HER2-Targeted Rx An Historical Perspective
Trastuzumab: Front Line Rx for MBC Median 20.3 v. 25.1 mo P = 0.046 HR 0.8 65% of control patients crossed over Slamon D, et al. N Engl J Med, 2001; 344:783
Trastuzumab:Front-line Rx MBC HO648 HO650 Chemo Chemo + Trastuzumab Trastuzumab
Trastuzumab Monotherapy, Front-line All Patients Enrolled assessable: 111 CR 7 PR 22 CR + PR 29 (26%) Clinical benefit 42 (38%) HER2 IHC 3+ patients Enrolled assessable: 87 CR 7 PR 22 CR + PR 29 (35%) Clinical benefit 40 (48%) Vogel C, et al. J Clin Oncol 2002; 20:719
Baseline Characteristics 80 70 650 648 60 50 40 30 20 10 0 HER2 2+.....
Baseline Characteristics 80 70 650 648 60 50 40 30 20 10 0 HER2 2+ HER2 3+....
Baseline Characteristics 80 70 650 648 60 50 40 30 20 10 0 HER2 2+ HER2 3+ 3 met sites...
Baseline Characteristics 80 70 650 648 60 50 40 30 20 10 0 HER2 2+ HER2 3+ 3 met sites Age..
Baseline Characteristics 80 70 650 648 60 50 40 30 20 10 0 HER2 2+ HER2 3+ 3 met sites Age Adjuvant Chemo.
Trastuzumab as First-Line Therapy Survival (Kaplan-Meier Estimate) 80 70 650 648 60 50 40 30 20 10 0 HER2 2+ HER2 3+ 3 met sites Age Adjuvant Chemo KPS 90
Trastuzumab as First-Line Therapy Survival (Kaplan-Meier Estimate) 100 80 HO 650 Trastuzumab 60 40 20 0 Median survival 24.4 mo Vogel et al, ASCO 2000 5 10 15 20 25 30 35 40 45 50 MONTHS
Trastuzumab as First-Line Therapy Survival (Kaplan-Meier Estimate) 100 80 HO 650 Trastuzumab 100 80 HO 648 T + C 60 60 40 24 mo 40 25 mo 20 0 Median survival 24.4 mo Vogel et al, ASCO 2000 Slamon et al, NEJM 2001 0 5 10 15 20 25 30 35 40 45 50 MONTHS 20 Median survival 25.1 mo 5 10 15 20 25 30 35 40 45 50 MONTHS
Trastuzumab as First-Line Therapy Survival (Kaplan-Meier Estimate) 100 80 HO650 Trastuzumab 100 80 HO648 T + C C 60 60 40 40 20 20 0 Vogel et al, ASCO 2000 Slamon et al, NEJM 2001 0 5 10 15 20 25 30 35 40 45 50 MONTHS 5 10 15 20 25 30 35 40 45 50 MONTHS
Trastuzumab as First-Line Therapy Survival (Kaplan-Meier Estimate) 100 80 60 HO650 Trastuzumab 100 80 60 HO648 T + C C?T 40 24 mo 40 25 mo 20 20 20 mo 0 Vogel et al, ASCO 2000 Slamon et al, NEJM 2001 0 5 10 15 20 25 30 35 40 45 50 MONTHS 5 10 15 20 25 30 35 40 45 50 MONTHS
Trastuzumab: Front-line Rx in MBC Conclusions; L 100 80 60 HO650 Trastuzumab 100 80 60 HO648 T + C C?T 40 40 20 20 0 Vogel et al, ASCO 2000 Slamon et al, NEJM 2001 0 5 10 15 20 25 30 35 40 45 50 MONTHS 5 10 15 20 25 30 35 40 45 50 MONTHS
CLEOPATRA OS now significant; SABCS 2012 HR.66 P=.0008 Crossover not allowed Baselga J, et al. N Engl J Med 2011 (10.1056/NEJMoa1113216)
CLEOPATRA Baselga J, et al. N Engl J Med 2011 (10.1056/NEJMoa1113216)
Gianni L, et al. Lancet Oncol 2012; 13: 25 Neosphere pcr in breast (%) 100 90 80 70 60 50 40 30 20 10 0 * 46 29 T + D T + D + P T + P P + D *p=0 014 vs group A. ^p=0 02 vs group A. +p=0 003 vs group B. ^ 17 + 24
Gianni L, et al. Lancet Oncol 2012; 13: 25 Neosphere pcr in breast ER/PR-neg (%) 100 90 80 70 60 50 40 30 20 10 0 63 37 27 30 T + D T + D + P T + P P + D
Gianni L, et al. Lancet Oncol 2012; 13: 25 Neosphere pcr in breast ER/PR-pos (%) 100 90 80 70 60 50 40 30 20 10 0 8 7 6 6 T + D T + D + P T + P P + D
AWP Trastuzumab: $50,000/yr Pertuzumab: 10,000/840 mg; load + 16 q 3 wk doses = $97,000/yr Docetaxel: $22/mg; avg 1.8 M2 patient x 75 mg/m2 = 135 mg x 22 = $3,000 x 6 doses = $18,000. 1 yr of Cleopatra = $165,000 + chair time, individual mark-ups, etc.
RV
RV July 2006: 48 yo TV reporter felt lump Infiltrating ductal, grade 2, 2.5 cm on imaging, ER neg, PR focally positive, HER2-amplified, node positive on imaging, liver mets, biopsy documented, and possibly bone AC x 2 with good response in axilla & stable liver disease on CT performed 8/22/06 @ OSH
RV 2 nd opinion at Rush: Stop AC, begin trastuzumab. Clinical complete remission Continued q 3 weekly trastuzumab, scans at 3, then 6 months. 5/16/13: re-staging evaluation: CR CR duration: 7 years.
RV Had this patient been diagnosed today, she would potentially receive docetaxel, trastuzumab & pertuzumab
EMILIA Study Design HER2+ (central) LABC or MBC (N=980) T-DM1 3.6 mg/kg q3w IV PD Prior taxane and trastuzumab Progression on metastatic tx or within 6 mos of adjuvant tx No prior cape or lap 1:1 Capecitabine 1000 mg/m 2 orally bid, days 1 14, q3w + Lapatinib 1250 mg/day orally qd PD Stratification factors: World region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral disease Primary end points: PFS by independent review, OS, and safety Key secondary end points: PFS by investigator, ORR, duration of response, time to symptom progression Blackwell et al., ASCO 2012
Proportion progression-free Progression-Free Survival by Independent Review 1.0 0.8 0.6 Median (mos) No. events Cap + Lap 6.4 304 T-DM1 9.6 265 Stratified HR=0.650 (95% CI, 0.55, 0.77) P<0.0001 0.4 T-DM1 c/w regimen most don t use 0.2 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time (mos) No. at risk by independent review: Cap + Lap 496 404 310 176 129 73 53 35 25 14 9 8 5 1 0 0 T-DM1 495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0 Unstratified HR=0.66 (P<0.0001). Blackwell et al., ASCO 2012
Marianne T+ chemo 1 ST LINE TDM1 T-DM1 + Pertuzumab
AWP T-DM1 + Pertuzumab Pertuzumab $97,000/yr T-DM1 8,387/252 mg = $142,579 T-DM1 + Pertuzumab = $239,000/yr
Who will pay for rational clinical trials in HER2+ MBC? T T + P T-DM1 1 ST LINE ER neg T+P+CHEMO Marianne Winner T-DM1
Who will pay for rational clinical trials in HER2+ MBC? 1 ST LINE ER pos T + hormone Rx T+P+CHEMO T + P T-DM1 T-DM1 Marianne Winner
Conclusions Single agent T produces a 35% response rate and a 48% clinical benefit rate in HER2 IHC 3+ patients in front line treatment of MBC. Single agent T is associated with excellent QOL ER/PR pos patients benefit less than ER/PR neg patients from neoadjuvant HER2-targeted agents; perhaps the same is true in the metastatic setting A sequential single agent approach, similar to that used in HER2-negative breast cancer may produce better QOL, be less costly and result in similar survival compared with chemo and multiple HER2-targeted agents up front.
Serum Tumor Markers To monitor MBC
ASCO Guidelines CA 15-3, CA 27.29, CEA Can be used in conjunction with diagnostic imaging, history, and physical examination. Data are insufficient to recommend use alone for monitoring response to treatment. But, if no measurable disease, an increasing marker may be used to indicate disease progression (guideline says treatment failure). Caution should be used when interpreting a rising serum tumor marker level during the first 4-6 weeks of a new therapy, since spurious early rises may occur. Harris, L; J Clin Oncol 2007; 25:5287
CA 15-3 & CA27.29 CA 15-3 and CA 27.29: Detect circulating MUC-1 antigen in peripheral blood.
ASCO Guidelines CEA & MUC-1 CEA levels are less commonly elevated than MUC-1 among patients with MBC CEA elevated: 50-60% MUC1 Ag : 75-90% Harris, L; J Clin Oncol 2007; 25:5287
ASCO Guidelines CEA & MUC-1 CEA levels are minimally complementary with MUC-1 levels. e.g., in one study CA15-3 elevated in 94% CEA elevated in 69% CEA was elevated in only 1 case in which CA 15-3 was not. Harris, L; J Clin Oncol 2007; 25:5287
ASCO Guidelines CEA & MUC-1 But, in several studies there have been selected cases in which CEA was elevated and MUC-1 was not. Like MUC-1 assays, CEA levels appear to track with disease status. Reasonable to evaluate one MUC-1 assay and CEA initially in a patient with MBC. If the MUC-1 assay is elevated, there appears to be no role for monitoring CEA, but if not, then CEA levels may provide supplementary information to clinicians in addition to clinical and radiographic investigations. Harris, L; J Clin Oncol 2007; 25:5287
NCCN Guidelines: Monitor MBC Reiterate ASCO guidelines
Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer Dawson SJ. N Engl J Med2013;368:1199
Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer 52 Women with MBC Tumor Tissue Serial scans Serial Blood Samples Dawson SJ. N Engl J Med2013;368:1199
Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer Tumor tissue: N=52 Identification of somatic genomic alterations Targeted sequencing of PIC3CA or TP53 mutations: N=52 Whole-genome sequencing to identify mutations, somatic variants (SVs), or both: N=9 Dawson SJ. N Engl J Med2013;368:1199
Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer Somatic genomic alterations Targeted sequencing of PIC3CA or TP53 mutations: N=52 Whole-genome sequencing to identify mutations, SVs, or both: N=9 25 had mutations 9 had mutations or SV Dawson SJ. N Engl J Med2013;368:1199
Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer Serial blood sampling of women with mutations or SVs 141 Samples from 30 women: Quantify circulating tumor DNA (ctdna) 126 Samples from 30 women: Count CTCs 114 Samples from 27 women: CA 15-3 Dawson SJ. N Engl J Med2013;368:1199
Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer 141 Samples from 30 women: Quantify ctdna 126 Samples from 30 women: Count CTCs 114 Samples from 27 women: CA 15-3 Compare circulating tumor ctdna vs. CTCs Compare circulating tumor DNA vs. CA 15-3 Dawson SJ. N Engl J Med2013;368:1199
Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer CA 15.3 ctdna: Sensitivity 96% Patients Detected Not Detected Total Elevated (>32) 21 0 21 Not Elevated 5 1 6 Total 26 1 27 Sensitivity 62% Dawson SJ. N Engl J Med2013;368:1199
Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer CTCs ctdna: Sensitivity 97% Patients Detected Not Detected Total Elevated ( 5) 18 0 18 Detected (1-4) 7 1 8 Not detected 4 0 4 Sensitivity ( 5): 60% Dawson SJ. N Engl J Med2013;368:1199
CA 15-3 (U/ml) Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer 10 4 r 2 =.36 P<.001 10 3 10 2 10 1 10 0 ND ND 10 0 10 1 10 2 10 3 10 4 10 5 10 6 ctdna (copies/ml) Dawson SJ. N Engl J Med2013;368:1199
# CTCs/7.5 ml blood Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer 10 4 r 2 =.61 P<.001 Median #of amplifiable copies of ctdna was 133 times the # of CTCs and had a greater dynamic range 10 3 10 2 10 1 10 0 ND ND 10 0 10 1 10 2 10 3 10 4 10 5 10 6 ctdna (amplifiable copies/3.75 ml plasma) Dawson SJ. N Engl J Med2013;368:1199
Circulating Biomarker Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer Days Dawson SJ. N Engl J Med2013;368:1199
Circulating Biomarker Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer Days Dawson SJ. N Engl J Med2013;368:1199
Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer Circulating tumor DNA (ctdna) shows superior sensitivity to that of other circulating biomarkers ctdna has a greater dynamic range that correlates with changes in tumor burden. ctdna often provides the earliest measure of treatment response Dawson SJ. N Engl J Med2013;368:1199
Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer ctdna identifies clones of tumor which may be progressing while others respond Monitoring of ctdna levels requires the identification of somatic alterations in individual patients. Cost of sequencing dropping quickly Newer methods may allow detection of ctdna without analyzing the original tumor. Dawson SJ. N Engl J Med2013;368:1199
Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer Limitations: Clinical utility has not been demonstrated Treatment, if effective, should cause a temporary increase in ctdna; optimal timing of measurement of ctdna with respect to treatment has not been defined. In the present study it was measured just before the next cycle of chemo so the impact of tumor lysis on ctdna level was minimized. Dawson SJ. N Engl J Med2013;368:1199
Circulating Tumor Cells (ctcs) Not currently recommended to monitor patients with MBC by ASCO or NCCN. Staging M0 cm0(i+): No clinical or radiographic evidence of distant metastasis but deposits of molecularly or microscopically detected tumor cells in circulating blood, bone marrow or other non-regional nodal tissue that are no larger than 0.2 mm in a patient without symptoms or signs of metastasis.