Raising the Bar in HER2-Positive Breast Cancer: Improving...

Kimberly L. Blackwell, MD

Course Director

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CME Raising the Bar in HER2-Positive Breast Cancer: Improving Patient Outcomes in the Neoadjuvant Setting

Message From the Course Director

Dear Colleague,

With the recent advances in HER2-directed therapies, HER2-positive breast cancers have become highly treatable in both the neoadjuvant and adjuvant clinical settings. Clinicians should seek to select the most appropriate HER2-directed agents and combinations in early-stage disease and provide individualized care in the neoadjuvant setting. Optimal patient selection, timing of therapy initiation, and selection of therapeutic options, including combination approaches, are important factors to consider.

Please join me in this two-part CME activity where I will examine contemporary evidence and best practice recommendations related to the management of patients with HER2-positive breast cancer in the neoadjuvant setting. In addition, I will discuss interdisciplinary collaboration strategies to maximize patient outcomes. I hope you find this educational activity useful in your daily practice.

Sincerely,

Kimberly L. Blackwell, MD

www.peerviewpress.com/QSA900

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Activity Information

Activity Description and Educational ObjectivesIn this activity, a breast cancer expert discusses the neoadjuvant treatment of patients with HER2-positive breast cancer.

Upon completion of this activity, participants should be better able to:• Discuss the efficacy and safety results from neoadjuvant clinical trials

evaluating current and emerging strategies for HER2-positive breast cancer• Summarize ongoing neoadjuvant clinical trials evaluating strategies for

HER2-positive breast cancer• Select HER2-targeting agents and potential combination therapies for

patients with HER2-positive breast cancer in the neoadjuvant setting according to latest evidence and guideline recommendations

• Develop strategies for effective interdisciplinary collaboration to maximize patient outcomes in the neoadjuvant setting

Target Audience This activity has been designed to meet the educational needs of oncologists, hematologist-oncologists, and other clinicians involved in the management of patients with breast cancer.

Requirements for Successful Completion In order to receive credit, participants must view the activity and complete the post-test and evaluation form. A score of 70% or higher is needed to obtain CME credit. There are no pre-requisites and there is no fee to participate in this activity or to receive CME credit. Statements of Credit are awarded upon successful completion of the post-test and evaluation form.

Media: Enduring MaterialRelease and Expiration Dates: July 21, 2016 - July 20, 2017Time to Complete: 30 minutes

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The associates of Medical Learning Institute, Inc., the accredited provider for this activity, and PVI, PeerView Institute for Medical Education do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME activity for any amount during the past 12 months.

Course DirectorKimberly L. Blackwell, MD Professor of Medicine Assistant Professor of Radiation Oncology Duke University Medical Center Duke Cancer Institute Durham, North Carolina

Kimberly L. Blackwell, MD, has a financial interest/relationship or affiliation in the form of: Consultant for F. Hoffmann-La Roche Ltd; Incyte Corporation; and Sandoz. Grant/Research Support from Celgene Corporation; Genentech, Inc.; Novartis Pharmaceuticals Corporation; and Pfizer Inc. Advisory Board for Amgen Inc.; Celgene Corporation; Eli Lilly and Company; Genentech, Inc.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; and Spectrum Pharmaceuticals, Inc.

Kimberly L. Blackwell, MD, does intend to discuss either non–FDA-approved or investigational use for the following products/devices: Targeted agents used as neoadjuvant therapy for HER2-positive breast cancer.

CME ReviewerVijaya R. Bhatt, MD University of Nebraska Medical Center Omaha, Nebraska

Vijaya R. Bhatt, MD, has no financial interests/relationships or affiliations in relation to this activity.

Medical DirectorKathryn B. Charalambous, PhD PVI, PeerView Institute for Medical Education

Kathryn B. Charalambous, PhD, has no financial interests/relationships or affiliations in relation to this activity.

DisclaimerThe information provided at this CME activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient's medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this program should be inferred.

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The Medical Learning Institute, Inc. designates this enduring material for a maximum of 0.5 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

ProvidershipThis CME activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education.

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3

Raising the Bar in HER2-Positive Breast Cancer: Improving Patient Outcomes in the Neoadjuvant Setting

Dr. Blackwell: Hi, I'm Kim Blackwell from Duke University Medical Center and the Duke Cancer Institute in Durham, North Carolina. I want to welcome you to this educational activity on HER2-positive breast cancer. After completing this activity, you can access the post-test and evaluation form by clicking the red "Get Certificate" button. I encourage you to download the slides, Practice Aids, and any other activity features that may interest you.

The first clinical trial of trastuzumab + chemotherapy showed significantlyimproved OS in patients with metastatic HER2+ BC2

Similar survival benefits were seen with trastuzumab in patients withearly-stage, locally advanced HER2+ BC,3-6 revolutionizing themanagement of HER2+ BC in adjuvant and neoadjuvant settings

Introduction1

1. Gollamudi J et al. Cancer Manag Res. 2016;8:21-31.2. Slamon DJ et al. N Engl J Med. 2001;344:783-792.3. Gianni L et al. Lancet. 2010;375:377-384.4. Piccart-Gebhart MJ et al. N Engl J Med. 2005;353:1659-1672.5. Slamon D et al. N Engl J Med. 2011;365:1273-1283.6. Tolaney SM et al. N Engl J Med. 2015;372:134-141.

Historically, HER2-positive breast cancers were considered to be the most aggressive female cancers, due to the hyperactivation of HER2 and its signaling systems in breast cancer cells. However, with the recent advent of HER2-directed therapies, this breast cancer subtype has become highly treatable in both the neoadjuvant and adjuvant clinical settings.

The first clinical trial that combined trastuzumab with chemotherapy showed significantly improved overall survival in patients facing metastatic HER2-positive breast cancers. Likewise, administering trastuzumab to patients with early-stage and locally advanced HER2-positive breast cancers demonstrated similar survival benefits, therefore revolutionizing the management of this type of breast cancer in both the adjuvant and the neoadjuvant settings.

Pertuzumab

T-DM1Trastuzumab

Lapatinib

Ligand

HER1

HER1/3/4HER2HER2

HER2

Endosome

Cytoplasm

Nucleus

Transcription downstreamCellular effects Proliferation, survival,

invasion, angiogenesis

Antibody

RAS

RAF

MEK

Pl3K

AKT

mTOR

ERK

DM1

DM1

Targeting the HER2 Family1

1. Teplinsky E, Jhaveri K. http://www.onclive.com/publications/contemporary-oncology/2014/February-2014/Antibody-Drug-Conjugates-and-T-DM1. Accessed June 9, 2016.

Because of the proven successes of trastuzumab, in other words, it was shown to improve survival in the metastatic and adjuvant setting, we've now discovered many other novel ways to target the HER2 family. Let's discuss neoadjuvant therapy for HER2-positive breast cancer and where the current evidence is.

Neoadjuvant Therapy for HER2-Positive Breast Cancer: Current Evidence

Kimberly L. Blackwell, MDDuke University Medical Center Duke Cancer Institute Durham, North Carolina



• Tumor downstaging in LABC and IBC – Inoperable → operable – Mastectomy → breast conservation• ↓ likelihood of positive axillary lymph nodes

• In vivo tumor response assessment – Identify unresponsive tumors and terminate ineffective therapy – Provide prognostic information• Ideal scenario to study tumor biomarkers and intermediate endpoints

ClinicalBenefits

Research/Drug DevelopmentBenefits

Rationale for Neoadjuvant Treatment

Well, the rationale for giving neoadjuvant treatment, or treatment before surgery, includes many clinical benefits. These include downstaging or shrinking the tumor in the locally advanced or the inflammatory breast cancer setting, turning an inoperable tumor into an operable tumor; converting someone who would need a mastectomy to breast conservation; and finally, for patients who have large axillary lymph node involvement, there's a decreased likelihood of having positive lymph nodes remaining.

Now the neoadjuvant setting also offers many research or drug development benefits—and these include an in vivo assessment of whether or not the treatment is working. A response to neoadjuvant therapy provides important prognostic information. And more on a societal basis, the neoadjuvant setting allows us to study promising tumor biomarkers and really quick turnaround endpoints for drug development.

• As part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel• With docetaxel and carboplatin• As a single agent following multimodality anthracycline-based treatment

Adjuvant Treatment of HER2-Overexpressing, Node-Positive orNode-Negative (ER-/PR- or with 1 high-risk feature) BC

• In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic BC• Single agent for treatment of HER2-overexpressing BC in patients who received ≥1 chemotherapy regimen for metastatic disease

Metastatic BC

Trastuzumab1

1. Herceptin (trastuzumab) Prescribing Information. http://www.gene.com/download/pdf/herceptin_prescribing.pdf. Accessed June 9, 2016.

So trastuzumab, our old friend, is a HER2-receptor antibody or antagonist, and it is indicated for the adjuvant treatment of HER2-overexpressing node-positive or node-negative breast cancer. It should be included as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel, or a non-anthracycline regimen such as docetaxel/carboplatin, or it can be used as a single agent following anthracycline-based therapy.

In the metastatic setting, trastuzumab is used in combination with paclitaxel—or is indicated in combination with paclitaxel—for the first-line treatment of HER2-overexpressing metastatic breast cancer, or as a single agent for the treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease.

a pCR (no invasive or in situ tumor in breast and nodes).

Trial Regimen Duration,wk pCR, % P

MDACC1

(N = 42)T → FEC

TH → FEC/H24 24

26 65.2

.016

NOAH2,3

(N = 235)AT → T → CMF

AT/H → TH → CMF/H35 35

22 43

.0007

GEPAR-QUATTRO4

(N = 445)

EC/H → DHEC/H → DXH

EC/H → DH → XH

24 24 36

32.9a

31.3a

34.6aNR

Neoadjuvant Trials ± Trastuzumab: pCR

1. Buzdar AU et al. J Clin Oncol. 2005;23:3676-3685.2. Gianni L et al. Lancet. 2010;375:377-384.3. Gianni L et al. Lancet Oncol. 2014;15:640-647.4. Untch M et al. J Clin Oncol. 2010;28:2024-2031.

We already discussed the clinical and research benefits of using trastuzumab in the neoadjuvant setting, and now we're going to examine the endpoints of pathologic complete response across a portfolio of neoadjuvant trials that have been performed.

So the MD Anderson study—when trastuzumab was added to an anthracycline/taxane regimen, the complete pathologic response rate was 65.2% compared to 26% in patients who did not receive neoadjuvant trastuzumab. This was a very important early study because it really demonstrated the benefits of adding trastuzumab in the neoadjuvant setting. Likewise, the NOAH study, looked at trastuzumab with chemo or chemotherapy alone. And as you can see, the complete pathologic response rate was 43% in those women that received trastuzumab compared to 22% in those women who did not, highly statistically significant. And


5


then finally, the German Cooperative Group, in a study known as GEPAR-QUATTRO, looked at trastuzumab in combination with chemotherapy in the neoadjuvant setting. And what you can see is that the pathologic complete response rate, meaning no tumor left, was somewhere between 31.3% and 34.6%, demonstrating that if you incorporate trastuzumab in the neoadjuvant setting, one out of three women just in general will have no invasive disease left at the completion of their neoadjuvant therapy.

So these are the three studies that historically set a standard for not only utilizing trastuzumab in the preoperative setting on top of a chemotherapy backbone, but also being able to establish a marker of efficacy, in this case a complete pathologic response.

Updated Results From NOAH: 5-Year EFS1

pCR was associated with EFS at 5 years in patients who received chemotherapy + trastuzumab vs chemotherapy alone

00

20

40

60

80

100

12

EFS,

%

Months24 36 48 60 72

49 (42) 62 (53)

Chemo + H(n = 117)

Chemo(n = 118)

58 (48-66) 43 (34-52)

84

117 110

Events, n (%)

Chemotherapy + HChemotherapy

5-y EFS, % (95% CI)

88 77 66 56 43 24118

Chemo + Hn at risk

Chemo 98 69 55 49 39 28 14

Fewer deaths in the trastuzumab group with the majority being from BC progression and recurrence

HR 0.64 (95% Cl, 0.44-0.93)Log rank P = .016

1. Gianni L et al. Lancet Oncol. 2014;15:640-647.

In 2014, Luca Gianni, on behalf of his colleagues, reported the updated results from the primary analysis of the NOAH. This is the neoadjuvant trastuzumab study, and really examined the long-term benefits of adding trastuzumab to neoadjuvant chemotherapy.

After median follow-up of 5.4 years, the event-free survival benefit from the addition of trastuzumab to chemotherapy was maintained in patients with HER2-positive breast cancer. For those patients who only received chemotherapy, the event-free survival was only 43% at five years, compared to a 58% 5-year event-free survival in the patients who received both chemotherapy and trastuzumab. More importantly, and as a demonstration of the importance of the neoadjuvant platform, event-free survival strongly was associated with a complete pathologic response in those patients who received trastuzumab. At the time of this final analysis from 2014, fewer patients had died in the trastuzumab group than in the chemotherapy-alone group. And as we're all interested, the majority of the deaths came from breast cancer progression and recurrence.

Pertuzumab1

Trastuzumab HER2

Pertuzumab HER1/3/4

Intracellulardomain

Subdomain II(“dimerization

domain”) Subdomain IV

1. O'Sullivan CC, Connolly RM. Oncology (Williston Park). 2014;28:186-194, 196.

Trastuzumab, at least in combination with chemotherapy, has a demonstrated benefit in the neoadjuvant setting and really set the stage for newer drugs that target HER2. One of these drugs is known as pertuzumab, and pertuzumab is very similar to trastuzumab in that it's a recombinant humanized monoclonal antibody directed at the extracellular domain of HER2. Its main mechanism of action is it prevents dimerization of HER2 with other HER family members, such as HER3 and HER1. By blocking this heterodimerization, this results in inhibited downstream signaling of two pathways, primarily apoptosis and growth and/or proliferation. In addition, this antibody pertuzumab—very similar to trastuzumab—has been demonstrated to augment antibody-dependent cellular-mediated cytotoxicity.

Neoadjuvant Trials Evaluating Addition of Pertuzumabto Trastuzumab: pCR

Trial Regimen Duration, wk pCR, % P

NeoSphere1

(N = 417)

DH PDH PH PD

12

29.0 (breast) 45.8 (breast) 24.0 (breast) 16.8 (breast)

.0141

TRYPHAENA2

(N = 225)

PH/FEC → PDHFEC → PDHDCarboHP

24 61.6 (breast) 57.3 (breast) 66.2 (breast)

NE

1. Gianni L et al. Lancet Oncol. 2012;13:25-32.2. Schneeweiss A et al. Ann Oncol. 2013;24:2278-2284.



So pertuzumab, just like its predecessor trastuzumab, has been studied in the neoadjuvant setting. And we can utilize a complete pathologic response rate to determine whether or not it's effective in this setting.

NeoSphere: Study Design and pCR Results1

DH

2026

63.2

36.8

5.9

27.330

17.4

PDH PH PD

DH PDH PH PD

DH (n = 107)D (75 → 100 mg/m2)H (8 → 6 mg/kg)

PDH (n = 107)P (840 → 420 mg)D (75 → 100 mg/m2)H (8 → 6 mg/kg)

PH (n = 107)P (840 → 420 mg)H (8 → 6 mg/kg)

PD (n = 96)P (840 → 420 mg)D (75 → 100 mg/m2)

Operable or locally advanced/inflammatorya

HER2+ BC

Chemo-naïveand primarytumors >2 cm(N = 417)

Study dosing: Q3W x 4

SURGERY

0

10

20

30

40

50

60

01020304050607080

tpCRbpCR

HR-HR+

bpC

R, %

± 9

5% C

IpC

R, %

± 9

5% C

I24

17.7

11.216.8

39.3

45.8

P = .0141 P = .003

P = .0198

21.5

29

a Operable = T2-3, N0-1, M0; LABC = T2-3, N2-3, M0 or T4ac, any N, M0; IBC = T4d, any N, M0.

1. Gianni L et al. Lancet Oncol. 2012;13:25-32.

So there are two large studies. The first study is known as the NeoSphere study, and again Luca Gianni led the way with this neoadjuvant study. This is a four-arm study and, the highest complete pathologic response was when pertuzumab was given in combination with trastuzumab and docetaxel. The complete pathologic response rate in this winning arm of the NeoSphere study was 45.8%. And somewhat disappointingly, the pathologic complete response to the two-antibody combination of pertuzumab and trastuzumab led to the lowest rates of complete pathologic response, 16.8% in the breast alone, and 11.2% if you look at clearance of both the breast and the axilla.

The NeoSphere study really demonstrated that you could layer on pertuzumab on top of trastuzumab and docetaxel and get a higher complete pathologic response compared to the docetaxel and trastuzumab or the historical control arm.

a Takes into account all follow-up. b 3 late events occurred: 2 cases of progressive disease at 63 and 71 mo; 1 death due to an unrelated CVA without progressive disease at 76 mo. c 2 late events occurred: 1 case of progressive disease at 67 mo; 1 death due to an unrelated CVA without progressive disease at 72 mo. d 1 late event due to progressive disease at 71 mo. e 1 death due to an unrelated CVA without progressive disease at 76 mo.

NeoSphere: Conclusions1,a

DH (n = 107)

PDH (n = 107)

PH (n = 107)

PD (n = 96)

5-y PFS, % (95% CI) 81 (71-87) 86 (77-91)b 73 (64-81) 73 (63-81)

5-y DFS, % (95% CI) 81 (72-88) 84 (72-91)c 80 (70-86) 75 (64-83)

tpCR No tpCR

5-y PFS, % (95% CI)

All Treatment Arms Combined, ITT Population

Subgroup Analysis, ITT Population

76 (71-81)d 85 (76-91)e

No new or long-term safety concerns, and no additional cardiotoxicity

with PDH

1. Gianni L et al. J Clin Oncol. 2015;33(suppl):abstr 505.

Now at ASCO in 2015, Dr. Gianni looked at the long-term results of NeoSphere. Now it's important to recognize that the primary endpoint of NeoSphere was the pathologic complete response but this was always a planned analysis. And what this outcomes analysis showed was that the combination of pertuzumab, trastuzumab, plus docetaxel had the best long-term outcomes and although the point estimates are consistent with the relationship with the pathologic complete response, there was no statistically significant difference between the four arms of the study. However, when you examine the estrogen receptor–negative patients, there appeared to be an even larger improvement in outcome as it correlated with their upfront pathologic complete response.

So I think where NeoSphere really set the standard was the addition of pertuzumab to standard chemotherapy and trastuzumab-based neoadjuvant therapy. But it also set a new standard that if we see a higher complete pathologic response in the neoadjuvant setting, that translates to improvement in outcome.

And finally, we did not see any safety signal with the addition of pertuzumab to standard chemotherapy and trastuzumab. And really NeoSphere set the standard for one of the reasons why pertuzumab is currently available in this setting.


7


HER2+ EBCcentrallyconfirmed(N = 225)

FEC

H to complete

1 y

D Cycles 1-3

• All 3 arms were experimentalCycles 4-6

HP

HP

FEC D

Carbo

D HP

C

B

A

500 mg/m2, 100 mg/m2, 600 mg/m2

AUC 6

8 mg/kg loading dose, 6 mg/kg maintenance

840 mg loading dose, 420 mg maintenance

75 mg/m2 (escalating to 100 mg/m2 if tolerated, in arms A and B only)

Study Dosing Q3W

SURGERY

H

P

FEC

Carbo

D

TRYPHAENA: Study Design1

1. Schneeweiss A et al. Ann Oncol. 2013;24:2278-2284.

Now the second neoadjuvant study looking at the addition of pertuzumab or the use of pertuzumab is known as TRYPHAENA. Now this was a multicenter, phase 2 study looking at early-stage breast cancer or locally advanced or inflammatory breast cancer. And the primary purpose of the TRYPHAENA study was to look at the feasibility or the tolerability of pertuzumab/chemotherapy combinations in the neoadjuvant setting.

TRYPHAENA: pCR Results1

pCR

, %

FEC/HP x 3 →DHP x 3(n = 73)

FEC x 3 →DHP x 3(n = 75)

DCarboHP x 6(n = 77)

0

20

40

60

80

100

61.6

ypT0/is

50.757.3

45.3

66.2

51.9

ypT0 ypN0


And as you can see, the complete pathologic response rate in the TRYPHAENA study was quite high in all three arms. The highest arm for complete pathologic response was the docetaxel/carboplatin, trastuzumab, and pertuzumab arm, giving us a pathologic complete response of 66.2% compared to 61.6% and 57.3% complete pathologic response rates with the anthracycline-containing regimens.

So my take on the TRYPHAENA study is that close to two out of three patients had a complete pathologic response rate when pertuzumab was added to trastuzumab. And if you remember just a few minutes ago, we said about one out of three patients achieved a complete pathologic response with the addition of trastuzumab.

Therefore these two studies, both the NeoSphere study and the TRYPHAENA study really demonstrated a significant improvement in complete pathologic response rate when pertuzumab was added to the regimens.

TRYPHAENA: Cardiac Events During Neoadjuvant Treatment1

FEC/HP x 3 →

DHP x 3(n = 72)

FEC x 3 → DHP x 3(n = 75)

DCarboHP x 6

(n = 76) Symptomatic LVSD(grade ≥3), n (%) 0 (0.0) 2 (2.7) 0 (0.0)

LVSD (all grades), n (%) 4 (5.6) 3 (4.0) 2 (2.6)

LVEF decline ≥10% points and <50%, n (%) 3 (4.2) 4 (5.3) 3 (3.9)


One of the primary endpoints of TRYPHAENA was to look at cardiac safety. And somewhat reassuringly, the cardiac events in the TRYPHAENA study, even when the pertuzumab and trastuzumab are given concurrent with the anthracycline, were quite low. There were only two patients who actually developed grade 3/4 left ventricular systolic dysfunction and that was actually when the HER2-targeted agents were not given concurrent with anthracycline, suggesting that the addition of pertuzumab to trastuzumab and chemotherapy does not add anything to the signal.



Indicated for use in combination with DH as neoadjuvant treatment ofpatients with HER2+ locally advanced, inflammatory, or early-stage BC(either >2 cm in diameter or node positive) as part of a completetreatment regimen for EBC

• 4 preoperative cycles of PDH followed by 3 postoperative cycles of FEC• 3 preoperative cycles of FEC alone followed by 3 preoperative cycles of PDH• 6 preoperative cycles of DCarboHP (escalation of D above 75 mg/m2

not recommended)

Administer Q3W for 3-6 cycles as part of 1 of the following treatmentregimens for EBC:

Pertuzumab Approved as Neoadjuvant Treatment for HER2+ BC1

1. Perjeta (pertuzumab) Prescribing Information. http://www.gene.com/download/pdf/perjeta_prescribing.pdf. Accessed May 10, 2016.

So how is pertuzumab actually approved throughout the United States? Well, it's approved as neoadjuvant treatment for HER2-positive breast cancer, and its indication is in use in combination with trastuzumab and docetaxel in the neoadjuvant setting for patients who have early-stage or locally advanced or inflammatory breast cancer.

I should point out that trastuzumab and pertuzumab are not interchangeable and that the indication really is to add pertuzumab to trastuzumab. Pertuzumab by itself hasn't been approved outside of in combination with trastuzumab.

“A pertuzumab-containing regimen may be administered preoperativelyto patients with ≥T2 or ≥N1, HER2+ BC”

NCCN: more aggressive stand on addition of pertuzumab to neoadjuvantor adjuvant therapy for patients with EBC

NCCN: Role of Pertuzumab1

1. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines). Breast Cancer. Version 2.2016.

Many of us use guidelines in considering regimens for our patients, including the National Comprehensive Cancer Network, or the NCCN, guidelines. The NCCN guidelines basically recommend the addition of pertuzumab to neoadjuvant or adjuvant therapy for patients with early-stage breast cancer. And in fact, in the guidelines it stated that a pertuzumab-containing regimen may be administered preoperatively to patients with either greater than T2—meaning greater than 2-centimeter tumor—or node-positive, HER2-positive breast cancer.

a Neoadjuvant treatment will take ~20 wks in cohort A and ~24 wks in cohort B.

Primary outcome measures• Incidence of cardiac events as assessed by investigator using NCI CTCAE v. 4.0

• Changes in LVEF assessed by echocardiogram or MUGA scan

ddAC Q2W x 4

T QW x 12

P 840 mg → 420 mgQ3W

H 8 mg/kg → 6 mg/kgQ3W

P 840 mg → 420 mgQ3W


P 420 mgQ3W

H 6 mg/kgQ3W

D Q3W x 4

P 840 mg → 420 mgQ3W


FEC Q3W x 4

Follow-up

Follow-up

Follow-up

Follow-up

Cohort A

Cohort B

Investigatorchoice

SURGERY

SURGERY

Ongoing Pertuzumab Trial: BERENICE1,a

1. https://clinicaltrials.gov/ct2/show/NCT02132949. Accessed June 9, 2016.

What should we expect over the next couple years as far as helping us understand even further the role of pertuzumab in the treatment of early-stage breast cancer? Well, I think there are two important studies.

So the BERENICE study is a multicenter, open-label, phase 2 study to evaluate the safety and efficacy of pertuzumab in combination with trastuzumab and anthracycline-based chemo as part of neoadjuvant therapy in women facing HER2-positive locally advanced, inflammatory, or early-stage breast cancer.

I think that this is an important study because it gives us the information we got from TRYPHAENA for pertuzumab, but in a more practical way, which is most of us, when we utilize an anthracycline, we use it in a sequential fashion.

So it's kind of a complicated schema, but the net is it's a two-arm study looking at the feasibility of an anthracycline-based regimen followed by a taxane, pertuzumab, and trastuzumab.

The primary outcomes of the BERENICE study include cardiac events, as assessed by the investigator, and also long-term follow-up, including patients who go on to get pertuzumab and trastuzumab.


9


T-DM1: Mechanism of Action1

Benefits of T-DM1

• Mild to moderate elevation in liver enzymes (5%-10% of patients)

• Mild to moderate increase in thrombocytopenia

• <1% incidence of nausea and vomiting

• No hair loss associated with T-DM1

P

P P

HER2

Emtansinerelease

Inhibition ofmicrotubule

polymerization

T-DM1

Nucleus

Internalization

Lysosome

1. Adapted from: LoRusso PM et al. Clin Cancer Res. 2011;17:6437-6447.

Dr. Blackwell: Now T-DM1 is the first antibody-drug conjugate approved for the treatment of any solid tumor in the United States and really throughout the world at this point. And it is a combination of our old friend trastuzumab linked to a cytotoxin, in this case DM1, a derivative of maytansine.

So I do tend to think of these ADCs [antibody-drug conjugates] just like carrier pigeons. They get in, they release their drug. And what's interesting about the ADCs is that, at least in the case of T-DM1, you still maintain free trastuzumab levels like you would if you were giving it outside of the antibody-drug conjugate.

Obviously delivering chemo or cytotoxics only to the cancer cells that have HER2 on their surface means that you're only delivering chemotherapy to the cancer cells themselves. And so what we see, even though it is chemotherapy, it's chemotherapy bound to trastuzumab, and therefore we see a very tolerable safety profile.

We can see a mild to moderate elevation in liver enzymes that occurs in somewhere between 5%-10% of patients. And you can see a mild to moderate, meaning grade 2 to 3 thrombocytopenia in patients receiving T-DM1. But other than that, there is really less than 1% incidence of nausea and vomiting. And probably most important for patients facing early-stage breast cancer, there's no hair loss associated with T-DM1.

• Primary endpoint: pCR (ypT0is, ypN0)• Secondary endpoints: EFS, IDFS, OS, rate of breast-conserving surgery, safety

• Treatment with T-DM1/P led to pCR in 44.4% of women, but DCarboH/P yielded a significantly higher pCR rate• T-DM1/P had a notably better safety profile, and HRQOL and physical functioning were maintained longer

RHER2+ Clinical stage II-III

(N = 432)

DCarboH/P

T-DM1/P

H/P

T-DM1/P

Phase 2 Study of T-DM1/P vs DCarboH/P

SURGERY

Ongoing Pertuzumab Trial: KRISTINE1

1. Hurvitz SA et al. J Clin Oncol. 2016;34:abstr 500.

Now the second study that I think is also going to be useful is the KRISTINE study. And this was a randomized, multicenter, open-label, two-arm study comparing a newer agent, T-DM1, plus pertuzumab to what has already been firmly established—chemotherapy, trastuzumab, and pertuzumab—in the treatment of early-stage, HER2-positive breast cancer.

Like all of the neoadjuvant studies we've discussed today, one of the primary outcome measures is a complete pathologic response rate with long-term outcomes to include event-free survival and overall survival, as well as the rate of breast conservation therapy, given that it was a preoperative therapy.

So KRISTINE's important because it will help us understand not only the role of docetaxel, carboplatin, trastuzumab, and pertuzumab, which is my standard neoadjuvant regimen currently, and comparing that with the T-DM1, pertuzumab regimen, which really does have some potential benefits, including the absence of hair loss.

Narrator: Results presented at ASCO 2016 showed that while treatment with T-DM1 plus pertuzumab led to a pathologic complete response in 44.4% of women, docetaxel/carboplatin with trastuzumab and pertuzumab yielded a significantly higher pathologic complete response rate. However, T-DM1 plus pertuzumab had a notably better safety profile, and health-related quality of life and physical functioning were maintained longer.



So what did the ADAPT show us in terms of complete pathologic response rates? In the T-DM1 monotherapy arm, the complete pathologic response rate was 41.0% and when endocrine therapy was layered on top of the T-DM1, the complete pathologic response rate was 41.5%, suggesting that adding endocrine therapy on top of HER2-based therapies does not achieve a lot more in terms of a complete pathologic response. And even more surprising is how ineffective the combination of trastuzumab and endocrine therapy were in the third arm of the study, where a complete pathologic response rate was only 15.1%.

My conclusions about the ADAPT study were that T-DM1 as a single agent led to very high complete pathologic response rates. That adding endocrine therapy on top of HER2-targeted agents really doesn't add much. And I think we're anxiously awaiting the long-term and secondary outcomes of this study to include event-free survival and overall survival, which I would imagine would come somewhere in the next 3 to 5 years.

T-DM1: I-SPY 2 Data From AACR1

Signature Estimated pCR Rate

(95% probability interval) Predictive Probability of

Success in Phase 3

T-DM1/P TH T-DM1/P TH

HER2+ 52% (36%-68%) 22% (5%-39%) 99.5% 94%

HER2+/HR+ 46% (26%-66%) 17% (0%-34%) 99.1% 93%

HER2+/HR- 64% (39%-88%) 33% (6%-59%) 98% 90%

Safety

Very few grade 3 or 4 AEs in either arm• ↑ rates of hypertension (45% vs 4%), neuropathy (45% vs 0%), and alopecia (58% vs 0%) among women assigned to TH vs T-DM1/P • ↑ ALT and AST levels occurred in patients randomized to T-DM1/P “but was low grade, and not clinically significant”

1. DeMichele AM et al. Proceedings of the 107th Annual Meeting of the American Association for Cancer Research (AACR 2016). Abstract CT042.

We also got some very interesting data about T-DM1 from the AACR meeting in 2016. Now T-DM1 had been included in a preoperative, really kind of a novel drug development trial known as the I-SPY 2 study. It confirmed the data that we saw in the ADAPT study, meaning when T-DM1 was added in the neoadjuvant setting the complete pathologic response rate was actually 52% in patients who had gotten T-DM1 and pertuzumab compared to 22% in patients who got the standard combination of paclitaxel/trastuzumab.

a Standard chemotherapy recommended after surgery/12-wk biopsy (in case of clinical non-pCR); trastuzumab to be completed, for a total of 1 y.

ADAPT HER2+/HR+: Trial Design1

pCR

vs

Surgerya

EOT pCR

Endpoint 1 2 3 4 5 6 7 8 9 10 11 12

T-DM13.6 mg/kg

Trastuzumab

pCR

vs

ET

T-DM13.6 mg/kg

3-wk therapy

R ET

Prognosis

BIOPSY

Efficacyeg, Ki-67

BIOPSY

1. Harbeck N et al. 2015 San Antonio Breast Cancer Symposium (SABCS 2015). Abstract S5-03.

The first study that fueled some enthusiasm about the use of T-DM1 in the preoperative or neoadjuvant setting is a study known as ADAPT. This is a large German-based study. It is considered an umbrella study in that it has different phenotypes. But what we're going to look at today is the HER2-positive arm of the ADAPT study.

So what's interesting about the HER2 component of the ADAPT study is that none of these patients got standard chemotherapy. Two-thirds of them got T-DM1 and two-thirds of them got endocrine therapy, either in combination with the T-DM1 or in combination with our old friend trastuzumab. And so this is, I think, a revolutionary study because we're basically taking early-stage breast cancer patients and treating them in the preoperative setting with non-traditional chemotherapy-based regimens.

ADAPT HER2+/HR+: pCR (no invasive tumorin breast and nodes)1

pCR

Rat

e, %

T-DM1 T-DM1 + ET H + ET

P < .001

P < .001

0

20

40

60

41.0% 41.5% 15.1%

48/117 51/123

18/119

1. Harbeck N et al. SABCS 2015. Abstract S5-03.


11


And finally, we're going to discuss lapatinib. Now lapatinib in the neoadjuvant setting has been studied in a series of studies. Lapatinib is a small molecule inhibitor that actively competes intracellularly with ATP to block downstream signaling. And so the fact that it has a different mechanism of action made it a very attractive drug over the past decade to combine with trastuzumab to see if combining two different mechanisms of action against HER2 would lead to greater efficacy.

a 1,500 mg/d. b 4 mg/kg → 2 mg/kg/wk. c L 1,000 mg/d, reduced to 750 mg/d with T. d T 80 mg/m2/wk.

• Randomized, multicenter, open-label phase 3 trial

HER2+primary BC;ECOG PS 0-1(N = 455)

La

HLc

Hb

TLd

THL

TH

L

HL

H

Wk 6 Wk 18

Surgery +adjuvant FEC x 3

Wk 52

NeoALTTO: Neoadjuvant Treatment With Lapatiniband/or Trastuzumab1

1. Baselga J et al. Lancet. 2012;379:633-640.

Now the large study that looked at the role of lapatinib in the neoadjuvant setting is known as NeoALTTO. The study schema was quite simple: lapatinib in one arm, IV trastuzumab in another arm, or the combination of lapatinib and trastuzumab for a period of 6 weeks. And a biopsy was done at enrollment and after the 6 weeks. Then women went on to receive 12 weeks of the targeted agents plus paclitaxel.

010203040506070

NeoALTTO Efficacy: pCR and tpCR1

Res

pons

e, %

pCR tpCR

L(N = 154)

P = .34

P < .001

P = .13

P = .001

H(N = 149)

HL(N = 152)

L(N = 150)

H(N = 145)

HL(N = 145)

24.7% 29.5% 51.3% 20.0% 27.6% 46.9%

1. Baselga J et al. Lancet. 2012;379:633-640.

This was really important because it compared our old combination of paclitaxel/trastuzumab to T-DM1 and pertuzumab. And because of the very high complete pathologic response rate, the study investigators concluded that the probability of T-DM1/pertuzumab wasn't just probable, it was superior to paclitaxel/trastuzumab with the pretest probability of about 99.5%. And that would predict success of the T-DM1/pertuzumab combination, and subsequent neoadjuvant studies at close to 94%.

Again, very similar to what we saw with ADAPT, very few grade 3/4 adverse events in either arm of the study. There was increased rates of hypertension, neuropathy, and alopecia in the women who were receiving standard paclitaxel/trastuzumab. The alopecia almost certainly from the paclitaxel, and the hypertension almost certainly from the steroids that are required with paclitaxel. In the T-DM1 and pertuzumab arm of the I-SPY 2 trial, we did see an elevation in the liver enzymes, which are known to occur with T-DM1, but the liver enzyme elevations were low grade and were not clinically significant.

So now two studies looking at the activity of T-DM1 in the preoperative setting, suggesting that it will play a role moving forward. Not yet indicated or approved in the United States but with the kind of efficacy data that we're seeing, very exciting and certainly warrants further studies of the use of T-DM1, either in combination with pertuzumab or in combination with other agents.

a pCR (no invasive tumor in breast and nodes); b in NeoALTTO, 6 wks of H or L preceding T.

Neoadjuvant Trials Evaluating the Addition of Lapatinibto Trastuzumab: pCR

Trial Regimen Duration, wk pCR, % P

GEPAR-QUINTO1

(N = 620) EC/H → DHEC/L → DL 24 30.3a

22.7a

.04

NeoALTTO2

(N = 455)

THb

TLb THLb

18 29.5 24.7 51.3

.34

.0001

CHER-LOB3

(N = 121)

TH → FEC/HTL → FEC/L

THL → FEC/HL 24

25a

26.3a

46.7a

NR .019

NSABP B-514

(N = 529)

AC → THAC → TL

AC → THL28

52.5 (breast) 53.2 (breast) 62 (breast)

.99

.095

CALGB 406015

(N= 305)

TL TH

THL 16

32 (breast) 40 (breast) 51 (breast)

.11

TRIO-US B076

(N = 128)

L → DCarboLH → DCarboH

HL → DCarboHL

25 47 52

.07 .02

1. Untch M et al. Lancet Oncol. 2012;13:135-144.2. Baselga J et al. Lancet. 2012;379:633-640.3. Guarneri V et al. J Clin Oncol. 2012;30:1989-1995.4. Robidoux A et al. Lancet Oncol. 2013;14:1183-1192.5. Carey LA et al. J Clin Oncol. 2013;31:abstr 500.6. Hurvitz S et al. SABCS 2013. Abstract S1-02.



H x 1 y L x 1 y H → L

Design 1Sequential

administration

Design 2Concomitant administration

Anthracycline/taxaneNon-anthracycline/taxane

HL

Anthracycline/taxane

Translational research effort(eg, tumor/blood collection → back to the lab)

DFS vs H:

Chemotherapy

87%(HR 0.96; P = .61)

88%(HR 0.84; P = .048)

ALTTO Trial: Adjuvant Therapy for Early-StageHER2+ BC (N = 8,381)1

1. Piccart-Gebhart MJ et al. J Clin Oncol. 2016;34:1034-1042.

The NeoALTTO study was partnered with a sister trial known as ALTTO. And this is a traditional adjuvant study looking at either lapatinib for a year, trastuzumab for a year, trastuzumab followed by lapatinib, or the doublet that we just examined from NeoALTTO, which is trastuzumab combined with lapatinib.

Now, one thing that was known very early on, about 2.5 years into the ALTTO having completed accrual, was that the patients who got chemotherapy plus lapatinib alone—the one arm that did not receive trastuzumab—the patients did not do well in that arm. And so the DSMB [Data and Safety Monitoring Board] actually shut down that arm and offered patients trastuzumab.

So the initial study results were released with about 4.5 years of follow-up. Although there was a trend to an improved [disease]-free survival in favor of the combination of lapatinib and trastuzumab compared to trastuzumab alone, it did not reach statistical significance. The P value was .048. And because of the multiple arms of the study, the predefined statistically significant value had to be less than .025. So basically, there was no statistically significant benefit for the addition of lapatinib to trastuzumab, and there was certainly no difference between the sequential use of lapatinib and trastuzumab and the doublet.

So short of another confirmatory study that reaches statistically significant endpoints, it's unlikely that lapatinib will become a standard of care in the neoadjuvant or adjuvant setting.

What did we see? The pCR rate was significantly higher when lapatinib and trastuzumab were added to paclitaxel than either trastuzumab alone or lapatinib alone. There was no difference between the lapatinib arm and the trastuzumab arm, so clearly lapatinib, trastuzumab, and paclitaxel led to a near doubling in the complete pathologic response compared to either trastuzumab/paclitaxel or lapatinib/paclitaxel. There were no major episodes of cardiac dysfunction.

a Test for interaction according to HR status not significant (P = .34 for EFS; P = .36 for OS).

NeoALTTO: Association of Survival Efficacy and pCR WithNeoadjuvant Lapatinib and/or Trastuzumab1

EFS, % pCR No pCR HR (CI); P

All patients 86 72 0.38 (0.22-0.63); .0003

HR+ 87 78 0.50 (0.18-1.13); .13

HR-a 85 65 0.34 (0.17-0.63); .001

OS, % pCR No pCR HR (CI); P

All patients 94 87 0.35 (0.15-0.70); .005

HR+ 96 93 0.85 (0.13-3.42); .84

HR-a 94 80 0.29 (0.11-0.62); .003

EFS, % pCR No pCR HR (CI); P

HL 91 73 0.32 (0.12-0.74); .012

L 83 72 0.43 (0.14-1.07);

.095

H 81 71 0.45 (0.17-1.03); .075

OS, % pCR No pCR HR (CI); P

HL 95 91 0.35 (0.07-1.27); .13

L 97 87 0.41 (0.06-1.53); .24

H 92 85 0.42 (0.12-1.20); .14

Patients who achieved pCR had significantly better EFS and OS compared with no pCR, regardless of treatment arm!

1. Piccart-Gebhart M et al. SABCS 2013. Abstract S1-01.

We've seen a number of analyses looking at how pCR correlates with long-term outcome in the NeoALTTO study. And basically, even though each of the arms was studied independently in the NeoALTTO study, those women who have a complete pathologic response always tend to have a significantly longer event-free survival and overall survival.

The importance of NeoALTTO, even though lapatinib is probably not going to be approved in the neoadjuvant setting, is it's yet another study that says if you achieve a complete pathologic response with whatever agents, it does correlate quite nicely with long-term outcome, either event-free survival or overall survival.


13


Neoadjuvant systemic therapy is considered to be as effective as adjuvantchemotherapy for earlier-stage disease

Preoperative model provides unique opportunities for developingindividualized treatment strategies and novel therapeutic agents alike

Need increased clinical and scientific collaboration, as well asguidelines for use of emerging treatment strategies

Improving Surgical/Medical Oncology Collaborationfor BC Treatment Planning1

1. Boileau JF et al. Curr Oncol. 2012;19:106-114.

Now one of the most practical aspects of utilizing preoperative or neoadjuvant HER2-targeted agents is just getting all of the doctors on the patient's care team on the same playing field. And it does require a fair amount of collaboration for treatment planning. Neoadjuvant therapy, in the old days and I mean like over 10 years ago, was really reserved for locally advanced or inoperable breast cancer. And at least in my opinion, it is now the standard of care for patients facing HER2-positive, earlier-stage breast cancer, not just confined to locally advanced. But when you know a patient needs chemotherapy and HER2-targeted therapy, there's really not a downside to offering it in the preoperative setting.

In addition, there are a number of clinical trials and correlative tissue studies that will help us understand the effects of HER2-targeted agents, and the patients participating in the trials and the patients that come after them will all benefit from the opportunity to use neoadjuvant therapy in order to get us to where we all want to be, which is personalized or precision medicine.

We still have a lot to learn about the use of neoadjuvant therapy, duration of therapy. Do we continue the pertuzumab after surgery? Is there a need for that? The NCCN guidelines suggest that we should consider that.

a H given in combination with an anthracycline is associated with cardiac toxicity; concurrent use of H and P with an anthracycline should be avoided. b TH may be considered for patients with low-risk stage I, HER2+ disease, particularly those not eligible for other standard adjuvant regimens due to comorbidities.

• AC → TH ± Pa (various schedules)• DCarboH ± P

• AC → DH ± Pa

• DCH• FEC → DHPa

• FEC → THPa

• THb

• DHP → FECa

• THP → FECa

PreferredRegimens

OtherRegimens

NCCN Guidelines: Preoperative/Adjuvant Therapy Regimensfor HER2+ Disease1

1. Adapted from: National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines). Breast Cancer. Version 2.2016.

Dr. Blackwell: What I want to end this discussion with is what are the practical recommendations for managing patients with HER2-positive breast cancer in the neoadjuvant setting?

The current NCCN guidelines list the following preferred regimens. AC followed by paclitaxel, trastuzumab, and pertuzumab. Docetaxel/carboplatin/trastuzumab plus pertuzumab. And they also list other regimens, including AC followed by docetaxel/trastuzumab and pertuzumab, FEC followed by docetaxel, trastuzumab, and pertuzumab, and then finally weekly paclitaxel and trastuzumab. The NCCN guidelines also suggest that we shouldn't utilize anthracyclines with HER2-targeted agents, given the increased risk of cardiac toxicity.

Putting Evidence Into Practice: Practical Recommendations for Managing Patients With HER2-Positive Breast Cancer in the Neoadjuvant Setting

Kimberly L. Blackwell, MDDuke University Medical Center Duke Cancer Institute Durham, North Carolina



a Typically 6-8 cycles of chemotherapy or 3-4 mo of endocrine therapy.

• Periodic clinical evaluations during treatment to assess response and ensure that tumor is not progressing• No formal guidelines exist regarding the ideal assessment strategy during neoadjuvant treatment

Clinical Response Assessment During Treatment

• Once a patient has completed neoadjuvant therapy,a assess tumor response to help guide surgical approach• Tumor size is typically assessed with WHO-UICC or RECIST criteria – Correlation between tumor measurements by physical examination, imaging (mammography, ultrasound, or MRI), and tumor size on final pathologic analysis is modest at best

Clinical Response Assessment After Treatment

Treatment Evaluation Considerations With NeoadjuvantTherapy for BC1

1. Connolly R, Stearns V. Oncology (Williston Park). 2010;24:135-143.

And I think nothing bears more importance to patient-centered care than when you're treating a patient in the preoperative setting where the medical oncologist does one thing, the surgeon does the next thing, the radiation oncologist does the next things, so it really does require a true multidisciplinary approach.

But even with all of these studies, there have been no formal guidelines regarding what should we absolutely need to do. I think the take-home message is make certain you know where you're starting with the size of the tumor and then assess halfway through therapy and then sometimes even before surgery, just so there are no surprises.

We also can assess response after treatment. And we've talked a lot about a complete pathologic response and how we correlate a complete pathologic response, which is basically the absence of tumor in the breast at the time of surgery. We look at tumor sizes. There are all kinds of other criteria, residual cancer burden that tries to take into account great responses where there's still cancer left, but at the end of the day the pathology report is really your gold standard for how well the treatment worked.

Addition of pertuzumab in the neoadjuvant setting approved by the FDA• Even higher pCR with not a lot of toxicity (NeoSphere)

Addition of lapatinib in the preoperative setting led to improvement inpCR in certain studies• No improvement in outcomes in adjuvant setting (ALTTO)

Consider neoadjuvant treatment for patients with HER2+ BC, especially candidates for chemotherapy, so they can receive benefits of preoperative HER2-based therapy• Implement a multidisciplinary approach to patient care to optimize the clinical benefits of HER2-based therapy

Conclusions

All right, well we've had a kind of a long journey but an exciting journey through the use of HER2-targeted therapies in the preoperative setting. We've demonstrated that pertuzumab in the neoadjuvant setting improves pathologic complete response, and at least in the neoadjuvant setting improved long-term outcomes such as event-free survival and overall survival, as was witnessed in the NeoSphere study.

We know that lapatinib led to an improvement in complete pathologic response rate when added to trastuzumab in the preoperative setting. That's the NeoALTTO study. But the ALTTO study failed to confirm the benefits of adding lapatinib.

And I'm hoping that with all of the data that we've gone through today, you have a good sense of the breadth of data that would support the use of neoadjuvant therapy for women facing HER2-positive breast cancer.


15


Notes Notes

CME Raising the Bar in HER2-Positive Breast Cancer: Improving Patient Outcomes in the Neoadjuvant Setting


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