm 2: • Cetuximab + carboplatin (same doses/schedule) • Desired 20% of patients undergo serial biopsy Carey LA, et al. SABCS 2007. Abstract 307.

  26. Arm 1 closes 3/07 Interim analysis Spring 2006 Study opens 10/07 Completed accrual Arm 1: 31 patients, 24 evaluable Arm 2: 69 patients, 44 evaluable Being reported SABCS 12/07 Data analysis in progress TBCRC 001: Cetuximab in Stage IVTriple Negative Breast CancerStudy Status Carey LA, et al. SABCS 2007. Abstract 307.

  27. TBCRC 001: Cetuximab in Stage IVTriple Negative Breast CancerPatient/Tumor Characteristics Carey LA, et al. SABCS 2007. Abstract 307.

  28. TBCRC 001: Toxicity

  29. TBCRC 001: Cetuximab in Stage IVTriple Negative Breast CancerEfficacy Arm 1 (ITT) Carey LA, et al. SABCS 2007. Abstract 307.

  30. TBCRC 001: Cetuximab in Stage IVTriple Negative Breast CancerConclusions • Single agent cetuximab is well tolerated, but only 2 RR of 31 evaluable patients were seen, prompting closure of Arm 1 according to a priori stopping rules. • Disease stabilization was seen in 16%, 1 durable • Two patients are still in PR at 69 and 42 weeks, respectively • Analysis of combination therapy on arm 1 reveals a 18% RR and 27% CB rate • This is encouraging in a largely pretreated population • Arm 2 analysis is in progress • Early progression limited treatment in some, supporting the biologically aggressive nature of triple negative breast cancer and potentially complicating efforts to treat Carey LA, et al. SABCS 2007. Abstract 307.

  31. SABCS Abstract 308 Randomized Phase II Study of Weekly Irinotecan/Carboplatin With or Without Cetuximab in Patients With Metastatic Breast Cancer O’Shaughnessy J; Weckstein DJ; Vukelja SJ; McIntyre K; Krekow L; Holmes FA; Asmar L; Blum JL

  32. Weekly Irinotecan/Carboplatin With or Without Cetuximab in Patients With MBCRationale • Irinotecan and carboplatin (ICb) is a synergistic antineoplastic combination in several cancers • Weekly irinotecan is an active agent in MBC1 • Epidermal growth factor receptor (EGFR) inhibition enhances antitumor activity of both irinotecan and cisplatin in breast cancer preclinical models2,3 • EGFR is overexpressed in over 50% of triple negative breast cancers4 and may be involved in endocrine-therapy resistance as well5 • It is hypothesized that the addition of cetuximab (E) to ICb will increase the overall response rate of the ICb combination and will prolong the median time to progression for patients with metastatic breast cancer References: 1Perez EA, Hillman DW, Mailliard JA, et al. J Clin Oncol. 2004;22:2849-2855. 2Ciardiello F, Bianco R, Damiano V, et al. Clin Cancer Res. 2000;6:3739-3747. 3Ciardiello F, Tortora G. Expert Opin Investig Drugs. 2002;11:755-768. 4Nielsen TO, Hsu FD, Jensen K, et al. Clin Cancer Res. 2004; 10:5367-5374. 5Johnston SR, Head J, Pancholi S, et al. Clin Cancer Res. 2003; 9:524S-532S.

  33. Weekly Irinotecan/Carboplatin With or Without Cetuximab in Patients With MBCKey Eligibility • Metastatic breast cancer measurable by RECIST • 0-1 chemotherapy regimens for metastatic disease • No prior irinotecan or platinum agent • If HER2-positive (HER2+), patients must have progressed on trastuzumab O’Shaughnessy J, et al. SABCS 2007. Abstract 308.

  34. RANDOMIZE *Irinotecan (I) 100 mg/m2 Carboplatin (Cb) AUC = 2.5 Day 1, 8 q 21 days Cetuximab (E) alone at progression STRATIFY Triple negative (ER-, PR-, HER2-negative) *Irinotecan (I) 100 mg/m2, D1, 8 q 21dCarboplatin (Cb) AUC = 2.5, D1, 8 q 21d Cetuximab (E) 400 mg/m2, D1, then 250 mg/m2 weekly thereafter *Starting ICb doses decreased to 90 mg/m2 and AUC = 2.0 midway through enrollment due to diarrhea with ICb + E Weekly Irinotecan/Carboplatin With or Without Cetuximab in Patients With MBCTreatment Schema O’Shaughnessy J, et al. SABCS 2007. Abstract 308.

  35. ICb ± E: Patient Characteristics

  36. Weekly Irinotecan/Carboplatin With or Without Cetuximab in Patients With MBCOverall Efficacy by Subset O’Shaughnessy J, et al. SABCS 2007. Abstract 308.

  37. Weekly Irinotecan/Carboplatin With or Without Cetuximab in Patients With MBCConclusions • Cetuximab did not improve the ORR, PFS and OS when added to irinotecan/carboplatin in MBC patients • On subset analysis, starting dose irinotecan/carboplatin plus cetuximab had a higher ORR than starting dose irinotecan/carboplatin alone • On subset analysis, the addition of cetuximab increased the ORR associated with irinotecan/carboplatin in triple negative metastatic breast cancer • Irinotecan/carboplatin is an active regimen for both HR+ and triple negative breast cancer • Single-agent cetuximab was minimally active following progression on irinotecan/carboplatin • Diarrhea is the primary toxicity associated with irinotecan/carboplatin and this was exacerbated by the addition of cetuximab O’Shaughnessy J, et al. SABCS 2007. Abstract 308.

  38. Treatment of Advanced Breast CancerClosing Comments William J. Gradishar, MD

More Related