Future Directions in the Treatment of Patients With HER2+ Breast Cancer: What Community Oncologists Need to Know
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Future Directions in the Treatment of Patients With HER2+ Breast Cancer: What Community Oncologists Need to Know

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Despite remarkable progress in the treatment of HER2+ breast cancer, management of this patient population continues to remain a challenge, both in the adjuvant and metastatic settings. An enhanced ...

Despite remarkable progress in the treatment of HER2+ breast cancer, management of this patient population continues to remain a challenge, both in the adjuvant and metastatic settings. An enhanced understanding of the treatment options available for HER2+ breast cancer patients in different settings is imperative to improving patient survival and quality of life. This activity consisting of didactic presentations and case illustrations will address treatment choices for HER2+ patients after trastuzumab progression; proposed mechanisms of resistance; combination treatment approaches; the role of anthracyclines and HER2-targeted agents in this population; and novel targeted agents under investigation, including mTOR inhibitors, antiangiogenic inhibitors, and HER2-targeted therapies.

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Review a downloadable slide deck by Kathy D. Miller, MD, covering the most clinically relevant new data reported from Future Directions in the Treatment of Patients With HER2+ Breast Cancer: What Community Oncologists Need to Know.

Target Audience
This activity is designed to meet the educational needs of oncologists and other healthcare professionals involved in cancer care.

Slide Deck Disclaimer
This slide deck in its original and unaltered format is for educational purposes and is current as of September 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.

Usage Rights
This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.

More information:
http://imeronline.com/867dsd

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  • BCIRG trial highlighted as the only trial to include a non-Anthracycline arm. Statistical analyses compared each Trastuzumab arm to AC>T but did NOT provide for direct comparison of the two Trastuzumab arms REF: Tripathy D (2011). Principles of HER2+ breast cancer management [Presentation]. Retrieved May 23, 2012, from http://www.oncologycongress.com/RNA/RNA_OncologyCongress_v2/documents/2011/session_presentations/Principles_of_HER2_Positive_Breast_Cancer_Management-Tripathy.pdf
  • Consistent improvement in HR for DFS despite differences in eligibility, regimen, and timing of trastuzumab REF: Metcalfe S, Evans J, & Priest G (2007). PHARMAC funding of 9-week concurrent trastuzumab for HER2+ early breast cancer. N Z Med J, 120(1256), U2593.
  • Final results of the BCIRG trial. Note that the trial was not designed to compare AC>TH to TCH thus we can not determine if the 3% difference in DFS at 5 years is significant REF: Slamon D, Eiermann W, Robert N, et al (2009). Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC -> T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC -> TH) with docetaxel, carboplatin, and trastuzumab (TCH) in HER2-neu+ early breast cancer patients: BCIRG 006 study [Presentation]. Proc San Antonio Breast Cancer Symp, Abstract 62.
  • Overall, among the 3222 patients who underwent randomization, there were only 29 more primary events in the TCH group (214 events) than in the group receiving AC-T plus trastuzumab (185 events). A comparison of the therapeutic indexes of the two trastuzumab-containing regimens and the standard-therapy regimen was performed on the basis of the numbers of distant breast-cancer recurrences, cases of congestive heart failure, and cases of acute leukemia occurring in each study group. In this comparison, the difference between the trastuzumab-containing regimens was even smaller than the difference in the number of primary events. REF: Slamon D, Eiermann W, Robert N, et al (2009). Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC -> T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC -> TH) with docetaxel, carboplatin, and trastuzumab (TCH) in HER2-neu+ early breast cancer patients: BCIRG 006 study [Presentation]. Proc San Antonio Breast Cancer Symp, Abstract 62.
  • CHF ranges from 2.0-3.8% with Anthracycline-based regimens versus 0.4% in the DCArboH arm of BCIRG 006 REF: *Smith I, Procter M, Gelber R, et al (2007). Two-year follow-up of trastuzumab after adjuvant chemotherapy in HER2+ breast cancer: A randomized controlled trial. Lancet , 369 (9555), 29–36. *Perez EA, Suman VJ, Davidson NE, et al (2008). Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial. J Clin Oncol , 26 (8), 1231–1238. *Slamon D, Eiermann W, Robert N, et al (2011). Adjuvant trastuzumab in HER2+ breast cancer. N Engl J Med , 365 (14), 1273–1283. * Rastogi P, Jeong J, Geyer CE, et al (2007) Five-year update of cardiac dysfunction on NSABP B-31, a randomized trial of sequential doxorubicin/cyclophosphamide (AC) / paclitaxel (T) versus AC / T with trastuzumab [Abstract]. J Clin Oncol , 25 (18 Suppl), Abstract LBA513.
  • Detailed analysis of cardiac toxicity from N9831 follows. This slide simply highlights the schema and timing of cardiac assessments REF: Perez EA, Suman VJ, Davidson NE, et al (2008). Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial. J Clin Oncol , 26 (8), 1231–1238.
  • Once the patients start Trastuzumab, they will be monitored at set intervals by MUGA scan. The above criteria must be followed for continuing or stopping Herceptin in patients who are asymptomatic. If a repeat MUGA scan is indicated, that MUGA scan must fall into one of the categories labeled “continue” (above) before the patient can proceed with further weekly Trastuzumab doses.
  • Relatively low rate of significant decline in cardiac function. However this does result in some patients NOT proceeding to Trastuzumab therapy REF: Perez EA, Suman VJ, Davidson NE, et al (2005). Exploratory analysis from NCCTG N9831: Do clinical and laboratory characteristics predict cardiac toxicity of trastuzumab when administered as a component of adjuvant therapy? [Abstract]. Proc San Antonio Breast Cancer Symp , Abstract 2038.
  • Trend to increased cardiac toxicity in older patients but not association with post-AC LVEF REF: Perez EA, Suman VJ, Davidson NE, et al (2005). Exploratory analysis from NCCTG N9831: Do clinical and laboratory characteristics predict cardiac toxicity of trastuzumab when administered as a component of adjuvant therapy? [Abstract]. Proc San Antonio Breast Cancer Symp , Abstract 2038.
  • Some patients seem to recover – unknown how many remain on medical therapy at the time of the follow-up assessment REF: Perez EA, Suman VJ, Davidson NE, et al (2005). Exploratory analysis from NCCTG N9831: Do clinical and laboratory characteristics predict cardiac toxicity of trastuzumab when administered as a component of adjuvant therapy? [Abstract]. Proc San Antonio Breast Cancer Symp , Abstract 2038.
  • REF: Perez EA, Suman VJ, Davidson NE, et al (2005). Exploratory analysis from NCCTG N9831: Do clinical and laboratory characteristics predict cardiac toxicity of trastuzumab when administered as a component of adjuvant therapy? [Abstract]. Proc San Antonio Breast Cancer Symp , Abstract 2038.
  • Older patient with prior cardiac history and acceptable though borderline cardiac function. Case chosen to highlight the need to balance risk of cancer versus risk of treatment-related toxicity
  • While AC > TH and TCH are both supported by phase III data, this patient is older, has pre-existing cardiac disease, and a normal though borderline baseline LVEF. These features suggest that she might be a greater risk of developing cardiac toxicity with Anthracycline/Trastuzumab regimens. I would suggest TCH as the best option for this patient. There is safety data from MSKCC using ddAC>TH and the CALBG 9741 trial did not find an increase in cardiac toxicity with the ddAC>T regimen. However there is no phase III data to support option 3. Option 4 has been reported in the neoadjuvant setting to produce high pCR rates with little cardiac toxicity. However there is not phase III data in the adjuvant or neoadjuvant setting to support this choice.
  • Note – clinical trials did not find any association with RT (right or left) and subsequent cardiac toxicity
  • The Trastuzumab adjuvant trials assessed LVEF every 3 months during Trastuzumab monotherapy. Treatment was held and patients re-evaluated for a decline in LVEF of >15% or a 10-15% decline associated with a LVEF <LLN. In this case the safest plan (and the one most consistent with the clinical trial schema) would be to hold Trastuzumab and reassess the LVEF in 4-6 weeks. Referral to cardiology to maximize her medical mamagement may certainly be helpful. There is no data to support the efficacy or safety of changing to Lapatinib in this situation. In this case her Trastuzumab was held, medical management of her HTN was optimized. Six weeks later her LVEF had returned to baseline at 53%. She completed the remaining planned Trastuzumab without difficulty
  • Schema for the Lapatinib registration study./ Not prior treatment requirements. REF: Geyer C, Forster J, Lindquist D, et al (2006). Lapatinib plus capecitabine for HER2+ advanced breast cancer. N Engl J Med , 355 (26), 2733–2743.
  • NO difference in OS reported in this trial REF: Geyer C, Forster J, Lindquist D, et al (2006). Lapatinib plus capecitabine for HER2+ advanced breast cancer. N Engl J Med , 355 (26), 2733–2743.
  • Accrual fell after the Germany approval of Lapatinib. REF : von Minckwitz G, du Bois A, Schmidt M, et al (2009). Trastuzumab beyond progression in human EGFR2+ advanced breast cancer: A German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol , 27 (12), 1999–2006.
  • Improvement in PFS did not reach statistical significance given the smaller than planned sample size REF : von Minckwitz G, du Bois A, Schmidt M, et al (2009). Trastuzumab beyond progression in human EGFR2+ advanced breast cancer: A German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol , 27 (12), 1999–2006.
  • Note the clinical benefit rate of ~25% for the combination. Prior treatment with Anthracycline, Taxane, Capecitabine, and Trastuzumab required. Disease must be actively progressing at the time of study entry. REF: Blackwell K, Burstein H, Storniolo A, et al (2010). Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2+, trastuzumab-refractory metastatic breast cancer. J Clin Oncol , 28 (7), 1124–1130.
  • 4.5 month improvement in OS in heavily pre-treated patients REF: Blackwell K, Burstein H, Sledge G, et al (2009). Updated survival analysis of a randomized study of lapatinib alone or in combination with trastuzumab in women with HER2+ metastatic breast cancer progressing on trastuzumab therapy [Abstract]. Proc San Antonio Breast Cancer Symp , Abstract 61
  • MANY new agents actively in development. Pertuzumab was recently approved and TDM1 is expected to be approved shortly
  • Significant activity in heavily pre-treated patients. REF: Krop I, LoRusso P, Miller K, et al (2009). A phase II study of T-DM1, a novel HER2 antibody–drug conjugate, in HER2+ metastatic breast cancer patients previously treated with conventional chemotherapy, lapatinib, and trastuzumab. Cancer Res , 69 (24 Suppl 3), Abstract 09-5090 [SABCS].
  • REF: Blackwell K, Miles D, Gianni L, et al (2012). Primary results from EMILIA, a phase III study of trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in HER2-positive locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane [Abstract]. J Clin Oncol , 30 (Suppl), Abstract LBA1.
  • Young patient with aggressive high risk disease and no comorbities. AC>TH regimen chosen to maximize potential efficacy of therapy in this patient at low risk for cardiac toxicity. Note recent GBG analysis suggesting substantial risk of subsequent recurrence in HER2+ patients who have residual disease after neoadjuvant Trastuzumab-based therapy.
  • DFI from completion of Trastuzumab therapy - currently no data available to guide choice of Trastuzumab versus Lapatinib-based regimens. Cleopatra trial (discussed in the next section) allowed prior adjuvant Trastuzumab if DFI >12 months but that accounted for only 10% of the patients.
  • There are several reasonable choices available for this patient She has had a 3 year disease-free interval so retreatment with Trastuzumab is certainly reasonable. Toxicity and cost will vary with the specific Taxane selected. All options would have alopecia Lapatinib is approved for patients with prior Anthracycline, Taxane, and Trastuzumab therapy. Though the registration trial required Trastuzumab administration in the metastatic setting, this remains a reasonable option. It would not be my choice given the increased toxicity of the regimen Not my first choice given the prior phase III BCIRG trial that did not find improvement with the addition of Carboplatin to Docetaxel in the metastatic setting. Recent trial found similar outcome with less toxicity with Vinorelbine + Trastuzumab compared to Docetaxel + Trastuzumab. This option would preserve activity while minimizing toxicity and eliminating alopecia. Improved survival compared to Lapatinib monotherapy in more heavily pretreated patients. Would be a reasonable option in those unfit for chemo, or those asymptomatic or minimally symptomatic patients who are reluctant to accept the options of chemotherapy. Not the best option for this young symptomatic patient
  • Increase risk of CNS involvement in patients with HER2+ disease
  • Resumption of her Vinorelbine would be reasonable if she had systemic progression alone. However neither agent has significant CNS penetration This combination has CNS penetration. Clinical trials have reported CNS response rates of 18-67% (varies based on extent of prior RT) in patients with active CNS disease. Trials have also reported lower rates of CNS progression with Lapatinib versus trastuzuma based regimens. Could be a reasonable option if she is reluctant to consider chemo Supported by the GBG trial data if the only issue was systemic progression. Would have less CNS penetration than cape/Lapatinib Little CNS penetration, reasonable for systemic progression alone while on Vinorelbine or with short DFI
  • Neoadjuvant trials evaluating combined HER2 blockade. (At least two other small trials found similar results for the Lapatinib + Trastuzumab combination)
  • Lapatinib arm in the adjuvant ALTTO trial discontinued for failing to reach noninferiority REF: Baselga J, Bradbury I, Eidtmann H, et al (2010). First results of the NeoALTTO trial: A phase III, randomized, open label, neoadjuvant study of lapatinib, trastuzumab, and their combination plus paclitaxel in women with HER2+ primary breast cancer [Abstract]. Proc San Antonio Breast Cancer Symp , Abstract S3-3.
  • ADCC, antibody-dependent cell-mediated cytotoxicity; ECD, extra cellular domain. REF: Baselga J, Cortés J, Kim S, et al (2012). Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med , 366 (2), 109–119.
  • Improved pCR with combined HER2 inhibition. Note substantial pCR rate without chemotherapy, esp in the ER- subset REF: Gianni L, Pienkowski T, Im YH, et al (2010). A phase II neoadjuvant study evaluating the effect of a novel combination regimen of pertuzumab and trastuzumab plus chemotherapy in women with early-stage HER2+ breast cancer [Abstract]. Proc San Antonio Breast Cancer Symp , Abstract S3-2.
  • ~10% of patients had received adjuvant or neoadjuvant Trastuzumab REF: *Baselga J, Cortés J, Kim S, et al (2012). Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med , 366 (2), 109–119. * Perjeta™ (prescribing information). South San Francisco, CA: Genentech, Inc.; 2012.
  • Significant improvement in PFS REF: *Baselga J, Cortés J, Kim S, et al (2012). Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med , 366 (2), 109–119.
  • <5% patients with PD as best response REF: *Baselga J, Cortés J, Kim S, et al (2012). Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med , 366 (2), 109–119.
  • REF: *Baselga J, Cortés J, Kim S, et al (2012). Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med , 366 (2), 109–119.
  • Preclinical studies suggested significant improvement with combined HER2 and VEGF inhibition. Co-expression documented in path series REF: Gianni L, Romieu G, Lichinitser M, et al (2011). First results of AVEREL, a randomized phase III trial to evaluate bevacizumab in combination with trastuzumab + docetaxel as first-line therapy for HER2+ locally recurrent/metastatic breast cancer [Abstract]. Proc San Antonio Breast Cancer Symp , Abstract S4-8.
  • Improvement in PFS less impressive than seen with the addition of Pertuzumab REF: Gianni L, Romieu G, Lichinitser M, et al (2011). First results of AVEREL, a randomized phase III trial to evaluate bevacizumab in combination with trastuzumab + docetaxel as first-line therapy for HER2+ locally recurrent/metastatic breast cancer [Abstract]. Proc San Antonio Breast Cancer Symp , Abstract S4-8.
  • REF: Gianni L, Romieu G, Lichinitser M, et al (2011). First results of AVEREL, a randomized phase III trial to evaluate bevacizumab in combination with trastuzumab + docetaxel as first-line therapy for HER2+ locally recurrent/metastatic breast cancer [Abstract]. Proc San Antonio Breast Cancer Symp , Abstract S4-8.
  • Metastatic disease identified at initial presentation. Patient without symptoms, normal organ function
  • Based on the results of the CLEOPATRA trial, options 3 may be optimal. It would be difficult to recommend an Anthracycline based regimen as initial therapy in a patient with HER2+ metastatic disease. TCH has been used in the adjuvant setting based on the BCIRG 006 trial but the addition of Carboplatin did not improve outcome in the metastatic setting. Trastuzumab + Lapatinib improves outcome in more heavily pretreated patients and may be considered in the first-line setting in patients who refuse chemo or are unfit for chemo. Vinorelbine + Trastuzumab would be a reasonable option for patients who will not accept alopecia but is likely less effective than a regimen with dual HER2 inhibition
  • Possible Discussion Topic during Question and Answers section at the end: Treatment of small tumors is often encountered in the community setting which involves the adjuvant management of small (T1a/T1bN0) Her-2 amplified tumors.

Future Directions in the Treatment of Patients With HER2+ Breast Cancer: What Community Oncologists Need to Know Future Directions in the Treatment of Patients With HER2+ Breast Cancer: What Community Oncologists Need to Know Presentation Transcript

  • DISCLAIMER This slide deck in its original and unaltered format is for educational purposes and is current as of September 2012. All materials contained herein reflect the views of thefaculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice,diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity. Usage Rights This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.
  • DISCLAIMERParticipants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline forpatient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. DISCLOSURE OF UNLABELED USEThis educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Albert Einstein College ofMedicine and IMER do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of Albert Einstein College of Medicine and IMER. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
  • Disclosure of Conflicts of Interest Kathy D. Miller, MDReported a financial interest/relationship or affiliation inthe form of: Contracted Research, Clovis Oncology, Inc.,Geron Corporation, Merrimack Pharmaceuticals, RochePharmaceuticals, Inc.; Consultant, Clovis Oncology, Inc.,Necktar Therapeutics, Roche Pharmaceuticals, Inc.
  • Future Directions in the Treatmentof Patients With HER2-Positive BreastCancer: What Community Oncologists Need to Know
  • Learning Objectives Upon completion of this activity, participants should be better able to: Identify treatment options for patients with HER2+ breast cancer that have failed trastuzumab Describe the significance of HER2 status in making clinical decisions Assess the optimal combinations of HER2-targeted therapy for treating patients with HER2+ breast cancer Identify proposed mechanisms of resistance to HER2-targeted therapies for treating HER2+ patients Cite new data from clinical trials on novel and emerging agents for treating HER2+ breast cancer including mTOR inhibitors, antiangiogenic inhibitors, and HER2-targeted therapies
  • Activity Agenda Activity Overview (5 mins) Anthracyclines or No Anthracyclines: Are Adjuvant Anthracyclines Necessary for the Treatment of HER2+ Breast Cancer? (10 mins) Trastuzumab Progression: Which Treatment Options Provide the Best Outcomes for Patients With HER2+ Breast Cancer After Progression on Trastuzumab? (20 mins) Combination Approaches: What Combination Approaches Are Options for Treating Patients With HER2+ Breast Cancer? (20 mins) Questions & Answers (5 mins)
  • HER2/neu Overview General Features of HER2/neu Characteristics of HER2 + Disease  Located on chromosome17q  Increased tumor size  Amplified in approximately 20% of  Positive nodal status primary breast cancers  Decreased ER and PR expression  Encodes for tyrosine kinase  Ductal rather than lobular histology transmembrane growth factor – High S-phase fraction receptor – High nuclear grade  Both a prognostic and predictive factor in early stage and advanced  Higher risk of recurrence breast cancer  More advanced stage at  HER2 overexpression seen in presentation DCIS but not in earlier premalignant lesionsDCIS = ductal carcinoma in situ; ER = estrogen receptor; PR = progesterone receptor.Gutierrez et al, 2011.
  • Anthracyclines or No Anthracyclines: Are Adjuvant Anthracyclines Necessaryfor the Treatment of HER2+ Breast Cancer?
  • Topics for Discussion Anthracyclines or nonanythracyclines combined with trastuzumab: Efficacy vs. risk factors? What risk factors and preexisting conditions define which regimen to use?
  • Adjuvant Trastuzumab Trial DesignsTripathy, 2011.
  • Trastuzumab Adjuvant Trial DFS Benefits Study FU (yrs) N HR 1 3,387 0.54 HERA 2 3,401 0.64 NSABP B-31/ 2 3,351 0.48 NCCTG 9831 4 3,968 0.48 BCIRG 006 3 3,222 0.61 FinHer 3 231 0.42 PACS 04 4 528 0.86 0 1 2 In favor of T In favor of Obs.DFS = disease-free survival; FU = follow-up; HR = hazard ratio.Metcalfe, 2007.
  • BCIRG 006 – Final AnalysisCI = confidence interval.Slamon et al, 2009.
  • Therapeutic Index for Critical Clinical Events Clinical Event Number of Events AC-T AC-T plus TCH Trastuzumab Total Events 201 146 149 Distant breast-cancer recurrence 188 124 144 Grade 3 or 4 congestive heart 7 21 4 failure Acute Leukemia 6 1 1  This is a compilation of the distant breast-cancer recurrences, cases of CHF, and cases of acute leukemia.CI = confidence interval, AC-T = doxorubicin and cyclophosphamide followed bydocetaxel, TCH = docetaxel, carboplatin, and trastuzumab..Slamon et al, 2011.
  • Clinical Cardiomyopathy in Trastuzumab Adjuvant TrialsH = trastuzumab; A = doxorubicin; C = cyclophosphamide; P = paclitaxel; T = docetaxel;LVEF = left ventricular ejection fraction; CHF = congestive heart failure.Smith et al, 2007; Perez et al, 2008; Slamon et al, 2011; Rastogi et al, 2007.
  • N9831: Schema and Cardiac Testing Arm A: AC Paclitaxel (q3wks x 4) (qwk x 12) R Arm B: AC (q3wks x 4) Paclitaxel (qwk x 12) H (qwk x 52) Arm C: AC Paclitaxel + H H (q3wks x 4) (qwk x 12) (qwk x 40) RT/Hormone as Indicated Time (mos) 0 3 6 9 18–21 LVEF Measurement Pre-AC Post-AC Post T or THRT = radiation therapy.Perez et al, 2008.
  • Asymptomatic Patients Rules for Trastuzumab Continuation Based on Serial LVEF Used in Trials Relationship of Absolute Absolute Decrease Absolute Decrease Decrease LVEF to LLN of 10%–15% ≥ 16% < 10% WNL Continue Continue *Hold 1%–5% below LLN Continue *Hold *Hold ≥ 6% below LLN *Continue *Hold *Hold * Repeat LVEF assessment after 4 wks – If criteria for continuation met – resume trastuzumab – If 2 consecutive holds, or total of 3 holds occur – discontinue trastuzumabWNL = within normal limits; LLM = lower limit of normal.
  • Post-AC LVEF Results for 2,999 Patients Arm A Arm B Arm C Total (n = 1,012; %) (n = 1,065; %) (n = 922; %) (N = 2,999; %) LVEF decrease ≥ 15% 3.8 1.7 2.3 2.6 LVEF decrease ≤ 15% to below LLN 3.1 2.5 1.6 2.4 Prohibited from receiving 6.9 4.2 3.9 5.0 trastuzumab (5.3–8.6) (3.1–5.6) (2.8–5.4) (4.3–5.8)Perez et al, 2005.
  • Cumulative Incidence Rate of Cardiac Events (Arms B and C)* Arm B Arm C n 1 yr 2 yrs n 1 yr 2 yrs Post-AC LVEF ≤ 55% Age ≤ 60 yrs 62 1.6% 3.6% 60 1.7% 1.7% Age ≥ 60 yrs 13 0% 0% 6 1.7% 1.7% Post-AC LVEF ≥ 55% Age ≤ 60 yrs 541 1.5% 2.1% 414 2.4% 2.4% Age ≥ 60 yrs 94 2.2% 4.5% 94 8.5% 8.5%*Among patients who enrolled prior to April 25, 2004 and had a satisfactorypost-AC cardiac evaluation.Perez et al, 2005.
  • Most Recent LVEF Levels for Patients Who Experienced CHF in Arms B and C Arm B (n = 16) Arm C (n = 18) LVEF (n) LVEF (n) < 50% 50%–59% ≥ 60% < 50% 50%–59% ≥ 60% Time since CHF diagnosis 1.0–0.59 mos 4 0 0 3 1 0 6.0–11.9 mos 2 2 2 1 2 1 ≥ 12 mos 2 1 3 3 4 3Perez et al, 2005.
  • Key Takeaways  Adjuvant trastuzumab after anthracycline-based chemotherapy leads to an approximate 3-yr cumulative incidence rate of 2.5%–3.5% of significant clinical cardiac events – The cardiac function in the majority of patients improved following medical treatment  Trend towards increased risk of cardiac toxicity with increased patient age  No correlation between radiation therapy cardiac toxicity  No correlation between post-AC LVEF and subsequent cardiac toxicity – Differs from analysis of NSABP B-31Perez et al, 2005.
  • Case Study 1  65-yr-old, postmenopausal woman presented with a palpable left axillary mass  Mammogram and ultrasound demonstrated a 1.8-cm left breast mass and 3.1-cm axillary mass  PATHOLOGY: Core biopsy: Poorly diff. IDC, ER+ (20%), PR-, HER2 “3+” on IHC, FISH 9.2 – CT of chest/abdomen and bone scan: No evidence of metastasis  COMORBIDITIES: Obesity, HTN, osteoarthritis, 3 yrs ago treated with thrombolytics and stent placement – LVEF normal (52%) by ECHO  PRIMARY SURGERY: Left modified radical mastectomy – Primary tumor 2.2 cm, margins negative – 1/15 LN involved, 3.2 cm with no extracapsular extensionIDC = invasive ductal carcinoma; ER = estrogen receptor; PR = progesterone receptor;IHC = immunohistochemistry; FISH = fluorescence in situ hybridization;CT = computed tomography; HTN = hypertension; ECHO = echocardiogram;LN = lymph node.
  • Case Study 1: Question 1What adjuvant therapy would you recommend? 1) AC > TH as in N9831 2) TCH as in BCIRG 006 3) Dose-dense AC > wkly paclitaxel + trastuzumab 4) Taxane > FEC with concurrent trastuzumab 5) Other trastuzumab-based regimen
  • Case Study 1 (cont.) She was treated with the TCH regimen. Docetaxel and carboplatin were dose reduced for neuropathy after Cycle 4 but she otherwise did well. – LVEF after TCH Cycle 6 was 50% Shecontinued trastuzumab and proceed with chest wall and regional node RT – 3 mos later (2 wks after completing RT) she complains of fatigue but otherwise feels well (LVEF was 42%)
  • Case Study 1: Question 2At this point you would: 1) Continue trastuzumab and refer to cardiology 2) Discontinue trastuzumab 3) Hold trastuzumab and repeat LVEF in 4–6 wks 4) Discontinue trastuzumab, complete planned adjuvant therapy with lapatinib
  • Key Takeaways Bothanthracycline and non-anthracycline regimens are supported by phase III data Riskof CHF is 2%–4% with anthracycline regimens – Higher risk in older patients Only1 trial evaluated a non-anthracycline regimen (TCH) – Risk of CHF ~ 0.5% – Lower risk for leukemia – Numerically higher risk of recurrence
  • Trastuzumab Progression:Which Treatment Options Provide the Best Outcomes for Patients With HER2+ BreastCancer After Progression on Trastuzumab?
  • Topics for Discussion Is continuation of HER2-targeted therapy with either trastuzumab or lapatinib recommended following progression on a trastuzumab-based regimen? When should you switch to lapatinib? What emerging options are available after relapse following trastuzumab/lapatinib treatment?
  • TKI After Trastuzumab? HER2+ LABC or MBC with Lapatinib 1,250 mg po qd continuously + prior exposure to an Capecitabine 2,000 mg/m2/d R po Days 1–14 q3wks anthracycline, a taxane, and trastuzumab* A (n = 163) N = 324 N D O M I Capecitabine 2,500 mg/m2/d Stratification po Days 1–14 q3wks Z • Disease sites E (n = 161) • Stage of disease Patients on treatment until progression or unacceptable toxicity, then followed for survival*Trastuzumab must have been administered for metastatic disease.TKI = tyrosine kinase inhibitor; LABC = locally advanced breast cancer;MBC = metastatic breast cancer.Geyer et al, 2006.
  • Lapatinib Increases TTP After TrastuzumabTTP = time to progression.Geyer et al, 2006.
  • Why Not Continue Trastuzumab? GBG 26/BIG 3-05 (Closed Early With Poor Accrual) Capecitabine 2,500 mg/m2/d Women with HER2+ on Days 1–14 q3wks Advanced Breast Cancer or MBC That Progressed on Trastuzumab Capecitabine 2,500 mg/m2/d (N = 156) on Days 1–14 q3wks + Trastuzumab 6 mg/kg q3wksvon Minckwitz et al, 2009.
  • Trastuzumab Remains Effective After Disease Progression Capecitabine Capecitabine + Trastuzumabvon Minckwitz et al, 2009.
  • Longer PFS With Lapatinib + Trastuzumab Vs. Lapatinib Alone in Trastuzumab-Refractory MBC Lapatin Lapatinib + ib Trastuzum PFS Outcome (n = ab 145) (n = 146) Progressed or 128 127 died, n Median, wks 8.1 12.0 HR (95% CI) 0.73 (0.57–0.93) p Value .008 Lapatini Lapatinib + Odds Response (%) p Value b Trastuzumab Ratio ORR 6.9 10.3 1.5 .46 CBR 12.4 24.7PFS = progression-free survival; ORR = overall response rate; CBR = clinical benefit rate. 2.2 .01Blackwell et al, 2010.
  • Updated Overall Survival in ITT L L+T N = 145 N = 146 Died, N (%) 113 (78) 105 (72) Median, mos 9.5 10 HR (95% Cl) 0.74 (0.57, 0.97) Log-Rank p Value 0.26 Patients at Risk L+T 148 121 88 64 43 25 1 L 148 102 65 47 28 13 –Blackwell et al, 2009.
  • Novel Agents: HER2HER1/2 TKI Neratinib (HKI-272), Afatinib (BIBW 2992), PKI-166, EKB-569Pan HER TKI Canertinib, BMS-599626HER1/2/VEGFR TKI XL647, AEE788HER2 dimerization Pertuzumab (FDA Approved 06/2012 – first-line HER2+ MBC)inhibitorBispecific antibody Ertumaxomab, MM111Conjugated antibodies Trastuzumab-MCC-DM1, Trastuzumab-A-Z-CINN 310-paclitaxelTargeted nanoparticles MM302HSP90 inhibitors Tanespimycin, alvespimycin, CNF2024, IPI-504, AUY922, SNX5422IGF-1R inhibitors (mAb, TKI)CP-751871, EM164, IMC-A12, NVP-ADW742, INSM- 18HDAC inhibitors Vorinostat, LBH589, Belinostat (PXD101), NVP-LAQ824, depsipeptide, CI-994, MS-275PI3K inhibitors SF1126, BEZ235, XL147, XL765, GDC-0941Akt inhibitors Perifosine, XL418mTOR inhibitors Sirolimus, temsirolimus, everolimus, ridaforolimusHER2 vaccines E75 vaccine
  • T-DM1  Multicenter phase II (N = 110) – Prior anthracycline, taxane, capecitabine, trastuzumab, lapatinib  ORR (by independent review) 34.4%  CBR (by independent review) 48.2%  Median PFS 6.9 mos – 7.3 mos in centrally confirmed HER2+Krop et al, 2009.
  • Phase III T-DM1 Vs. Capecitabine + Lapatinib in HER2+ MBC (EMILIA) HER2+ T-DM1 (centrally confirmed) (3.6 mg/kg) q3wks IV LABC or MBC Previously Received Trastuzumab- Lapatinib Based Therapy (n = 980) (1,250 mg/day) Days 1–21 po bid + Capecitabine (1,000 mg/m2) Days 1–14 q3wks po qd 2Primary end points: OS, PFS, SafetySecondary end point: QOLKey inclusion criteria– Prior treatment to include a taxane and trastuzumab in adjuvant, locally advanced or metastatic setting– Documented progression of disease during or after treatment for advanced/metastatic disease or within 6 mos of completing adjuvant therapy QOL = quality of life.Blackwell et al. 2012
  • Case Study 2  38-yr-old patient presented with inflammatory breast cancer – ER- and PgR- – HER2+ by FISH (ratio 8.9) – Imaging with PET/CT found regional nodal involvement but was otherwise negative  She was treated with neoadjuvant AC > TH followed by mastectomy (2 cm residual disease, LN-) and RT. She completed 1 yr of trastuzumab.PgR = progesterone receptor; PET = positron emission tomography.
  • Case Study 2 (cont.) 3 yrs later she reports a persistent cough and increased fatigue – Imaging finds several lung lesions with mediastinal and hilar adenopathy – Biopsy confirms metastatic disease that remains ER-/PgR-/HER2+ – CBC, total bilirubin, AST, ALT, calcium, albumin: All normal – LVEF 62% by MUGACBC = complete blood count; AST = aspartate aminotransferase;ALT = alanine aminotransferase; MUGA = multi-gated acquisition scan.
  • Case Study 2: Question 1Which of the following treatment optionswould you recommend for this patient? 1) Taxane-based chemotherapy + trastuzumab 2) Capecitabine + lapatinib 3) Docetaxel + carboplatin + trastuzumab 4) Vinorelbine + trastuzumab 5) Trastuzumab + lapatinib
  • Case Study 2 (cont.) She was treated with vinorelbine + trastuzumab – She had an excellent partial response with resolution of symptoms – Vinorelbine discontinued after 9 cycles due to increased neuropathy (continued trastuzumab) 10mos later, she develops headache and diplopia – Imaging finds a large cavernous sinus met with several other small cerebral lesions
  • Case Study 2 (cont.)  She is started on steroids and completes whole brain radiation therapy – CNS symptoms resolve – Additional imaging finds asymptomatic progression of her systemic disease with increased lung nodulesCNS = central nervous system.
  • Case Study 2: Question 2Which of the following strategies would yourecommend for this patient at this point? 1) Resume vinorelbine with continued trastuzumab 2) Capecitabine + lapatinib 3) Trastuzumab + lapatinib 4) Capecitabine + trastuzumab 5) Alternate chemotherapy + trastuzumab
  • Key Takeaways Continued HER2 blockade through multiple lines of therapy is important for patients with HER2+ disease Optimal sequence not defined Lapatinib may have unique role in patients with CNS disease Several new agents have activity and are likely to be available soon
  • Combination Approaches:What Combination Approaches Are Options for Treating HER2+ Breast Cancer?
  • Topics for Discussion Lessons from the neoadjuvant setting Dual regimens of HER2-targeted therapies Combined VEGF and HER2-targeted therapies
  • Lessons Neoadjuvant Trials Trast + Docetaxel Pertuz + Docetaxel NEO-R SPHERE Pertuz + Trast + Docetaxel n ~ 400 Pertuz + Trast Trast Trast + Paclitaxel NEO-R Lapatinib Lapatinib + Paclitaxel ALTTO n ~ 450 Trast/Lap Trast/Lap + Paclitaxel
  • Pathologic Response in Neo-ALTTO No Difference in Proportion of Patients Undergoing Breast ConservationBaselga et al, 2010.
  • Pertuzumab and Trastuzumab: Complementary Mechanisms of Action HER2 HER 1/3/4 Trastuzumab Pertuzumab Dimerization domain Subdomain IV Trastuzumab Pertuzumab  Inhibits ligand-independent  Inhibits ligand-dependent HER2 HER2 signaling dimerization and signaling  Activates ADCC  Activates ADCC  Prevents HER2 ECD sheddingBaselga et al, 2012.
  • Pathologic CR Rates in NeoSphereITT = intent-to-treat.Gianni et al, 2010.
  • CLEOPATRA: Study Design  Primary end point: PFS (independently Stratified by geographic region assessed) and previous (neo)adjuvant chemotherapy  Secondary end points: PFS (investigator assessment), ORR, OS, Safety Trastuzumab 6 mg/kg q3wks* + Women with Docetaxel 75–100 mg/m2 q3wks† + previously Pertuzumab 420 mg q3wks‡ Treatment until untreated, HER2+ (n = 402) disease locally recurrent or progression or Trastuzumab 6 mg/kg q3wks* + unacceptable MBC Docetaxel 75–100 mg/m2 q3wks† + toxicity (N = 808) Placebo q3wks (n = 406) Pertuzumab was FDA Approved June 2012 based on the result of the CLEOPATRA trial for first-line treatment of HER2+ MBC in combination with trastuzumab and docetaxel.*Trastuzumab 8 mg/kg loading dose given.†Minimum of 6 docetaxel cycles recommended; < 6 cycles permitted for unacceptabletoxicity or disease progression.‡Pertuzumab 840 mg loading dose given.Baselga et al, 2012; Perjeta™ prescribing information, 2012.
  • CLEOPATRA: Independently Assessed PFSBaselga et al, 2012.
  • CLEOPATRA: Response Data 100 4.2 5.5 90 80 70 ORR ORR CR Patients (%) 60 65.2 69.3% 74.6 80.2% PR 50 SD 40 PD 30 Not evaluable 20 20.8 10 14.6 1.5 1.5 8.3 3.8 0 Trastuzumab + Docetaxel Trastuzumab + + Pertuzumab Docetaxel + Placebo (n = 343) (n = 336)CR = complete response; PR = partial response; Sde = stable disease;PD = progressive disease.Baselga et al, 2012.
  • CLEOPATRA: SafetyNR = not reported.Baselga et al, 2012.
  • AVEREL: Study Design  Primary end point: PFS (investigator assessed)  Secondary end points: OS, ORR, DOR, TTF, Safety Stratified by previous (neo)adjuvant taxane, Treatment until disease progression adjuvant trastuzumab, hormone receptor status, measurable disease or unacceptable toxicity* Trastuzumab 6 mg/kg† + Docetaxel 100 mg/m2 + Women with Bevacizumab 15 mg/kg, previously all given q3wks untreated HER2+ (n = 216) locally recurrent or Trastuzumab 6 mg/kg† + MBC (N = 424) Docetaxel 100 mg/m2, both given q3wks (n = 208)*Planned minimum of 6 docetaxel cycles administered.†Trastuzumab 8 mg/kg loading dose given.OS = overall survival; DOR = duration of response; TTF = time to treatment failure.Gianni et al, 2011.
  • AVEREL: PFS, Interim OS Analysis, and Response  ORR similar between T + Doc + Bev and T + Doc in investigator assessment (74.3% vs. 69.9, respectfully; p = .3492)  ORR significantly higher for with addition of Bev in IRC assessment (76.5% vs. 65.9, respectfully; p = .0265)Gianni et al, 2011.
  • AVEREL Takeaways  Addition of bevacizumab to first-line treatment with trastuzumab and docetaxel may prolong PFS – Findings not significant according to investigator- assessed PFS (p = .0775) – Findings significant according to independent review of PFS (p = .0162)  Bevacizumab-associated AEs led to higher incidence of discontinuation of any study drugAE = adverse events.Gianni et al, 2011.
  • Case Study 3  52-yr-old postmenopausal woman presented with a 3-cm mass in the right breast, clinically LN Negative  Biopsy found a grade III invasive ductal cancer, HER2 3+ by IHC, ER 0, PR 0  At surgery sentinel node was positive leading to completion axillary dissection – Total 11/15 LNs involved  Post-operative imaging found 5 liver lesions (biopsy confirmed diagnosis of metastatic disease, ER 0, PR 0, HER2 + by FISH with ratio 13.5) – Liver enzymes and Bili normal, ECOG PS = 0ECOG = Eastern Cooperative Oncology Group; PS = performance status.
  • Case Study 3: Question 1Assuming all of these options were available,what systemic therapy would you recommend? 1) AC > TH 2) TCH 3) Docetaxel + trastuzumab + pertuzumab 4) Trastuzumab + lapatinib 5) Vinorelbine + trastuzumab
  • Case Study 3 (cont.) Sheis treated with docetaxel + trastuzumab + pertuzumab on the Cleopatra trial – She has a complete response – Docetaxel discontinued after 6 cycles, continued trastuzumab + pertuzumab
  • Key Takeaways Neoadjuvant trials suggested combined HER2 inhibition was beneficial. Similar results seen in the metastatic setting. – Improved survival with trastuzumab + lapatinib in heavily pretreated patients – Improved ORR, DFS with addition of pertuzumab in the first-line setting Combined HER2 and VEGF inhibition had less activity than was hoped
  • Key Takeaways (cont.)  T-DM1 demonstrated a CBR of 48% in heavily pre-treated patients with HER2+ metastatic disease  In the reported adjuvant trials, the risk of CHF with sequential anthracycline chemotherapy followed by trastuzumab ranged from 2%–3.8%  Older age has been consistently associated with cardiac toxicity in patients receiving adjuvant trastuzumab  In the GBG trial, ORR and PFS were improved for patients continuing trastuzumab after progressing on trastuzumab  In the neoadjuvant setting, combined pertuzumab and trastuzumab increased pCR rate with chemotherapy compared to trastuzumab + chemotherapy  Toxicities increased with the triple-drug combination pertuzumab, docetaxel, and trastuzumab. These included febrile neutropenia, diarrhea, mucosal inflammation, and skin rash.CBR = clinical benefit rate