5Trastuzumab Combinations as First-line Therapy for MBC: Pivotal Phase III Trial Paclitaxel(n = 96)PreviousadjuvantACPatients with HER2+ (IHC 2+/3+) MBC, no previous chemotherapy, measurable disease, KPS ≥ 60%(N = 469)Trastuzumab+ Paclitaxel(n = 92)AC(n = 138)No previousadjuvantACTrastuzumab+ AC(n = 143)Slamon DJ, et al. N Engl J Med. 2001;344:Slamon et al. N Engl J Med. 2001;344:783.Herceptin® (trastuzumab) PI. November 2006.
6Trastuzumab in MBC: The Pivotal Trial TreatmentObjective Response Rate, %Median TTP, MosMedian OS, MosChemo324.620.3Chemo + Trastuzumab507.425.1P < .001 for all comparisons.Slamon DJ, et al. N Engl J Med. 2001;344:
7Trastuzumab in Recommended First-line Combinations for HER2+ MBC HER2+ disease without previous trastuzumab: trastuzumab plusPaclitaxel ± carboplatinDocetaxelVinorelbineCapecitabineNCCN. Clinical practice guidelines in oncology: breast cancer. v
8Trastuzumab in Triple-Combination Regimens: Response Rates Yardley et al, 2004 (N = 24)H + V + TUntch et al, 2004 (N = 25)H + E90 + CUntch et al, 2004 (N = 26)H + E60 + CDirix et al, 2006 (N = 34)H + Carbo + TChan et al, 2007 (N = 34)H + V + XFountzilas et al, 2004 (N = 40)H + G + PYardley et al, 2006 (N = 41)H + G + CarboMiller et al, 2002 (N = 45)H + G + PVenturini et al, 2006 (N = 45)H + E + TPerez et al, 2005 (N = 43)H + Carbo + P every 3 wksPerez et al, 2005 (N = 48)H + Carbo + P every wkCortes et al, 2004 (N = 54)H + TLC D-99 + PYardley et al, 2002 (N = 61)H + Carbo + TPegram et al, 2004 (N = 59)H + Carbo + TPegram et al, 2004 (N = 62)H + Cisplatin + TRobert et al, 2006 (N = 92)H + Carbo + PWardley et al, 2006 (N = 111)H + X + TForbes et al, 2006 (N = 130)H + Carbo + T102030405060708090100ORR (%)
15Continued HER2 blockade NCCN: Treatment of HER2+ MBC Beyond First Line With Previous Trastuzumab ExposureContinued HER2 blockadeChemotherapy + trastuzumabTrastuzumab + lapatinibCapecitabine + lapatinibNCCN. Clinical practice guidelines in oncology: breast cancer. vNational Comprehensive Cancer Network Clinical Practice Guidelines in Oncology – v2.2006; Breast Cancer. At: Accessed December 2005.
16EGF100151 Phase III Study: Lapatinib + Capecitabine in Advanced Breast Cancer 1250 mg/day PO +Capecitabine mg/m2/day onDays 1-14 every 21 daysPatients with HER2+ progressive MBC or stage IIIB/IIIC LABC with T4 lesion and unlimited previous therapies*Capecitabine 2500 mg/m2/day onDays 1-14 every 21 daysPrimary endpoint: TTPSecondary endpoints: OS, PFS, ORR*No previous capecitabine and must have included trastuzumab (MBC) or anthracycline/taxane (MBC or adjuvant).Geyer C, et al. N Engl J Med. 2006;355:
17Lapatinib + Capecitabine in HER2+ MBC: TTP TTP With 1 Previous Trastuzumab RegimenTTP With > 1 Previous Trastuzumab Regimen1001008080Capecitabine Lapatinib + capecitabineCapecitabine Lapatinib + capecitabine6060Cumulative Progression Free (%)Cumulative Progression Free (%)404020202040608020406080WksWksReproduced with permission of The Oncologist, from Lapatinib plus capecitabine in women with HER-2–positive advanced breast cancer: Final survival analysis of a phase III randomized trial, Cameron D, et al., Vol 15, 2010; permission conveyed through Copyright Clearance Center, Inc.Cameron D, et al. Oncologist. 2010;15:
18Lapatinib + Capecitabine in HER2+ MBC: Efficacy ResultCapecitabine(n = 201)Capecitabine + Lapatinib(n = 207†)HRP ValueMedian TTP, wks18.631.30.50< .001OS, wks56.671.40.79.077ORR, %13.923.7--.017Brain mets as site of first progression,* n (%)13 (6)4 (2).045† n=198 in 2008 study.*Exploratory analysis.1. Cameron D, et al. Oncologist. 2010;15: Cameron D, et al. Breast Cancer Res Treat. 2008;112:
19Combining Lapatinib and Trastuzumab Increases Antitumor Activity 1600Treatment with lapatinib plus trastuzumab resulted in complete tumor remission in mouse modelEffect was durable: no tumor relapse observed at 8 mos after treatmentLapatinib induced accumulation of inactive HER2 at plasma membraneTrastuzumab-mediated cytotoxicity was higher with the addition of lapatinib in MCF7/HER2 cellsIn vivo activity was consistent with in vitro data demonstrating the combination as synergistic14001200Control Trastuzumab Lapatinib Trastuzumab + lapatinib1000Tumor Volume (mm3)800*600†*400†‡†2001316192123Days After Injection*P < .05; †P < .01 vs control; ‡P < .05 vs trastuzumab; §P < .01 vs both lapatinib and trastuzumab.Scaltriti M, et al. Oncogene. 2009;28: Konecny GE, et al. Cancer Res. 2006;66: Xia W, et al. Oncogene. 2004;23:Reprinted by permission from Macmillan Publishers Ltd: Oncogene; Scaltriti, et al. 28: , copyright 2009.
20Pivotal Trial EGF104900 R Lapatinib 1500 mg/day PO Patient Population HER2+ MBCMultiple lines of trastuzumabProgression on trastuzumab at study entryRCrossover at the time of progressive diseaseLapatinib 1000 mg/day PO + trastuzumab 4 mg/kg then 2 mg/kg IV q wkPrimary endpoint: PFSSecondary endpoints: OS, ORR, CBRBlackwell KL, et al. J Clin Oncol. 2012;30:
22Mos From Randomization EGF104900: Overall SurvivalL + T (n = 148)L(n = 148)n146145Median OS, mos14.09.5HR (95% CI)0.74 ( )Stratified log-rank P value.026100Survival(%)80%8070%6056%6-mo OS52% of patients in the L arm crossed over to L + T4041%12-mo OS205101520253035Mos From RandomizationPts at risk, n Lap 1000/Tras Lap 150087 6463 4642 2825 131Blackwell KL, et al. J Clin Oncol. 2012;30:
23Trastuzumab Beyond Progression in HER2+ MBC: BIG 03-05 Phase III Trial 6 mg/kg every 3 wks +Capecitabine 2500 mg/m2/day onDays 1-14 every 21 days(n = 78)Patients with progressive MBC or LABC, HER2 overexpression, previous trastuzumab within 6 wks, and LVEF ≥ 50(N = 156*)Capecitabine 2500 mg/m2/day onDays 1-14 every 21 days(n = 78)Primary endpoint: TTPSecondary endpoints: OS, ORR, safety*Study closed at 156 patients due to slow accrual following FDA approval of lapatinib for this indication.von Minckwitz G, et al. J Clin Oncol. 2009;27:23
26Pertuzumab and Trastuzumab: Mechanisms of Action HER2TrastuzumabHER1/3/4Dimerization domainSubdomain IVTrastuzumab:Inhibits ligand-independent HER2 signalingActivates ADCCPrevents HER2 ECD sheddingPertuzumab:Inhibits ligand-dependent HER2 dimerization and signalingActivates ADCCFerguson KM, et al. Mol Cell. 2003;11: Olayioye MA, et al. EMBO J. 2000;19: Hynes NE, et al. Nat Rev Cancer. 2005;5: Rowinsky EK. Annu Rev Med. 2004;55:
27Phase II Trial of Pertuzumab + Trastuzumab in HER2+ MBC: Efficacy SDResponses were durable:Median duration of response: 5.8 mosMedian PFS (all patients): 5.5 mos60PRCR5040Patients (%)302010All Patients (N = 66)Baselga J, et al. J Clin Oncol. 2010;28:
28CLEOPATRA Study Design Docetaxel (≥ 6 cycles recommended)Centrally confirmed HER2-positive locally recurrent, unresectable or MBC≤ 1 hormonal regimen for MBCPrior (neo)adjuvant systemic Rx, including trastuzumab and/or taxane allowed if followed by DFS ≥ 12 mosBaseline LVEF ≥ 50%; no CHF or LVEF < 50% during or after previous trastuzumabN = 406TrastuzumabPlaceboR1:1Docetaxel (≥ 6 cycles recommended)TrastuzumabN = 402PertuzumabPrimary endpoint: Independently assessed PFSBaselga J, et al. N Engl J Med. 2012;366:
32NCCN: First-line Treatment of HER2+ MBC With No Previous Trastuzumab Exposure Preferred regimensDocetaxel + trastuzumab + pertuzumab (category 1)Paclitaxel + trastuzumab + pertuzumabOther regimensChemotherapy + trastuzumabNCCN. Clinical practice guidelines in oncology: breast cancer. VNational Comprehensive Cancer Network Clinical Practice Guidelines in Oncology – v2.2006; Breast Cancer. At: Accessed December 2005.
35EMILIA Phase III Study: T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC Stratified by world region, number of previous chemotherapy regimens for MBC or unresectable locally advanced breast cancer, presence of visceral diseaseT-DM1 3.6 mg/kg by IV every 3 wks (n = 495)Patients with HER2-positive locally advanced or MBC* (N = 980)PDCapecitabine 1000 mg/m2 orally twice daily on Days 1-14, every 3 wks + Lapatinib 1250 mg/day orally continuously (n = 496)*All pts received previoustaxane and trastuzumabPrimary endpoint: PFS by IRF, OS, safetySecondary endpoints: QoL (FACT B), DOR, PFS by investigator assessmentVerma S, et al. NEJM 2012;367:
36T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC (EMILIA): PFS Median, MosEvents, n1.0Capecitabine/lapatinib T-DM13042650.8Stratified HR: (95% CI: ; P < .0001)0.6Proportion Progression Free0.4T-DM1Capecitabine/ lapatinib0.224681012141618202224262830MosVerma S, et al. NEJM 2012;367:
37Overall Survival – Second Interim Analysis Verma S, et al. NEJM 2012;367:
38T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC (EMILIA): Adverse Events Capecitabine + Lapatinib(n = 488)All GradesGrades ≥ 3NonhematologicDiarrhea23.31.679.720.7Hand-foot syndrome1.258.016.4Vomiting19.00.829.34.5Hypokalemia126.96.36.199Fatigue35.12.427.93.5Nausea188.8.131.52Mucosal inflammation184.108.40.206.3Increased AST220.127.116.11Increased ALT18.104.22.168.4HematologicNeutropenia5.92.0Febrile neutropenia1.0Anemia10.42.78.0Thrombocytopenia28.012.8Verma S, et al. NEJM 2012;367:
39T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC (EMILIA): Expert Perspectives T-DM1 showed improved efficacy vs capecitabine plus lapatinibSignificant PFS improvement (HR: 0.650; P < .0001)OS benefit (HR: 0.68; P =<0.001)Favorable safety profileT-DM1 is an important new therapeutic option for patients with HER2+ MBC that has been previously treated with trastuzumab.Verma S, et al. NEJM 2012;367:
40Ongoing Clinical Trials for Metastatic Breast Cancer
41Phase III MARIANNE Study: T-DM1 ± Pertuzumab in HER2+ MBC PDTrastuzumab + Taxane(n = 364)Patients with HER2+, previously untreated MBC(N = 1092)T-DM1 + Pertuzumab(n = 364)T-DM1 + Placebo(n = 364)Primary endpoints: PFS as assessed by IRF, AEsSuperiority design with a noninferiority analysesInterim futility analysis: option to drop experimental armSecondary endpoints: OS, TTF by IRF, ORR, CBR, DORClinicalTrials.gov. NCT41
42mTOR Inhibition May Overcome Trastuzumab Resistance Increased signaling through IGF-1RIGF-1REGFR/HER2NutrientsTruncated HER2PI3KPTENConstitutive PI3K/AKT activationLKB1AKTAbsent or low PTENAMPKTSC1TSC2Elevated AKT or pAKTRHEBmTORmTOR inhibitorDownstream inhibition with mTOR inhibitor counters these resistance mechanismsSynergy of mTOR inhibition and trastuzumab in vitro and in vivoGrowth &proliferationAngiogenesisCellmetabolismWidakowich C, et al. Anticancer Agents Med Chem. 2008;8:Miller TW, et al. Clin Cancer Res. 2009;15:
43BOLERO-1 Phase III Study: Paclitaxel + Trastuzumab Everolimus in HER2+ MBC Stratification by previous adjuvant or neoadjuvant trastuzumab and presence of visceral metastases28-day cycle2:1Patients with HER2-overexpressing, unresectable locally advanced or metastatic breast cancer, no previous trastuzumab or chemotherapy within 12 mos for advanced disease(N = 717)Everolimus 10 mg/day PO +Paclitaxel 80 mg/m2 on Days 1, 8, 15 +Trastuzumab 4 mg → 2 mg/kg on Days 1, 8, 15, 22Paclitaxel 80 mg/m2 on Days 1, 8, 15 +Trastuzumab 4 mg → 2 mg/kg on Days 1, 8, 15, 22+ Placebo PO dailyPrimary endpoint: PFSSecondary endpoints: OS, ORR, CBR, safety, PK, biomarkersClinicalTrials.gov. NCT
44Conclusions Multiple effective and available options in HER2+ MBC TrastuzumabPertuzumabLapatinibPreferred first-line regimens include dual HER2 inhibition with pertuzumab and trastuzumabOther HER2 inhibition agents continue to have a role outside the first-line setting including the new availability of TDM-1.
47GeparQuinto: HER2-Positive (n=615) Core biopsy(d21-d35 after last infusion)SurgeryDocRDoc*ECTrastuzumab (T)Lapatinib (L)E: Epirubicin 90 mg/m²C: Cyclophosphamide 600 mg/m²Doc: Docetaxel 100mg/m² *+ G-CSFT for 6 mosT for 12 mosT: Trastuzumab 6 (8) mg/kgL: mg/d p.o.(all 3 week cycles)This presentation is the intellectual property of the author/presenter.Contact them for permission to reprint and/or distribute.Untch M, et al. Cancer Res. 2010;70(Nr. 24 Suppl):81s. Abstract # S3-1.
48pCR Rates According to Other Definitions No invasive residualin breast & nodesP<0.05in breastThis presentation is the intellectual property of the author/presenter.Contact them for permission to reprint and/or distribute.Untch M, et al. Cancer Res. 2010;70(Nr. 24 Suppl):81s. Abstract # S3-1.
49Neo-ALTTO TrialJosé Baselga, Ian Bradbury, Holger Eidtmann, Serena DiCosimo, Claudia Aura, Evandro de Azambuja, Henry Gomez, Phuong Dinh, Karine Fauria, Veerle Van Dooren, Paolo Paoletti, Aron Goldhirsch, Tsai-Wang Chang, Istvan Lang, Michael Untch, Richard D. Gelber and Martine Piccart-Gebhert on behalf of the Neo-ALTTO Study TeamDecember 10, 2010*FDA approved in combination with capecitabine, for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.Baselga J, et al. Cancer Res. 2010;70 (24 Suppl): Abstract S3-3.
50Study DesignBaselga J, et al. Cancer Res. 2010;70 (24 Suppl): Abstract S3-3.
51Efficacy – pCR and to tpCR Baselga J, et al. Cancer Res. 2010;70 (24 Suppl): Abstract S3-3.
52pCR by Hormone Receptor Status Baselga J, et al. Cancer Res. 2010;70 (24 Suppl): Abstract S3-3.
53*Pertuzumab is not approved by the FDA for treatment of breast cancer. Gianni L, et al. Cancer Res. 2010;70 (24 Suppl): Abstract [S3-2].
54NeoSphere Study Design and Objectives Gianni L, et al. Cancer Res. 2010;70 (24 Suppl): Abstract [S3-2].
55NeoSphere pCR Rates: ITT Population Summary Gianni L, et al. Cancer Res. 2010;70 (24 Suppl): Abstract [S3-2].
56NeoSphere: pCR and Hormone Receptors Status Gianni L, et al. Cancer Res. 2010;70 (24 Suppl): Abstract [S3-2].
57NSABP B-41: Lapatinib in Neoadjuvant Treatment of HER2+ Breast Cancer Tissue biopsy for biomarker analysisDoxorubicin/Cyclophosphamide 60/600 mg/m2 q21d x 4 cycles → Weekly Paclitaxel 80 mg/m2 q28d x 4 cycles + Trastuzumab weekly until 1 wk before surgery(n = 178)Tissue biopsy for biomarker analysisPatients with HER2+, operable breast cancer(N = 529)Doxorubicin/Cyclophosphamide 60/600 mg/m2 q21d x 4 cycles → Weekly Paclitaxel 80 mg/m2 q28d x 4 cycles + Lapatinib 1250 mg/day until 1 day before surgery(n = 173)SurgeryTrastuzumab1 yrDoxorubicin/Cyclophosphamide 60/600 mg/m2 q21d x 4 cycles → Weekly Paclitaxel 80 mg/m2 q28d x 4 cycles + Trastuzumab weekly until 1 wk before surgery + Lapatinib 750 mg/day until 1 day before surgery(n = 173)Primary endpoint: pCRSecondary endpoints: pCR in N0, toxicity, cCR, RFS, OSRobidoux A, et al. ASCO Abstract LBA506.
58Lapatinib in Neoadjuvant Treatment of HER2+ Breast Cancer (NSABP B-41): pCR RegimennpCR*, %P Value†AC → WP + T17649.4AC → WP + L17147.4.78AC → WP + T + L60.2.056*Absence of invasive tumor in resected breast specimen and histologically negative axillary nodes.†Relative to AC → WP + T regimen.Robidoux A, et al. ASCO Abstract LBA506.
60NCCTG N9831 Trial Incorporating Trastuzumab in Adjuvant Therapy Group AACTRANDOMIZEGroup BHER2 positive (FISH+ or IHC 3+)ACTHGroup Cn=3,505ACTH= AC (doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4)= T (paclitaxel 80 mg/m2/wk × 12)= H (trastuzumab 4 mg/kg loading dose + 2 mg/kg/wk × 51)Romond et al. N Engl J Med. 2005;353:1673.Herceptin® (trastuzumab) PI. November 2006.
61NSABP B-31 Trial Incorporating Trastuzumab in Adjuvant Therapy Group 1ACTRANDOMIZENode positiveHER2 positive (FISH+ or IHC 3+)Group 2N=2,006ACTH= AC (doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4)= T (paclitaxel 175 mg/m2 q3w × 4 or 80 mg/m2/wk × 12)= H (trastuzumab 4 mg/kg loading dose + 2 mg/kg/wk × 51)Romond et al. N Engl J Med. 2005;353:1673.Herceptin® (trastuzumab) PI. November 2006.
62Joint Analysis of HER2+ Adjuvant Trials 2 Arms of N9831 + B-31 Control Group (n=1,979): AC TACTN9831 Group AACTB-31 Group 1Trastuzumab Group (n=1,989): AC T+HACTN9831 Group CHACTB-31 Group 2H= AC (doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4)= T (paclitaxel 80 mg/m2/wk × 12)= T (paclitaxel 175 mg/m2 q3w × 4 or 80 mg/m2/wk × 12)= H (trastuzumab 4 mg/kg loading dose + 2 mg/kg/wk × 51)Herceptin® (trastuzumab) PI. November 2006.Data on file. Genentech, Inc.
68Breast Cancer International Research Group (BCIRG) 006 Trial: Treatment Schema DOMIZEAC T (n=1073)SURGERYHER2-positive tumor (FISH+);node-positive or high-risk node-negative diseaseAC TH (n=1074)52 weeksTCH (n=1075)52 weeksEndpoints1°: Disease-free survival (DFS)2°: Overall survival, toxicity, pathologic and molecular markers= H = Trastuzumab 4 mg/kg loading dose= H = Trastuzumab 2 mg/kg qw= H = Trastuzumab 6 mg/kg q3w= AC = doxorubicin/cyclophosphamide 60/600 mg/m2 q3w= T = docetaxel 100 mg/m2 q3w= TC = docetaxel 75 mg/m2/carboplatin target AUC 6 mg/mL· minRadiation therapy and/or hormonal therapy may be given after completion of chemotherapy if indicatedSlamon et al. 29th Annual San Antonio Breast Cancer Symposium, 2005; Herceptin® (trastuzumab) PI. March 2009.Herceptin® (trastuzumab) PI. March 2009.
76Controversies in Use of Anthracyclines Authors suggest TCH should not be a preferred regimen for HER2+ early breast cancer.BCIRG 006 not powered to show equivalence or non-inferiority between the two H-based regimensNumerically fewer recurrences and deaths in the ACTH arm than TCH.
77Controversies in Use of Anthracyclines Authors encourage use of anthracycline-based adjuvant trastuzumab regimens as a mainstay of therapy for women with higher-risk HER2+ tumors.TCH should only be considered for women with lower-risk HER2+ tumors or in women with clinical reasons to avoid anthracyclines.
92BETH Phase III Study: Chemotherapy + Trastuzumab ± Bevacizumab 6 x docetaxel and carboplatinTCH(Group 1A)RTHER2+, N+ or high-risk N-Stratified by Ns and HRS(N ~ 3500)1 yr of trastuzumab6 x docetaxel and carboplatinTCHB(Group 1B)RT1 yr of trastuzumabPrimary endpoint: IDFSSecondary endpoints: DFS, OS, RFI, DRFI, toxicity1 yr of bevacizumabClinicalTrials.gov. NCT
93ALTTO Trial DesignTrastuzumab 8 mg/kg IV (loading dose)* 6 mg/kg every 3 wks for 1 yr Paclitaxel 80 mg/m2 IV once wkly x 12Women with centrally determined HER2-positiveinvasive breast cancer(N = 8381 accrued)Surgery, adjuvant anthracycline-based therapy for 4 cycles;LVEF ≥ 506-week wash-outTrastuzumab 4 mg/kg IV (loading dose) 2 mg/kg once wkly x 11 Paclitaxel 80 mg/m2 IV once wkly x 12Lapatinib1500 mg orally once daily x 34 wksLapatinib 1500 mg/kg orally once daily x 51 wks Paclitaxel 80 mg/m2 IV once wkly x 12(This arm closed in 9/2011 due to inferiority)*For concomitant dosing with paclitaxel, trastuzumab will be given on a weekly schedule (4 mg/kg IV loading dose followed by 2 mg/kg IV weekly). Trastuzumab will revert to the 3-weekly schedule (6 mg/kg without loading dose).Trastuzumab 8 mg/kg (loading dose) 6 mg/kg every 3 wks for 1 yrLapatinib 1000 mg orally once daily x 51 wks Paclitaxel 80 mg/m2 IV once wkly x 12
94APHINITY: Study Schema S U R G E R YRANDOMIZTFOLWUP10YRSChemotherapy + trastuzumab and pertuzumabAnthracycline or non-anthracycline–based chemotherapy allowedN = 3806N = 3806Central confirmationof HER2 statusChemotherapy + trastuzumab and placeboAnthracycline or non-anthracycline–based chemotherapy allowedRandomization within 7 wks of surgeryStart treatment within 1 wkAnti-HER2 therapy for a total of 1 yr (52 wks)Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapyClinicalTrials.gov Identifier: NCT
95ConclusionsTrastuzumab in addition to chemotherapy remains the standard for all “high-risk” HER-2+ early breast cancer.Controversies exist regarding the following:Use of anthracyclinesDefinition of “high-risk”Role of additional biologic agents to trastuzumabOptimal duration of trastuzumab
96Final ThoughtsThe addition of anti-HER2 therapy has changed the natural history of HER2+ early and metastatic breast cancer.Combining different anti-HER2 agents in these settings also appears to have an improved outcome.Pertuzumab and TDM-1 are newly approved for women with HER2+ metastatic breast cancer.Their role in the adjuvant/neoadjuvant setting depends upon the maturation of current clinical trials.