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ADJUVANT TREATMENT: TARGET THERAPIES

BELGIAN BREAST MEETING 13-14 October 2006 Brussels, Belgium. ADJUVANT TREATMENT: TARGET THERAPIES. Fatima Cardoso, MD Jules Bordet Institute & TRANSBIG. ENDOCRINE THERAPY First example of TARGETED THERAPY. Aromatase inhibitors. ER. The target. The ligand. SERMS & ER DOWN REGULATORS.

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ADJUVANT TREATMENT: TARGET THERAPIES

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  1. BELGIAN BREAST MEETING 13-14 October 2006 Brussels, Belgium ADJUVANT TREATMENT: TARGET THERAPIES Fatima Cardoso, MD Jules Bordet Institute & TRANSBIG

  2. ENDOCRINE THERAPYFirst example of TARGETED THERAPY Aromatase inhibitors ER The target The ligand SERMS & ER DOWN REGULATORS

  3. TRASTUZUMAB IN THE ADJUVANT SETTINGSUMMARY OF THE FOUR MAJOR TRIALS Trastuzumab upfront in combination with platinum/taxane(BCIRG 006) Only trial with a non-A arm Trastuzumab after 3 months of AC, in combination with taxane(NSABP-B31) weekly & 3-weekly Trastuzumab for 1 year Selection of the subgroup most likely to benefit: IHC 3+ or FISH positive in all trials Trastuzumab monotherapy after 6 months of AC → T or in combination with taxane(NCCTG-N9831) 3-weekly Trastuzumab monotherapy after 6 months of standard chemotherapy (HERA Trial) Trastuzumab for 1 or 2 years Total 12,000 women + FinHER Trial

  4. ADJUVANT TRASTUZUMAB TRIALS EFFICACY RESULTS AT  2 YEARS MEDIAN FU Favors trastuzumab Reduction in relapses (DFS) of 52% to 68% Similar results in DDFS

  5. ADJUVANT TRASTUZUMAB TRIALS EFFICACY RESULTS AT  2 YEARS MEDIAN FU Favors trastuzumab 44% reduction in mortality risk

  6. No T Doce taxel, Carboplatin and T 9 wks T with Anti-micro-tubules then FEC x 3 Sequential A-based CTX then T AC x 4then T combined with taxane Treatment strategy 4.1 3.5 Risk of CHF NYHA Class 3-4 2.5 1.6 00.8 0.6 0.4 0 Control arms BCIRG 006 FinHER HERA N-9831 BCIRG 006 N-9831 B31 Median f-up 2 y 39m 1 y 2 y 2 y 2 y 3 y 1239m N at risk 1056 116 1677 718 1068 579 846 >4000 ADJUVANT TRASTUZUMAB TRIALS CARDIOTOXICITY RISKS M. Piccart used with permission

  7. ADJUVANT TRASTUZUMAB TRIALS CARDIOTOXICITY RESULTS REASONS FOR DIFFERENT CARDIOTOXICITY RESULTS AMONG ADJUVANT TRIALS • Different follow-up • Different sample size (FinHER) • No use of anthracyclines (BCIRG 006 TCH arm) • Sequential administration of chemotherapy  trastuzumab (HERA) • Sequential administration of radiotherapy  trastuzumab (HERA)

  8. IMPAIRMENT IN TRASTUZUMAB ADMINISTRATION BECAUSE OF CARDIAC PROBLEMS KEY MESSAGES FOR CLINICAL PRACTICE • Depending on age, between 1.3% and 4% of women younger than 65 cannot be started on upfront trastuzumab, in view of • cardiac risk factors or cardiac diseases • If anthracycline is given, an additional 6% to 7 % will not access trastuzumab and an additional 5% to 20% will not be able to complete 1 year of treatment, depending on the schedule of administration with taxane • An LVEF entry criterion of 55% after CT and RT (HERA trial) precludes access to trastuzumab to another 5-6% of women M. Piccart –ESMO 2006-used with permission

  9. UNANSWERED / OPEN QUESTIONS • The benefit versus harm ratio remains unknown for women with cardiac risk factors, age above 70 and / or small (1cm) node negative tumors (ATTENTION WHEN DESIGNING CLINICAL TRIALS) • Optimal duration of trastuzumab treatment (9 ws vs. 1 vs. 2 years) • Optimal timing to initiate trastuzumab • Optimal schedule (sequential vs. concomitant with CT) • Is CT always necessary? Role of HT + Trastuzumab • Mechanisms of resistance to trastuzumab (MBC: only at the most 50% of HER-2-positive BC respond & median duration response 9 ms)

  10. CO-AMPLIFICATION OF cMYC AND HER-2 PREDICTS FOR TRASTUZUMAB’S BENEFIT (S. PAIK, SABCC 2005) M. Piccart –ESMO 2006-used with permission

  11. m-TOR, PTEN AND SENSITIVITY TO TRASTUZUMAB IN HER-2 (+) CANCER CELLS Pandolfi, 2004

  12. HER-2 P95 POSITIVE TUMORS RESPOND LESS TO TRASTUZUMAB N= 36 patients treated with trastuzumab Courtesy J. Baselga

  13. LAPATINIB IN (NEO) ADJUVANT THERAPY OF HER-2 + BREAST CANCER: RATIONALE • Trastuzumab only partially active • Lapatinib: • Has a different mechanism of action • Active in trastuzumab resistant patients • May be active in HER2 p95 positive tumors • High level of activity in single agent first line setting • Preclinical synergy with the combination of lapatinib and trastuzumab. Encouraging activity of the combination in patients with prior therapy with trastuzumab • May be active against brain (micrometastatic) disease CONFIDENTIAL – NOT FOR DISTRIBUTION

  14. ASCO 2006 METASTATIC BREAST CANCER HER-2 + BREAST CANCER New drugs: LAPATINIB In combination with capecitabine (X) improves TTP in women pretreated with anthracycline/taxanes and trastuzumab (late breaking) As single agent shows modest but real activity against brain metastases in trastuzumab "failures" (abstr # 503) In a review of 3127 lapatinib-treated patients, shows very little cardiotoxicity (abstr # 585) Single agent Lapatinib active inrelapsed/refractory IBC (abstr # 502)

  15. NEOADJUVANT ADJUVANT 2007 2010 2011 2008 2009 Neo-Adjuvant Adjuvant Build translational research hypothesis and validate them Build confidence in lapatinib (interim look) CONFIDENTIAL – NOT FOR DISTRIBUTION

  16. FEC FEC FEC NEO-ADJUVANT: RANDOMIZED PHASE II TRIAL 450 PTS (150 x arm) Trastuzumab x 34 weeks Trastuzumab x 6 weeks Trastuzumab + paclitaxel x 12 weeks R ANDOMIZA T I O N S U R G ERY HER2 3+ Tumors > 2 cm (N=450) Lapatinib x 6 weeks Lapatinib + paclitaxel x 12 weeks Lapatinib x 34 weeks Trastuzumab Trastuzumab + lapatinib Trastuzumab + lapatinib x 34 weeks + Lapatinib x 6 weeks + paclitaxel x 12 weeks Translational research Disease-free survival pCR rate Biopsy (Pet Scan) Week 2: Biopsy (Pet Scan) CONFIDENTIAL – NOT FOR DISTRIBUTION

  17. ADJUVANT DESIGN – HERA MODEL 8000 PTS Locally-determined HER2-positive invasive breast cancer (For patients with neoadjuvant treatment, the Her2 determination should be done on a tissue sample taken before the treatment is started) Centrally-determined HER2 + Surgery, complete (neo)adjuvant anthracycline-based chemotherapy (selected from an approved list); complete adjuvant radiation therapy (if given) LVEF  50 RANDOMIZATION Trastuzumab 3-weekly for 6 months Trastuzumab 3-weekly + lapatinib for 1 year Trastuzumab for 1 year Lapatinib for 1 year  Lapatinib for 6 months • Women considered candidates for adjuvant taxanes receive weekly paclitaxel concomitantly with the biologic therapy. • Patients with ER or PgR-positive tumors receive endocrine therapy selected accordingly to menopausal status; administered concurrent with biologics and continuing for at least 5 years. • N=8000 women HR 0.78 between experimental-arm and trastuzumab; (3 pair wise comparisons; 80% power; 691 events for each comparison) CONFIDENTIAL – NOT FOR DISTRIBUTION

  18. DESIGN – high risk patients: taxanes Locally-determined HER2-positive invasive breast cancer (For patients with neoadjuvant treatment, the Her2 determination should be done on a tissue sample taken before the treatment is started) Centrally-determined HER-2 + Surgery, complete (neo)adjuvant anthracycline-based chemotherapy LVEF  50 RANDOMIZATION 1 Y E A R Weekly paclitaxel 12 weeks  Weekly trastuzumab 12 weeks  Weekly paclitaxel 12 weeks  Lapatinib Weekly paclitaxel 12 weeks  3-weekly trastuzumab 6 months  Weekly paclitaxel 12 weeks  Lapatinib + Weekly trastuzumab 12 weeks  Radiotherapy (if indicated) 3-weekly trastuzumab Radiotherapy (if indicated) Radiotherapy (if indicated) Radiotherapy (if indicated) Lapatinib + 3-weekly trastuzumab Lapatinib 6 months CONFIDENTIAL – NOT FOR DISTRIBUTION

  19. The Breast Cancer Observatory:Innovation and care in the next 12 months View of a Medical Oncologist and a Clinical/Translational Researcher 1) … 2) … 3) Lapatinib and Bevacizumab will be the next targeted therapies to be tested in the breast adjuvant setting, with the possibility of Lapatinib taking the place of Trastuzumab. TUMOR VASCULATURE N Engl J Med 351 (3): 216, 2004

  20. BEVACIZUMAB IN METASTATIC BREAST CANCER IMP since always RARE in MBC

  21. Differences in Study Populations … could (partially) explain different results of trials • ECOG 2100 Capecitabine trial • Prior chemo for MBC 0% 85% • Prior chemo 64% 100% • Prior A + T minority 100% • HER-2+ hardly any 25% • Prior trastuzumab hardly any 23% Once again: IMPORTANCE OF GIVING THE BIOLOGICAL AGENT EARLY

  22. Bevacizumab: A “Targeted Therapy” Without A Target ??!!…and an expensive one… Unlike trastuzumab, to date, no predictive factors of response to bevacizumab, including VEGF expression, have been identified

  23. HER-2 TESTING IN N9831 • Modest level of concordance between local and central laboratories for both IHC and FISH (n=1815 pts) • 802 with HercepTest™: 81% (78-83%) • 550 with FISH: 87% (84-90%) • 463 with non-HercepTest: 74% (70-80%) • High level of agreement between central and reference laboratory results for HER-2 Updated from Perez EA, et al. ASCO 2004 (abstract 567)

  24. “THE HERCEPTIN HYPE” Balanced enthusiasm is also OUR responsibility Cancerworld, Anna Wagstaff, March-April2006

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