ADJUVANT TREATMENT: TARGET THERAPIES

ADJUVANT TREATMENT: TARGET THERAPIES BELGIAN BREAST MEETING13-14 October 2006Brussels, BelgiumFatima Cardoso, MDJules Bordet Institute & TRANSBIG

ENDOCRINE THERAPYFirst example of TARGETED THERAPYERThe targetThe ligandAromataseinhibitorsSERMS & ER DOWN REGULATORS

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)Trastuzumabfor 1 yearTrastuzumabfor 1 or 2 yearsTotal 12,000 womenSelection of the subgroup most likely to benefit: IHC 3+ or FISH positive in all trialsTRASTUZUMAB IN THE ADJUVANT SETTING SUMMARY OF THE FOUR MAJOR TRIALS3-weeklyweekly&3-weeklyOnly trial with a non-A armFinHER Trial+

ADJUVANT TRASTUZUMAB TRIALS EFFICACY RESULTS AT 2 YEARS MEDIAN FUFavors trastuzumabReduction in relapses (DFS) of 52% to 68% Similar results in DDFS

44% reduction in mortality riskADJUVANT TRASTUZUMAB TRIALS EFFICACY RESULTS AT 2 YEARS MEDIAN FUFavors trastuzumab

ADJUVANT TRASTUZUMAB TRIALSCARDIOTOXICITY RISKSM. Piccart used with permission

ADJUVANT TRASTUZUMAB TRIALSCARDIOTOXICITY RESULTSREASONS 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)

IMPAIRMENT IN TRASTUZUMAB ADMINISTRATION BECAUSE OF CARDIAC PROBLEMSKEY 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 womenM. Piccart ESMO 2006-used with permission

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)

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

BackgroundHER-2 and cMYC: only independent prognostic factors in NSABP-B2825% of HER-2+ patients have coamplification of cMYCNSABP-B31 Coamplification of cMYCNoYesTrastuzumabs benefitHR DFS 0.63 2p = 0.0070.24 2p < 0.0001HR O.S.NO GAIN0.36 2p = 0.012HypothesisTrastuzumab turns on the pro-apoptotic function of deregulated cMYC

m-TOR, PTEN AND SENSITIVITY TO TRASTUZUMAB IN HER-2 (+) CANCER CELLSPandolfi, 2004

HER-2 P95 POSITIVE TUMORS RESPOND LESS TO TRASTUZUMABN= 36 patients treated with trastuzumabCourtesy J. Baselga

LAPATINIB IN (NEO) ADJUVANT THERAPY OF HER-2 + BREAST CANCER: RATIONALETrastuzumab only partially activeLapatinib: Has a different mechanism of action Active in trastuzumab resistant patients May be active in HER2 p95 positive tumorsHigh level of activity in single agent first line settingPreclinical synergy with the combination of lapatinib and trastuzumab. Encouraging activity of the combination in patients with prior therapy with trastuzumabMay be active against brain (micrometastatic) disease

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 CANCERHER-2 + BREAST CANCERNew drugs: LAPATINIBSingle agent Lapatinib active in relapsed/refractory IBC(abstr # 502)

NEOADJUVANTADJUVANT20072008200920102011Neo-AdjuvantAdjuvantBuild confidence in lapatinib (interim look)Build translational research hypothesis and validate them

NEO-ADJUVANT: RANDOMIZED PHASE II TRIALRA N D O M I Z ATIONHER2 3+Tumors> 2 cm(N=450)Trastuzumab x 6 weeksTrastuzumab + paclitaxel x 12 weeksLapatinib x 6 weeksLapatinib + paclitaxel x 12 weeks+ Lapatinib x 6 weeksTrastuzumab+ paclitaxel x 12 weeksTrastuzumab + lapatinibSURGE R YTrastuzumabx 34 weeksLapatinibx 34 weeksTrastuzumab+ lapatinibx 34 weeksBiopsy(Pet Scan)Week 2: Biopsy(Pet Scan)pCR rateTranslationalresearchDisease-free survival450 PTS (150 x arm)

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)ADJUVANT DESIGN HERA MODELTrastuzumabfor 1 yearLapatinibfor 1 yearLapatinibfor 6 monthsTrastuzumab 3-weekly + lapatinib for 1 yearCentrally-determined HER2 +Surgery, complete (neo)adjuvant anthracycline-based chemotherapy (selected from an approved list); complete adjuvant radiation therapy (if given) LVEF 50RANDOMIZATIONLocally-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 months8000 PTS

DESIGN high risk patients: taxanesLocally-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 chemotherapyLVEF 50

1

YEAR

Lapatinib + 3-weekly trastuzumab

Lapatinib +Weekly trastuzumab12 weeks

Weekly trastuzumab12 weeks

Lapatinib

3-weekly trastuzumab6 months

Weekly paclitaxel12 weeks

3-weekly trastuzumab

Lapatinib6 months

Radiotherapy (if indicated)







RANDOMIZATION

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.View of a Medical Oncologist and a Clinical/Translational ResearcherThe Breast Cancer Observatory:Innovation and care in the next 12 monthsTUMOR VASCULATUREN Engl J Med 351 (3): 216, 2004

BEVACIZUMAB IN METASTATIC BREAST CANCERIMP since always RARE in MBC

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 trastuzumabhardly any 23%Once again: IMPORTANCE OF GIVING THE BIOLOGICAL AGENT EARLY

Bevacizumab: A Targeted Therapy Without A Target ??!!and an expensive oneUnlike trastuzumab, to date, no predictive factors of response to bevacizumab, including VEGF expression, have been identified

HER-2 TESTING IN N9831Modest 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-2Updated from Perez EA, et al. ASCO 2004 (abstract 567)

THE HERCEPTIN HYPECancerworld, Anna Wagstaff, March-April2006Balanced enthusiasm is also OUR responsibility

Figura 17. Representacin grfica de los tumores con expresin de la forma truncada y completa del receptor HER2 y su correlacin con respuesta al tratamiento con trastuzumab. Se demuestra la presencia de los CTF de HER2 en un 6.25% de las pacientes con respuesta al tratamiento con trastuzumab (1/15 casos), mientras que este porcentaje se eleva hasta un 30% de las pacientes sin beneficio al tratamiento (6/14 casos) (Chi cuadrado p=.0.59).Conclusions: There was high level of discordance by either IHC or FISH between local and central laboratories: 20% for protein analysis when Herceptest was used locally, and 15% with FISH. When the discordant cases were retested there was a high level of agreement between central and the independent reference laboratory for both IHC and FISH.

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ADJUVANT TREATMENT: TARGET THERAPIES