Presentation on theme: "Challenges and Success: Treatment of Metastatic Breast Cancer 2012"— Presentation transcript:
1 Challenges and Success: Treatment of Metastatic Breast Cancer 2012 Hope S. RugoUniversity of California San Francisco Helen Diller Family Comprehensive Cancer CenterThis presentation is the intellectual property of the presenter. Contact for permission to reprint and/or distribute
2 2012: What’s New? HER2+ disease Reversing hormone resistance A wealth of richesReversing hormone resistanceNew treatments for triple negative diseaseThe futureMoving forward from intrinsic subtypesConsensus building
3 HER2 Positive MBC The problem Can we improve up-front therapy? Despite high response rates, almost all patients eventually develop progressive disease in viscera or brainCan we improve up-front therapy?Combined signal blockadeCurrent standardsContinue HER2 directed therapy through progressionCapecitabine + lapatinib > capecitabine (Geyer et al)Capecitabine + trastuzumab > capecitabine (von Minckwitz et al)Lapatinib + trastuzumab > lapatinib (Blackwell et al)
4 Dimerization domain of HER2 Trastuzumab and Pertuzumab Bind to Different Regions on HER2 and Have Synergistic ActivityHER2 receptorPertuzumabTrastuzumabDimerization domain of HER2Subdomain IV of HER2Pertuzumab inhibits HER2 forming dimer pairsSuppresses multiple HER signaling pathwaysFlags cells for destruction by the immune systemActivates ADCCTrastuzumab continually suppresses HER2 activityFlags cells for destruction by the immune systemActivates ADCC4
5 Cleopatra: Study Design and Patients Double-blind, placebo controlled phase III trialDocetaxel 75 mg/m2 escalated to 100 as tolerated, about 6 cyclesTrastuzumab and pertuzumab/placebo q 3 weeksPrimary endpointIndependently assessed PFS808 patients with treatment naïve centrally confirmed HER2+ MBCAdjuvant therapy53% no prior chemo10% prior trastuzumab49% ER+, 24% received endocrine therapyBaselga et al, SABCS 2011 and NEJM, 2011
6 Primary Endpoint: Independently Assessed PFS n = 433 PFS events 102030405060708090100Ptz + T + D: median 18.5 monthsPla + T + D: median 12.4 monthsProgression-free survival (%)HR = % CI 0.51‒0.75 p<0.00016.1 month gain in PFS to > 18 monthsDefinition of independently assessed PFS:PFS was defined as the time from randomization to- the first documented radiographic PD according to RECIST or- death from any cause, if within 18 weeks of the patient’s last tumor assessment by the IRF.510152025303540Time (months)n at riskPtz + T + D402345267139833210Pla + T + D4063112099342177Stratified by prior treatment status and regionD, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumabBaselga et al, SABCS 2011 and NEJM, 2011
7 N = 165 out of 385 OS events required for HR 0.75 (193 expected) Overall Survival: Predefined Interim Analysis Median follow-up: 19.3 months100908070HR = 0.64* 95% CI 0.47‒0.88 p = *60N = 165 out of 385 OS events required for HR 0.75 (193 expected)Overall survival (%)50403020Ptz + T + D: 69 events10Pla + T + D: 96 eventsA preplanned interim analysis of OS was performed at the time of the primary analysis of PFS-IRF. The interim overall survival analysis did not cross the pre-specified O’Brien-Fleming stopping boundary (HR ≤0.603; p≤0.0012).51015202530354045Time (months)n at riskPertuzumab + T + D40238736725116187314Placebo + T + D40638334722814367242* The interim OS analysis did not cross the pre-specified O’Brien-Fleming stopping boundary (HR ≤0.603; p ≤0.0012)D, docetaxel; OS, overall survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumabBaselga et al, SABCS 2011 and NEJM, 2011
8 Additional Data/Conclusions PFS benefit seen in essentially all predefined subsetsComplete responses rare at 4 to 5.5% (partial response 65 to 75%) suggests presence of alternate resistance pathwaysMinimal additional toxicity with pertuzumabSurvival impact is practice changingApproved 6/2012 in the US
9 Historical Timeline: First-Line Treatment of HER2+ Disease – Slamon1N=469*Marty2N=186Cleopatra3N=808Averel4N=424-Tr+Tr-P+P-B+BPFS/TTP (mo)220.127.116.11.712.418.513.716.5OS (mo)20262331med FU 19.3 mo38.338.5Slamon: q 3 wk paclitaxel or AC, all others q 3 week docetaxel* FISH + subsetSlamon et al, NEJM 2001 and Mass et al, Clin Breast CA Marty et al, JCO 2005.3. Baselga et al, NEJM, Gianni, SABCS 2011
10 APHINITY ADJUVANT TRIAL TCa x 6TCa x 6TCa = 6 cycles of docetaxel and carboplatin
11 T-DM1 selectively delivers DM1 to HER2-positive tumor cells Targeted intracellular delivery of a potent antimicrotubule agent, DM1Spares normal tissue from toxicity of free DM1Trastuzumab-like activity by binding to HER2T-DM1 binds to the HER2 protein on cancer cellsHER2Receptor-T-DM1 complex is internalized into HER2-positive cancer cellPotent antimicrotubule agent is released once inside the HER2-positive tumor cell
12 EMILIA Study Design Capecitabine + Lapatinib HER2+ (central) LABC or MBC (N=980)Prior taxane and trastuzumabProgression on metastatic tx or within 6 mos of adjuvant txT-DM13.6 mg/kg q3w IVPD1:1Capecitabine1000 mg/m2 orally bid, days 1–14, q3w+Lapatinib1250 mg/day orally qdPDStratification factors: World region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral diseasePrimary end points: PFS by independent review, OS, and safetyKey secondary end points: PFS by investigator, ORR, duration of response, time to symptom progressionStatistical considerations: Hierarchical statistical analysis was performed in pre-specified sequential order: PFS by independent review → OS → secondary end pointsVerma et al, NEJM 2012
13 Progression-Free Survival by Independent Review 0.00.20.40.60.81.024681012141618202224262830Proportion progression-freeTime (mos)Median (mos)No. eventsCap + Lap6.4304T-DM19.6265Stratified HR=0.650 (95% CI, 0.55, 0.77)P<0.00014964043101761297353352514985149541934123618313010172544430183Cap + LapT-DM1No. at risk by independent review:Unstratified HR=0.66 (P<0.0001).Median follow-up, mos (range): Cap + Lap, 12.4 (0–35); T-DM1, 12.9 (0–34)
14 Overall Survival: Confirmatory Analysis Median (months)No. of eventsCap + Lap25.1182T-DM130.9149Stratified HR=0.682 (95% CI, 0.55, 0.85); P=0.0006Efficacy stopping boundary P= or HR=0.7271.085.2%0.878.4%64.7%0.6Proportion surviving51.8%0.40.20.024681012141618202224262830323436Time (months)496471453435403368297240204159133110866345271774495485474457439418349293242197164136111623828135Cap + LapT-DM1No. at risk:Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012).
15 Overview of Adverse Events Cap + Lap(n=488)T-DM1(n=490)All-grade AE, n (%)477 (97.7)470 (95.9)Grade ≥3 AE, n (%)278 (57.0)200 (40.8)AEs leading to treatment discontinuation (for any study drug), n (%)52 (10.7)29 (5.9)AEs leading to death on treatment, n (%)a5 (1.0)1 (0.2)LVEF <50% and ≥15-point decrease from baseline, %b7 (1.6)8 (1.7)aCap + Lap: CAD, multiorgan failure, coma, hydrocephalus, ARDS;aT-DM1: metabolic encephalopathy.bEvaluable pts: 445 (Cap + Lap); 481 (T-DM1).Cap and Lap: More grade 3 diarrhea (21 vs 1.6%), hand foot syndrome (16 vs 0%)TDM1: More transaminiitis (4 vs 1%), grade 3/4 thrombocytopenia (13 vs 0%)
16 Emilia and Ongoing Trials T-DM1 superior to cap/lapPFS, OS, response, safetyWill clearly be a new standard in this settingApproval expected towards the end of 2012/early 2013Marianne (n=1092, untreated HER2+ MBC)Three armsTrastuzumab + taxaneTDM1 + pertuzumabTDM1 plus placeboTh3RESA (n=795)Prior trastuzumab/lapatinib/anthra/taxane/cape2:1 randomization to TDM1 v TPC
17 Trials in Early Stage Disease Post-neoadjuvant cooperative groupNeoadjuvant company sponsoredAdjuvant small tumors: ATTEMPT TrialTolaney PI (DFCI)Trastuzumab emtansine q 3 weeks x 17N=3753Stage I BCHER2+N=500Randomize3:1Paclitaxel + Trastuzumab weekly x 12Trastuzumab every 3 weeks x 13N=1251
20 Confirmatory Study Schema: MERiDiAN Core presentationCore presentationCore presentation02_Core Eff-Saf_(CE)Core presentationCore presentationCore presentationCore presentationCore presentationCore presentationCore presentation4/6/20174/6/2017 2:25 PM4/6/2017 2:25 PM4/6/2017 2:25 PM4/6/2017Confirmatory Study Schema: MERiDiANMBC, HER2-Negative Chemo-naïve N=480Stratification• VEGF-A (low/high)• Adjuvant therapy (yes/no)• Hormonal status (ER +/-)Paclitaxel 90 mg/m2 weekly x 3 q4 weeks / Bevacizumab 10 mg/kg q2wR A N D O M I Z E DPaclitaxel 90mg/m2 weekly x 3 q4 weeks / Placebo 10 mg/kg q2wCo-Primary Endpoints: PFS (All Patients) , PFS (VEGF high subset)Secondary Endpoints: OS; ORR; Symptoms/QoL; SafetyDRAFTDRAFTDRAFTDRAFTDRAFTDRAFTDRAFTDRAFTDRAFTDRAFTDRAFTRaptiva DODAC – Efficacy 4/6/2017202020202020
21 The Problem in ER+ Tumors is Endocrine Therapy Resistance About 50% of hormone receptor-positive breast cancers are de novo resistant to endocrine therapyAlmost all patients with advanced disease will develop acquired resistance to endocrine therapiesThe mechanisms of de novo and acquired resistance are likely similar, but are not completely understoodChanging patterns of adjuvant therapy have decreased efficacy and reduced time to progession in the metastatic settingIs there a way to reverse hormone resistance in HER2 normal disease?
22 Anastrozole + fulvestrant A Phase III Randomized Trial of Anastrozole versus Anastrozole and Fulvestrant as First-Line Therapy for MBC. SWOG S0226: Efficacy (Intent-to-Treat)Anastrozole (n = 345)Anastrozole + fulvestrant(n = 349)Hazard ratiop-valueMedian PFS13.5 mos15.0 mos0.80.007Median OS41.3 mos47.7 mos0.810.049Grade ≥3 AE12.7%14.5%*—NSNo prior adjuvant tamoxifen (n = 414)(n = 208)(n = 206)Median PFS12.6 mos17 mos0.740.0055Median OS39.7 mos47.7 mos0.0362Mehta RS et al. San Antonio Breast Cancer Symposium 2011;Abstract S1-1.
23 The PI3K/AKT/mTOR Pathway Growth factors includingIGF-1, VEGF, ErbBmTOR (mammalian target of rapamycin) signaling plays a key role inCell growthCell proliferationRegulation ofApoptosisAngiogenesisLymphocytesHomeostasisMetabolismPI3KOxygen, energy, and nutrientsPTENEstrogen receptorAKTTSC2TSC1Ras/Raf pathway kinasesmTORS6K14E-BP1Protein productionelF-4ES6Cell growthand proliferationNutrient uptake and metabolismAngiogenesis1. Bjornsti MA, et al. Nat Rev Cancer. 2004;34(5): ; 2. Crespo JL, et al. Microbiol Mol Biol Rev. 2002;66(4): ; 3. Huang S, et al. Cancer Biol Ther. 2003;2(3): ; 4. Mita MM, et al. Clin Breast Cancer. 2003;4(2): ; 5. Wullschleger S, et al. Cell. 2006;124(3): ; 6. Johnston SR. Clin Cancer Res. 2005;11(2 Pt 2):889S-899S.23
24 TAMRAD (Phase II): Tamoxifen ± Everolimus in Advanced BC 111 postmenopausal women with ER+ advanced BC previously treated with an AI were randomized in a phase II trial1.00.00.10.18.104.22.168.22.214.171.12446810121416182022242628303234Probability of ProgressionTAM: 4.5 mosTAM + EVE: 8.6 mosMonthsHR = 0.54Log-rank P = 0.002AI = aromatase inhibitor; BC = breast cancer; ER+ = estrogen receptor-positive; EVE = everolimus; TAM = tamoxifen.Bourgier C et al. ECCO/ESMO 2011 (Abstract #5005)
25 Bolero-2: Phase III Trial of Exemestane +/- Everolimus 724 PM women with ER+ MBCProgression on letrozole or anastrozoleUp to two prior hormone agents84% sensitive to hormone therapyEVE 10 mg daily+EXE 25 mg daily (n = 485)PlaceboEXE 25 mg daily (n = 239)R2:1N = 724Postmenopausal ER+Unresectable locally advanced or metastatic BCRecurrence or progression after letrozole or anastrozoleRugo et al, ASCO Breast Symposium, Baselga et al, NEJM 2011
26 PFS Based on Local Assessment at 18-month Follow-Up EVE 10 mg + EXEPBO + EXENumber of Patients Still at Risk20406080100Time, week612182430364248546672788490961021081141204854363663042572211851581249150352213108212391901326739211553Censoring timesEVE 10 mg + EXE (n/N = 310/485)PBO + EXE (n/N = 200/239)Hazard ratio = 0.45 (95% CI: )Log-rank P <Kaplan-Meier medians EVE 10 mg + EXE: 7.8 monthsPBO + EXE: 3.2 monthsProbability of PFS, %PFS Based on Local Assessment at 18-month Follow-Up in BOLERO-2 Confirms Earlier ReportsThe study met its primary endpoint (ie, PFS evaluated by RECIST, based on local radiology assessment). The primary efficacy analysis resulted in an estimated 55% risk reduction for PFS per investigator assessment (hazard ratio = 0.45). This corresponded to a clinically meaningful 4.6-month prolongation in median PFS: from 3.2 months in patients receiving PBO + EXE to 7.8 months in patients receiving the combination of EVE + EXEAbbreviations: EVE = everolimus; EXE = exemestane; PBO = placebo; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumors.Abbreviations: CI = confidence interval; EVE = everolimus; EXE = exemestane; PBO = placebo.
27 BOLERO-2 (18 mo f/up): Response & Clinical Benefit PercentResponse rates per local assessment were 12.0% and 1.3% in the combination and EXE arms, respectively, and central assessment showed consistent results. This represents a 9.2-fold increase in response rates between treatment arms.Activity of EVE plus EXE also was confirmed by superior CBR (50.5% vs 25.5% in the control arm), representing a 2-fold increase. The higher CBRs (in both arms but particularly in EVE + EXE) compared with the interim analysis are because of additional follow-up time.P <
28 BOLERO-2 (18 mo f/up): Most Common Adverse Events Everolimus + Exemestane (n = 482), %Placebo + Exemestane(n = 238), %All GradesGrade 3Grade 4Stomatitis59811<1Rash3916Fatigue36427Diarrhea33219Appetite decreased3012Nausea2928Weight decreased25CoughHortobagyi G et al. SABCS 2011 (Abstract #S3-7), Baselga et al, 2011
29 EVE Bone Turnover Marker Levels at 6 and 12 Weeks (Overall Population) Bone metastases at BLa: 76% versus 77%Bisphosphonate use at BLa: 44% versus 54%Δ26%Δ56%Δ36%Δ22%Δ68%Δ41%Abbreviations: BL, baseline; BSAP, bone-specific alkaline phosphatase; CTX, C-terminal cross-linking telopeptide of type I collagen; EVE, everolimus; EXE, exemestane; PBO, placebo; P1NP, amino-terminal propeptide of type I collagen.Data from full analysis set.a Proportions of patients with bone metastases or bisphosphonate use reflect the status at study entry among patients with baseline bone marker assessments.
30 Everolimus Decreases Disease Progression in Bone Overall Population (N=724)Patients with Bone Metastases at Baseline (N=554)
31 New ChemotherapyEribulin approved for later during the course of advanced cancerCALGB 40502Compared Taxol (paclitaxel) to Ixabepilone to Abraxane (nab-paclitaxel as treatment for metastatic disease.More toxicity and less or similar efficacy compared to arms 2 and 3
32 Progression-Free Survival By Treatment Arm CALGB 40502Progression-Free Survival By Treatment ArmComparisonHRP-value95% CInab vs. pac1.190.12ixa vs. pac1.53<paclitaxelnab-paclitaxelixabepiloneAnalysis of PFS failed to demonstrate superiority of either experimental arm compared to paclitaxel. Weekly ixabepilone appeared to be significantly inferior to weekly paclitaxel.AgentNMedian PFSpaclitaxel28310.6nab-Paclitaxel2719.2ixabepilone2457.6
33 Summary and New Directions HER2 positive diseasePertuzumab a new standard of care for advanced HER2+ breast cancerTDM1 superior to lapatinib and capecitabineOther combinations (MTOR, PIK3CA, etc)ER+MTOR inhibition in the second-line settingA new standard – FDA approvedMove to earlier stage setting for higher risk diseaseExplosion of new agents targeting this pathway in clinical trialsCombined inhibitorsCritical to find markers that predict response to specific treatments
34 What Does the Future Hold? Genomic testingLooking at the DNA of a tumor (or in normal cells) for mutations or deletionsGene expression testingLooks at RNA for specific genesRecent dataAnalysis of breast cancer through the Cancer Genome Atlas NetworkIdentified 4 main breast cancer classesIdentified some of the most common mutationsWhat does this mean today?Studies such as these help to identify potential targets for individualized cancer therapyGiven complexity of tumor alterations, combinations of therapies are likely to be most effective approach
35 PARP Inhibition Novel mechanism – inhibition of DNA damage repair Kick’em when they’re down therapeutic strategyIs there functional defect in the BRCA1 pathway in some sporadic cancersIf not, what is it? Cite AACR poster and modelNovel mechanism – inhibition of DNA damage repairEfficacy in BRCA-associated cancerEllisen LW. Cancer Cell. 2011;19(2):
36 PARP Inhibitors in Development AgentCompanyRouteCurrent TrialsRucaparibClovisIV/OralBRCA+, post-neoadjuvant TNBC +cisplatinOlaparibAstraZenecaOralBRCA+VeliparibAbbottBRCA+, TNBC + paclit/carboIniparibBSI-201BiPar/Sanofi-AventisIVDose escalationLT673 (2011)Biomarin-INO-1001InotekMK4827MerckCEP-9722CephalonE7016EisaiPlummer R BCR 2011 vol. 13 (4) pp with edits
37 Leukocytes in Breast Cancer: Targets for Therapy ? Inv. Ductal CarcinomaCTX naiveDistal normalIncreased macrophage presence correlates with increased vessel density & decreased survival (Tsutsui et al., 2005; Bingle et al., 2002, Campbell et al, 2010)Age (days)H&EPaclitaxel (10 mg/kg, i.v.)PLX3397tMMTV-PyMTVehiclePTXPLX3397PLX PTXCD45Tumor volume (mm3)Age (days)CD45: leukocyte common antigenRuffell et al., PNAS (2011)
38 CD68/CD8 mRNA Ratio Correlates with OS Overall Survival50100150200250300Time (months)10 yearp<0.010.20.40.60.81.0Gene expression from22 data sets >4000 PatientsDeNardo et al., Cancer Discovery (2011)US Patent #61/420,718
39 Phase II Study: Metastatic TNBC Phase 1b Study: all BCPLX3397 oral daily dosingEribulin: 1.4 mg/m2 iv, day 1 and 8Each cycle of treatment lasts 21 daysKomen Promise Grant:Coussens, Rugo, Hwang, SamsonCollaborators: Blackwell (Duke), Mayer (Vanderbilt)First Cohort = 600 mg/day3-6 patientsSecond Cohort = 800 mg/day3-6 patientsPhase II Primary Endpoint:PFS at 12 weeksThird Cohort = 1000 mg/day3-6 patientsPhase II Study: Metastatic TNBCLead in period of 5-7d with PLX3397 at MTD oral daily dosing (day -7/5 to day 0)Biopsy for immune profilingStarting Day 1Add Eribulin 1.4 mg/m2 iv day 1 and 8Each cycle of treatment lasts 21 daysPI: Hope Rugo M.D., UCSF
41 Consensus Building: ABC1 30 International breast cancer experts organized by Fatima CardosoQ2: From onset of diagnosis of MetaBC, patients should be offered personalised appropriate psychosocial, supportive and symptom-related interventions as a routine part of their care100% vote yesMore next year!