Presentation is loading. Please wait.

Presentation is loading. Please wait.

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

Similar presentations


Presentation on theme: "ADJUVANT TREATMENT: TARGET THERAPIES BELGIAN BREAST MEETING 13-14 October 2006 Brussels, Belgium Fatima Cardoso, MD Jules Bordet Institute & TRANSBIG."— Presentation transcript:

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

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

3 Trastuzumab upfront in combination with platinum/taxane (BCIRG 006) Trastuzumab after 3 months of AC, in combination with taxane (NSABP-B31) Trastuzumab monotherapy after 6 months of AC → T or in combination with taxane (NCCTG-N9831) Trastuzumab monotherapy after 6 months of standard chemotherapy (HERA Trial) Trastuzumab for 1 year Trastuzumab for 1 or 2 years Total  12,000 women Selection of the subgroup most likely to benefit: IHC 3+ or FISH positive in all trials TRASTUZUMAB IN THE ADJUVANT SETTING SUMMARY OF THE FOUR MAJOR TRIALS 3-weekly weekly & 3-weekly Only trial with a non-A arm 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 44% reduction in mortality risk ADJUVANT TRASTUZUMAB TRIALS EFFICACY RESULTS AT  2 YEARS MEDIAN FU Favors trastuzumab

6 ADJUVANT TRASTUZUMAB TRIALS CARDIOTOXICITY RISKS No T 9 wks T with Anti- micro- tubules then FEC x 3 Doce taxel, Carbopl atin and T Sequential A- based CTX then T AC x 4  then T combined with taxane 0  Controlarms BCIRG 006 HERAN-9831BCIRG006 Risk of CHFNYHA Class FinHER Median f-up 12  39m 2 y 39m 1 y 2 y N at risk > Treatmentstrategy N-9831B y 846 M. Piccart used with permission

7 ADJUVANT TRASTUZUMAB TRIALS CARDIOTOXICITY RESULTS REASONS FOR DIFFERENT CARDIOTOXICITY RESULTS AMONG ADJUVANT TRIALS Different follow-up Different follow-up Different sample size (FinHER) Different sample size (FinHER) No use of anthracyclines (BCIRG 006 TCH arm) No use of anthracyclines (BCIRG 006 TCH arm) Sequential administration of chemotherapy  trastuzumab (HERA) Sequential administration of chemotherapy  trastuzumab (HERA) Sequential administration of radiotherapy  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 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 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 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 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) 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 duration of trastuzumab treatment (9 ws vs. 1 vs. 2 years) Optimal timing to initiate trastuzumab Optimal timing to initiate trastuzumab Optimal schedule (sequential vs. concomitant with CT) Optimal schedule (sequential vs. concomitant with CT) Is CT always necessary? Role of HT + Trastuzumab 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) 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) Background HER-2 and cMYC: only independent prognostic factors in NSABP-B28 HER-2 and cMYC: only independent prognostic factors in NSABP-B28 25% of HER-2+ patients have coamplification of cMYC 25% of HER-2+ patients have coamplification of cMYCNSABP-B31 Coamplification of cMYC Coamplification of cMYC NoYes Trastuzumab’s benefit HR DFS p = p < HR O.S. NO GAIN p = Hypothesis Trastuzumab turns on the pro-apoptotic function of deregulated cMYC 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 CONFIDENTIAL – NOT FOR DISTRIBUTION LAPATINIB IN (NEO) ADJUVANT THERAPY OF HER-2 + BREAST CANCER: RATIONALE Trastuzumab only partially active Trastuzumab only partially active Lapatinib: 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

14 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) ASCO 2006 METASTATIC BREAST CANCER HER-2 + BREAST CANCER New drugs: LAPATINIB Single agent Lapatinib active in relapsed/refractory IBC (abstr # 502)

15 CONFIDENTIAL – NOT FOR DISTRIBUTION NEOADJUVANTADJUVANT Neo-Adjuvant Adjuvant Build confidence in lapatinib (interim look) Build translational research hypothesis and validate them

16 CONFIDENTIAL – NOT FOR DISTRIBUTION NEO-ADJUVANT: RANDOMIZED PHASE II TRIAL R RRANDOMIZAANDOMIZATTIIOONNRRANDOMIZAANDOMIZATTIIOONNTION HER2 3+ Tumors > 2 cm (N=450) Trastuzumab x 6 weeks Trastuzumab + paclitaxel x 12 weeks Lapatinib x 6 weeks Lapatinib + paclitaxel x 12 weeks + Lapatinib x 6 weeks Trastuzumab + paclitaxel x 12 weeks Trastuzumab + lapatinib SURG SSUURRGGERYERYSSUURRGGERYERY Trastuzumab x 34 weeks Lapatinib x 34 weeks Trastuzumab + lapatinib x 34 weeks Biopsy (Pet Scan) Week 2: Biopsy (Pet Scan) pCR rate Translationalresearch Disease-free survival FEC FEC FEC 450 PTS (150 x arm)

17 CONFIDENTIAL – NOT FOR DISTRIBUTION Women considered candidates for adjuvant taxanes receive weekly paclitaxel concomitantly with the biologic therapy. 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. 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) N=8000 women HR 0.78 between experimental-arm and trastuzumab; (3 pair wise comparisons; 80% power; 691 events for each comparison) ADJUVANT DESIGN – HERA MODEL Trastuzumab for 1 year Lapatinib for 1 year Lapatinib for 6 months Trastuzumab 3-weekly + lapatinib for 1 year Centrally-determined HER2 + Surgery, complete (neo)adjuvant anthracycline-based chemotherapy (selected from an approved list); complete adjuvant radiation therapy (if given) LVEF  50 RANDOMIZATION 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) Trastuzumab 3-weekly for 6 months  8000 PTS

18 CONFIDENTIAL – NOT FOR DISTRIBUTION DESIGN – high risk patients: taxanes 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 1YEAR1YEAR Lapatinib + 3-weekly trastuzumab Lapatinib + Weekly trastuzumab 12 weeks  Weekly trastuzumab 12 weeks  Lapatinib 3-weekly trastuzumab 6 months  Weekly paclitaxel 12 weeks  3-weekly trastuzumab Lapatinib 6 months Radiotherapy (if indicated) Weekly paclitaxel 12 weeks  Radiotherapy (if indicated) Weekly paclitaxel 12 weeks  Radiotherapy (if indicated) Weekly paclitaxel 12 weeks  Radiotherapy (if indicated) RANDOMIZATION

19 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. The Breast Cancer Observatory: Innovation and care in the next 12 months TUMOR VASCULATURE N Engl J Med 351 (3): 216, 2004

20 BEVACIZUMAB IN METASTATIC BREAST CANCER AuthorN of ptsTreatmentRR (%)PFS (mo)OS (mo) Miller (2005) 462 (pretreated) Capecitabine ± Bevacizumab 20 vs. 9 (p=0.001) 5 vs 4 (p=0.98) 15 vs.15 (p=nr) Miller (2005) 715 (1st line) Weekly paclitaxel ± Bevacizumab 29 vs. 14 (p<0.0001) 11 vs 6 (p<0.001) HR 0.67 (p=0.01) IMP since always RARE in MBC

21 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 trastuzumabhardly any 23% Differences in Study Populations … could (partially) explain different results of trials 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” Cancerworld, Anna Wagstaff, March-April2006 Balanced enthusiasm is also OUR responsibility


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

Similar presentations


Ads by Google