12/4/2014
`
`Oncology Consultations™: Management of HER2-Positive Metastatic Breast Cancer
`
`Home
`
`Login
`
`Register
`
`Type a Keyword
`
`Conferences
`International Congress on Hematologic Malignancies®
`Miami Breast Cancer Conference®
`Miami Lung Cancer Conference™
`Interdisciplinary Prostate Cancer Congress®
`International Congress on the Future of Breast Cancer®
`International Lung Cancer Congress®
`International Congress on Targeted Therapies in Cancer®
`Melanoma and Other Cutaneous Malignancies
`International Symposium on Ovarian Cancer and Gynecologic Malignancies®
`School of Breast Oncology®
`Annual New York Lung Cancer Symposium®
`
`Online CME
`
`PER® Executive Board
`
`Journal
`The American Journal of Hematology/Oncology® (AJHO)
`
`Manage My CME
`
`About PER®
`PRESS
`
`View all Online CME
`View all Oncology
`Consultations CME
`
`Share a PER® activity with
`your colleagues or
`friends. Connect with the
`PER® social network.
`
`
`
`
`
`Continuing Education
`Information
`
`Physicians’ Education
`Resource®, LLC is accredited by
`the Accreditation Council for
`Continuing Medical Education to
`provide continuing medical
`education for physicians.
`
`This activity is not approved
`for AMA PRA Category 1
`Credit™.
`
`Commercial Supporter
`
`This activity is supported by an
`educational grant from
`Genentech.
`
`Oncology Consultations™: Management of HER2-Positive Metastatic Breast Cancer
`
`Resources
`
`PER Pulse™ Recap
`Three PER Pulse™ Recaps presenting key breast cancer treatment topics.
`
`PER Pulse™ Recap
`
`Medical Writer: Jennifer Klem, PhD
`
`1 of 3
`PER Pulse™ Recap
`Incorporation of Pertuzumab Into Management of HER2-Positive Metastatic Breast Cancer
`
`http://www.gotoper.com/online-cme-activities/oncology-consultations/Oncology-Consultations-Management-of-HER2-Positive-Metastatic-Breast-Cancer
`
`1/4
`
`IMMUNOGEN 2260, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Oncology Consultations™: Management of HER2-Positive Metastatic Breast Cancer
`12/4/2014
`The online CME activity, Oncology Consultations™: Management of HER2-Positive Metastatic Breast Cancer,
`featured breast cancer experts Drs. Joyce O’Shaughnessy and Sandra Swain commenting on a case of a woman
`diagnosed with early-stage breast cancer in 1998 that metastasized 3 years after adjuvant chemotherapy and tamoxifen.
`They discussed the ongoing management of that patient, as well as current therapy options if that patient were being
`treated today. This first of 3 PER Pulse™ Recaps focused on Oncology Consultations™examines the incorporation of
`pertuzumab into the management of HER2-positive metastatic breast cancer (MBC).
`
`The patient who was presented in the case study progressed to MBC after being treated in the adjuvant setting with
`chemotherapy and tamoxifen for her early-stage hormone receptor-positive disease (HER2 status unknown at the time).
`After biopsy revealed HER2-positive and hormone receptor-negative MBC, the patient was treated in the first line with
`trastuzumab plus vinorelbine; however, Dr. O’Shaughnessy pointed out that trastuzumab plus chemotherapy is no longer
`the standard of care for first-line HER2-positive MBC treatment, and the CLEOPATRA trial is the reason for this.
`
`The phase III CLEOPATRA trial was designed to evaluate dual HER2 inhibition through the addition of pertuzumab, a
`HER2-directed antibody, to trastuzumab and docetaxel for HER2-positive MBC. Results showed that the pertuzumab-
`containing regimen had a 6.1-month advantage in median progression-free survival (PFS; P < .0001), as well as an
`overall survival (OS) advantage compared with the placebo-containing regimen (median not reached in the pertuzumab
`arm; P = .0008). The toxicity profiles of the two treatment groups were similar, and Dr. Swain pointed out that cardiac
`toxicity was not increased in the pertuzumab arm, providing reassurance of the cardiac tolerability of dual HER2
`inhibition.
`
`As a result of this trial, pertuzumab plus trastuzumab plus docetaxel was approved by the US Food and Drug
`Administration, and pertuzumab plus trastuzumab plus taxane has been recommended by the National Comprehensive
`Cancer Network as a preferred regimen for the first-line treatment of HER2-positive MBC. While both Drs. Swain and
`O’Shaughnessy agreed that dual HER2 blockade is the new standard of care for first-line HER2-positive MBC, both also
`clarified that they would combine pertuzumab and trastuzumab with weekly paclitaxel, based on personal preference for
`paclitaxel over docetaxel, and based on a phase II trial of the paclitaxel-containing regimen, which showed a 76% PFS
`rate at 6 months and a favorable safety profile.
`
`In addition to being combined with trastuzumab, pertuzumab is also being studied in combination with ado-trastuzumab
`emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the cytotoxic agent DM1. The three-arm
`MARIANNE trial compares ado-trastuzumab emtansine in combination with pertuzumab or placebo versus the control
`regimen of trastuzumab combined with a taxane in patients with newly diagnosed MBC. This trial is fully accrued but is
`not expected to be completed until 2016.
`
`Drs. Swain and O’Shaughnessy also discussed the use of pertuzumab in later lines of therapy, a setting that is currently
`off-label. Dr. O’Shaughnessy explained that limited data in the relapsed/refractory setting show clinical benefit of dual
`HER2 inhibition, leading her to suggest that it is a reasonable approach to the management of relapsed/refractory HER2-
`positive MBC. However, she cautioned that randomized data might be necessary if a dual HER2 inhibition regimen is to
`become a standard of care. Dr. Swain countered that randomized data may not even be necessary, suggesting that well-
`designed phase II trials in later lines of therapy could provide sufficient evidence.
`
`For additional commentary about these topics and others, visit www.gotoper.com to access archived video of Dr. Swain
`and Dr. O’Shaughnessy from Oncology Consultations™: Management of HER2-Positive Metastatic Breast Cancer.
`
` 2
`
` of 3
`PER Pulse™ Recap
`Trastuzumab for Long-Term Non-Progressors
`
`The online CME activity, Oncology Consultations™: Management of HER2-Positive Metastatic Breast Cancer,
`featured breast cancer experts Drs. Joyce O’Shaughnessy and Sandra Swain commenting on a case of a woman
`diagnosed with early-stage breast cancer in 1998 that metastasized 3 years after adjuvant chemotherapy and tamoxifen.
`They discussed ongoing management of that patient, as well as current therapy options if that patient were being treated
`today. This second of 3 PER Pulse™ Recaps from Oncology Consultations™ focuses on the subset of patients with
`metastatic breast cancer (MBC) who derive long-term clinical benefit from trastuzumab.
`
`For patients with HER2-positive MBC, trastuzumab therapy is typically continued, alone or in combination with
`chemotherapy, until progression or unacceptable toxicity. In the observational registHER study of over 1000 patients
`with newly diagnosed HER2-positive MBC, median progression-free survival (PFS) with trastuzumab-based therapy in
`the first-line setting was 11.0 months. However, a subset of these patients has been identified that receives long-term
`clinical benefit from trastuzumab.
`
`Several case reports and retrospective studies have described patients with MBC who have maintained remissions on
`trastuzumab for durations ranging from 3 years to nearly 12 years. However, as with the patient featured in this
`Oncology Consultations™, there are multiple examples of recurrence after discontinuation of trastuzumab.
`
`Dr. O’Shaughnessy discussed how these data suggest to her that trastuzumab discontinuation for these patients is
`dangerous due to the risk of recurrence, but she acknowledged that other clinicians have interpreted these data
`differently. She shared an example of a clinician who realized that following discontinuation after receiving long-term
`benefit from trastuzumab, patients could quickly return to a complete remission upon reintroduction of trastuzumab and
`chemotherapy. Moreover, these patients typically showed no new organ sites of metastases upon recurrence, leading the
`clinician to conclude that this break from trastuzumab is not harmful to the patient and can be viewed instead as
`http://www.gotoper.com/online-cme-activities/oncology-consultations/Oncology-Consultations-Management-of-HER2-Positive-Metastatic-Breast-Cancer
`
`2/4
`
`IMMUNOGEN 2260, pg. 2
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`12/4/2014
`intermittent therapy.
`
`Oncology Consultations™: Management of HER2-Positive Metastatic Breast Cancer
`
`As Dr. Swain mentioned, little is known about the clinicopathologic features associated with patients who derive long-
`term clinical benefit from trastuzumab therapy, and efforts need to be made to collect and analyze tumor tissues from
`these patients to search for molecular predictors of long-term benefit. A recent retrospective study of 164 patients
`receiving trastuzumab for advanced HER2-positive breast cancer discovered that prolonged trastuzumab treatment
`duration, a surrogate for trastuzumab benefit, was associated with hormone receptor-positive disease (P = .032) and a
`reduced likelihood of having received adjuvant trastuzumab (P = .043).
`
`An important concern regarding the long-term use of trastuzumab is the cardiac tolerability of this approach. This drug
`is associated with cardiac toxicity, but most trastuzumab-related cardiac events are manageable and reversible, and they
`can be mitigated by careful patient selection and close monitoring. Moreover, patients who receive trastuzumab beyond
`progression (often for a prolonged period of time) have infrequent and primarily asymptomatic cardiac events.
`
`For additional commentary about these topics and others, visit www.gotoper.com to access archived video of Dr. Swain
`and Dr. O’Shaughnessy from Oncology Consultations™: Management of HER2-Positive Metastatic Breast Cancer.
`
` 3
`
` of 3
`PER Pulse™ Recap
`Treatment of Relapsed or Refractory HER2-Positive MBC
`
`The online CME activity, Oncology Consultations™: Management of HER2-Positive Metastatic Breast Cancer,
`featured breast cancer experts Drs. Joyce O’Shaughnessy and Sandra Swain commenting on a case of a woman
`diagnosed with early-stage breast cancer in 1998 that metastasized 3 years after adjuvant chemotherapy and tamoxifen.
`They discussed the ongoing management of this patient, as well as current therapy options if that patient were being
`treated today. This third and final PER Pulse™ Recap from Oncology Consultations™ focuses on the treatment of
`relapsed or refractory HER2-positive metastatic breast cancer (MBC).
`
`The patient who was presented in the case study was treated with trastuzumab and chemotherapy in the first line for her
`HER2-positive MBC. After 4 years of combination therapy and 6 more of trastuzumab alone, the patient discontinued
`all treatment and developed a solitary liver metastasis within 12 months. She then initiated pertuzumab plus trastuzumab
`plus nab-paclitaxel and has tolerated this regimen well. As discussed in the first PER Pulse™ Recap of this Oncology
`Consultations™, dual inhibition with pertuzumab and trastuzumab is approved in the first-line setting for HER2-positive
`MBC, but this use of pertuzumab in the second line is off-label. Were this patient treated for newly diagnosed HER2-
`positive MBC today, she would likely have received a pertuzumab/trastuzumab-containing regimen upfront, and then
`moved to a different HER2-targeted regimen upon progression.
`
`The value of continuing HER2 inhibition beyond progression has now been firmly established, and several such
`regimens can be used in the relapsed/refractory setting. The first of these to be approved was lapatinib plus capecitabine,
`a regimen indicated for trastuzumab-resistant disease based on a 4.0-month improvement in median time-to-progression
`(TTP) compared with capecitabine alone. Dr. O’Shaughnessy commented that with the recent approvals of pertuzumab,
`T-DM1 (ado-trastuzumab emtansine), and the new indication for lapatinib plus trastuzumab, she prefers to use lapatinib
`plus capecitabine primarily in patients with brain metastases. She further clarified that she tries to use it before patients
`undergo whole-brain radiation therapy (WBRT) because the LANDSCAPE trial demonstrated a much greater response
`rate in these patients than did the combination as reported by Nancy Lin and colleagues in patients after WBRT. Dr.
`Swain cautioned that the CEREBEL trial showed no advantage for using lapatinib over trastuzumab in patients with
`newly diagnosed brain metastases, a fact that has made her reconsider her use of lapatinib in this setting.
`
`The antibody-drug conjugate T-DM1 earned its FDA approval for relapsed/refractory disease from the phase III
`EMILIA trial, which showed a 3.2-month improvement in median progression-free survival (PFS) and a 5.8-month
`improvement in median overall survival (OS) with T-DM1 compared with lapatinib/capecitabine in the
`relapsed/refractory advanced disease setting. Dr. Swain emphasized the excellent safety profile with T-DM1, saying that
`toxicities are minimal. Dr. O’Shaughnessy added that cardiac toxicity with T-DM1 is no different than would be
`expected from trastuzumab. The National Comprehensive Cancer Network (NCCN) breast cancer guidelines list T-DM1
`as the preferred treatment option for taxane- and trastuzumab-exposed HER2-positive disease.
`
`Other regimens recommended by the NCCN for relapsed/refractory HER2-positive MBC are combination regimens that
`include continuation of trastuzumab. Trastuzumab plus capecitabine is one example that has shown significantly greater
`response rates and prolonged TTP compared with capecitabine alone in this setting. Another is lapatinib plus
`trastuzumab, which has demonstrated both a significant but modest median PFS benefit (< 1 month; P = .011) and a
`significant and substantial median OS benefit (4.5 months; P = .026) compared with lapatinib alone. As might be
`expected, serious adverse events were more frequent in the combination arm, but the overall incidence of symptomatic
`cardiac events was low in both arms. Dr. O’Shaughnessy commented that she favors this treatment in later lines of
`therapy for patients with less tumor burden and more indolent disease because it lacks a cytotoxic agent.
`
`The final regimen to be discussed for trastuzumab-resistant MBC is everolimus in combination with trastuzumab and
`vinorelbine, which was examined in the BOLERO-3 trial. The addition of everolimus produced a modest 1.2-month
`improvement in median PFS, and OS data are still immature. However, Dr. O’Shaughnessy was impressed with the
`improvement in PFS among patients with estrogen receptor-negative disease (HR = 0.65), so she has added it to her list
`of therapeutic options for that patient population. She also mentioned that since everolimus penetrates the central
`nervous system (CNS), she will also consider this regimen in patients with CNS disease.
`
`http://www.gotoper.com/online-cme-activities/oncology-consultations/Oncology-Consultations-Management-of-HER2-Positive-Metastatic-Breast-Cancer
`
`3/4
`
`IMMUNOGEN 2260, pg. 3
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Oncology Consultations™: Management of HER2-Positive Metastatic Breast Cancer
`12/4/2014
`For additional commentary about these topics and others, visit www.gotoper.com to access archived video of Dr. Swain
`and Dr. O’Shaughnessy from Oncology Consultations™: Management of HER2-Positive Metastatic Breast Cancer.
`
`
`
`Physicians' Education Resource®, LLC is accredited by the Accreditation Council for Continuing Medical Education to
`provide continuing medical education for physicians.
`
`This activity is not approved for AMA PRA Category 1 Credit™.
`
`Supported by an educational grant from Genentech.
`
`Our Mission | Accreditation | Privacy Policy | Terms & Conditions of Use | Contact PER®
`
`
`Copyright © 2014 Physicians' Education Resource®, LLC. All rights reserved.
`Contact PER®
`Physicians' Education Resource®, LLC
`666 Plainsboro Rd. Suite 356
`Plainsboro, NJ 08536
`
`Phone (609) 378-3701
`Fax (609) 257-0705
`info@gotoper.com
`
`
`
`http://www.gotoper.com/online-cme-activities/oncology-consultations/Oncology-Consultations-Management-of-HER2-Positive-Metastatic-Breast-Cancer
`
`4/4
`
`IMMUNOGEN 2260, pg. 4
`Phigenix v. Immunogen
`IPR2014-00676
`
`