Novel Her-2- neu Targeted Agents

Jame Abraham, M.D, FACPBonnie Wells Wilson Distinguished Professor

Chief, Section of Hematology-OncologyWest Virginia University

Morgantown, WV

• 55 year old woman was diagnosed with IIB breast cancer in 2001

• ER/PR positive and her-2 neu positive

• Developed metastatic disease involving bone, lung and lymph nodes about 6 years back

• Brain mets for the past 3 years

• Treated with variety of trastuzumab and lapatinib containing regimens

• Taxanes, Ixabepilone, navelbine, capecitabine, gemcitabine, carboplatin, liposomal doxorubicin, faslodex, letrozole, tamoxifen, bevacizumab etc.

Potential Mechanisms of Trastuzumab Resistance

• Altered receptor-antibody interactions• Increased signaling through other HER

family receptors (EGFR, HER3)• Increased signaling due to PI3K/Akt

pathway changes• Increased signaling through alternate

growth regulatory pathways (IGF-1R, VEGF)

What is next?

• T-DM1 (Antibody drug conjugate)

• Pertuzumab (HER2 dimerisation inhibitor)

• Neratinib (pan-ErbB receptor tyrosine kinase inhibitor of ErbB-1,-2,-4)

Three drugs• Phase II/III

• Phase II/III

• Phase II/III

• T-DM1

• Pertuzumab

• Neratinib

Trastuzumab-MCC-DM1– Binds to HER2 with affinity similar to trastuzumab– Provides intracellular delivery of mertansine

• Derivative of maytansine, a natural-product microtubule polymerization inhibitor

• 20-100 more potent than vincristine

Higa et al. Expert Anti Can 2010

Phase II Study of Trastuzumab-DM1 (T-DM1), a Novel HER2 Antibody–Drug

Conjugate, in Patients with HER2+ Metastatic Breast Cancer Previously

Treated with an Anthracycline, a Taxane, Capecitabine, Lapatinib, and Trastuzumab

Krop I, LoRusso P, Miller KD,Krop I, LoRusso P, Miller KD, Modi S,Modi S, Yardley D,Yardley D, Rodriguez G, Agresta S,Rodriguez G, Agresta S,

Zheng M,Zheng M, Amler L, Rugo HAmler L, Rugo H

Presented at the 32nd Annual San Antonio Breast Cancer Symposium. December 9-13, 2009. Abstract 5090.

TDM4374g: Study DesignTDM4374g: Study Design

T-DM1 3.6 mg/kg IV q 3 weeks

HER2-positive patients with metastatic breast cancer

n=110

• Primary endpoint: ORR by IRF

• Secondary endpoints: ORR by INV; PFS, DoR, CBR by INV and IRF

• Primary efficacy analysis data cut at 24 weeks post-LPI

• Follow-up: 30 days post-last dose unless SAE (90 days)

ORR=objective response rate; IRF=independent review facility; INV=investigator assessment; DoR=duration of response; CBR=clinical benefit rate; LPI=last patient in; SAE=serious adverse event.

9

Krop I, et al. Presented at the 32nd Annual San Antonio Breast Cancer Symposium. December 9-13, 2009. Abstract 5090.

Multi-institutional, Open-label, Single-arm Phase II Trial

Median number of agents for metastatic disease (range)* 7.0 (1–15)

Median number of agents in all therapy setting (range)* 8.0 (1–19)

Number of patients with 5 prior agents, n (%)** 109 (99.1)

Prior trastuzumabMedian duration of prior trastuzumab in metastatic setting, months (range) 19.4 (2–116)

Prior lapatinibMedian duration of prior lapatinib in metastatic setting, months (range) 6.9 (0–23)

*Includes all agents intended for the treatment of breast cancer except hormonal therapy.

* * One patient did not receive a taxane.

TDM4374: Prior Chemotherapy and TDM4374: Prior Chemotherapy and Anti-HER2 TherapyAnti-HER2 Therapy

10

Krop I, et al. Presented at the 32nd Annual San Antonio Breast Cancer Symposium. December 9-13, 2009. Abstract 5090.

TDM4374: Efficacy ConclusionsTDM4374: Efficacy Conclusions• Single agent T-DM1 demonstrated robust anti-tumor activity in a predefined

population that had a median time from metastatic diagnosis of over 3 years and received over 2 years of prior HER2-directed therapy

– ORR: 32.7% (as per independent review); 30% (as per investigator)

– CBR: 44.5% (as per independent review); 40% (as per investigator)

• Substantial clinical benefit was seen in this prespecified patient population that has not been previously studied

– Pre-defined treatment with an anthracycline, a taxane, capecitabine, trastuzumab, and lapatinib

– Received two HER2-directed regimens in the metastatic setting

– Progressive disease on last regimen received

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Krop I, et al. Presented at the 32nd Annual San Antonio Breast Cancer Symposium. December 9-13, 2009. Abstract 5090.

TDM4374: Safety ConclusionsTDM4374: Safety Conclusions• T-DM1 is well-tolerated by patients at the

dose and schedule tested with no dose-limiting cardiotoxicity or new safety signals– One patient died from hepatic dysfunction

• Toxicities observed are acceptable and manageable in this patient population

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Krop I, et al. Presented at the 32nd Annual San Antonio Breast Cancer Symposium. December 9-13, 2009. Abstract 5090.

• Randomized, phase II, international, open-label study• HER2-positive, measurable disease required• Stratification factors

– World region, prior adjuvant trastuzumab therapy, disease-free interval • Primary endpoints: PFS by INV, safety• Key Secondary endpoints: ORR, clinical benefit, OS, QOL, symptom control

Phase III Study Design

1:1 HER2-positive, recurrent locally advanced BC or MBC (n=137)

T-DM13.6 mg/kg Q3W until PD

Trastuzumab 8 mg/kg dose; 6 mg/kg Q3W + Docetaxel 75 or 100 mg/m2 Q3W

CrossoverT-DM1PD

Perez EA, et al. Abstr LBA3. ESMO 2010

Study Status

• Study fully enrolled with N=137, Sept 2008-Dec 2009

• Clinical data cutoff date for analysis is April 2nd, 2010 – Median duration of follow-up

– 5.9 months in the trastuzumab + docetaxel arm– 6.1 months in the T-DM1 arm

• Only clinical data prior to T-DM1 cross-over were included in efficacy and safety analyses

Perez EA, et al. Abstr LBA3. ESMO 2010

Objective Response by Investigator (ITT)Randomized Patients

T-DM1(n=67)

Trastuzumab + Docetaxel

(n=70)

Patients with an Objective Response,* n (%) 32 (47.8) 29 (41.4)

95% CI (35.4, 60.3) (30.2, 53.8)

Patients with Clinical Benefit,† n (%) 37 (55.2) 40 (57.1)

95% CI (43.1, 67.2) (44.8, 68.9)

Perez EA, et al. Abstr LBA3. ESMO 2010

HER2-positive, locally advanced or metastatic BC;previously receivedtrastuzumab-based therapy

Lapatinib (1250 mg/day)

(Days 1–21)

+Capecitabine (1000 mg/m2)

(Days 1–14 q3w)

T-DM1 (3.6 mg/kg) q3w

Study TDM4370g: T-DM1 vs. Capecitabine + Lapatinib Study TDM4370g: T-DM1 vs. Capecitabine + Lapatinib in HER2-positive MBC (EMILIA)in HER2-positive MBC (EMILIA)

• Randomized, Phase III multicenter (n=260 sites), open-label study• Enrollment began February 2009• Planned total enrollment: 580 patients

Primary end point: PFS Secondary end points: OS, quality of life

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Source: http://www.clinicaltrials.gov

Three drugs

• Phase II/III

• Phase II/III

• Phase II/III

• T-DM1

• Pertuzumab

• Neratinib

Pertuzumab HER2 Dimerisation Inhibitor

• By blocking HER2 dimerisation, pertuzumab inhibits key HER signalling pathways that mediate cancer cell proliferation and survival1–4

• Pertuzumab prevents the formation of HER2:HER3 receptor pairs1,5

HER2

Dimerisationdomain

1. Agus et al. Cancer Cell 2002;2:127–137; 2. Baselga. Cancer Cell 2002;2:93–95; 3. Citri et al. Exp Cell Res 2003;284:54–65. 4. Franklin et al. Cancer Cell 2004;5:317–328;

5. Hughes et al. Mol Cancer Ther 2009;8:1885–1892

Pertuzumab

HER3

Neoadjuvant pertuzumab (P) and Trastuzumab (H):

Antitumor and Safety Analysis of a Randomized Phase II study

(‘NeoSphere’)

L Gianni, T Pienkowski, Y-H Im, L Roman, L-M Tseng, M-C Liu,A Lluch-Hernandez, V Semiglazov, T Szado, G. Ross

on behalf of the ‘NeoSphere’ Investigators

San Antonio Breast Cancer Symposium, Dec 10, 2010

NeoSphere: Study Design

THP (n=107)Docetaxel + Herceptin +Pertuzumab

HP (n=107)Herceptin + Pertuzumab

TP (n=96)Docetaxel + Pertuzumab

S

U

R

G

E

R

Y

Docetaxel q3w x 4→FEC q3w x 3 Herceptin q3w cycles 5–17

FEC q3w x 3Herceptin q3w cycles 5–17

FEC q3w x 3Herceptin q3w cycles 5–17

FEC q3w x 3Herceptin q3w cycles 5–21

Study dosing: q3w x 4

TH (n=107)Docetaxel + Herceptin

Patients with operable or locally advanced /inflammatory* HER2-positive BC Chemo-naïve & primary tumours >2cm (N=417)

BC, breast cancer; FEC, 5-fluorouracil, epirubicin and cyclophosphamide*Locally advanced=T2–3, N2–3, M0 or T4a–c, any N, M0; operable=T2–3, N0–1, M0; inflammatory = T4d, any N, M03

NeoSphere: Study Design and Objectives

THP (n=107)Docetaxel (75100 mg/m2) Herceptin (86 mg/kg) Pertuzumab (840420 mg)

HP (n=107)Herceptin (86 mg/kg) Pertuzumab (840420 mg)

TP (n=96)Docetaxel (75100 mg/m2) Pertuzumab (840420 mg)

Study dosing: q3w x 4

TH (n=107)Docetaxel (75100 mg/m2)Herceptin (86 mg/kg)

S

U

R

G

E

R

Y

Patients with operable or locally advanced /inflammatory* HER2-positive BC Chemo-naïve & primary tumours >2cm (N=417)

BC, breast cancer; FEC, 5-fluorouracil, epirubicin and cyclophosphamide*Locally advanced=T2–3, N2–3, M0 or T4a–c, any N, M0; operable=T2–3, N0–1, M0; inflammatory = T4d, any N, M04

• Phase II design

• Primary End Point:comparison of pCR rates TH v. THPTH v. HP THP v. TP

• Secondary End Points:Clinical responseDFSBreast Conservation rateBiomarker evaluation

NeoSphere pCR rates: ITT population summary

p = 0.014150

40

30

20

10

0TH THP HP TP

pCR,

%

95%

CI

p = 0.0198p = 0.0198

p = 0.003

Treatment

29.0%

45.8%

16.8%24.0%

6

NeoSphere: pCR and Hormone Receptors Status

7

0

10

20

30

40

50

60

70

TH THP HP TP

% pCR

ER or PR pos ER and PR neg

20

26

17

37

2730

6

63

95% CI

Summary• Significantly higher pCR rate with Herceptin +

pertuzumab when combined with docetaxel (THP)

• Substantial antitumor activity and a very favourable therapeutic ratio for the Herceptin + pertuzumab doublet without chemotherapy

• Consistently higher pCR rates in ER and PR negative tumors than in ER and/or PR positive tumors, including those treated with HP without chemotherapy

• Excellent tolerability and lack of any meaningful increase in cardiac risk with the addition of pertuzumab over a short course of 4 cycles of neoadjuvant therapy

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CLEOPATRAPhase III Study of Trastuzumab + Pertuzumab in HER2+

MBC

1:1 randomization

HER2+ MBC N = 800

Docetaxel + Herceptin+ placebo

Docetaxel + Herceptin + pertuzumab

An international Phase III randomized, double-blind, placebo-controlled study (approximately 250 sites worldwide)

Endpoints: • Progression-free survival• Overall survival• Biomarker analysis

Three drugs

• Phase II/III

• Phase II/III

• Phase II/III

• T-DM1

• Pertuzumab

• Neratinib

Neratinib : Irreversible TKI of ErbB family

• Potent, low molecular weight, orally administered, irreversible pan-ErbB receptor tyrosine kinase inhibitor of ErbB-1,-2,-4.

P

EGFR

P

ErbB3

PP P PP P

gefitinib (or erlotinib)

trastuzumab

IGF-1R

P

X

HER2

HKI-272

P

Neratinib: pan-inhibitor of ErbB receptor kinase family

reversibleirreversible

(Lapatinib reversible)

Comparison of Lapatinib and Neratinib across Phase II studies

LapatinibORR%

NeratinibORR%

HER2-positive, Trastuzumab

refractory5.1% 26%

HER2-positive, Trastuzumab

naive35% 56%

Clinical outcomes of patients with prior trastuzumab (T) or no prior T treatment:

Burstein H J et al. JCO 2010;28:1301-1307

©2010 by American Society of Clinical Oncology

Objective response rates were

24% in patients who had trastuzumab

56% in trastuzumab naïve patients

Efficacy of Neratinib/Paclitaxel in HER2+ Metastatic Breast Cancer

• 102 patients w. MBC, 1st to 4th-line

• Neratinib 240mg qd in combination with Paclitaxel 80mg/m2 days 1,8,15 of 28-d cycle

Gupta et al. SABCS abstract 5081, 2009

Response dataPrior Rx Overall Response

Rate

All evaluable patients

61 of 97(67%)

Prior Taxane 43 of 60 (72%)

Prior Herceptin 55 of 97 (57%)

Prior Lapatinib 9 of 13 (69%)

Gupta et al. SABCS abstract 5081, 2009

FB-7: A Phase II Randomized Clinical Trial

Evaluating Neoadjuvant Therapy Regimens with Weekly Paclitaxel and

Neratinib or Trastuzumab Followed by Doxorubicin and

Cyclophosphamide with Postoperative Trastuzumab in

Women with Locally Advanced HER2-Positive

Breast cancer

STUDY SCHEMA

Randomization to a Preoperative Regimen

Surgery (lumpectomy or mastectomy; evaluation of axilla)

Clinical Stage IIIA, IIIB, or IIIC HER2-Positive Invasive Breast Cancer Diagnosed by Core Needle Biopsy or Limited Incisional Biopsy with Palpable Mass in Breast or Axilla ≥ 2.0 cm or Inflammatory Breast Cancer

Group 1

Cycles 1-4:

Paclitaxel 80 mg/m2 IVon Days 1, 8, and 15 q 28 days+Trastuzumab IV weekly:4 mg/kg loading dose, then2 mg/kg weekly for 15 doses(for a total of 16 doses)↓Cycles 5-8:

AC* q 21 days

Group 2

Cycles 1-4:

Paclitaxel 80 mg/m2 IVon Days 1, 8, and 15 q 28 days+Neratinib 240 mg PO dailyuntil 7 days afterlast dose of paclitaxel↓Cycles 5-8:

AC* q 21 days

Her-2 positive Stage II-IIIC patients

Completed Trastuzumab Within 1 year

Neratinib daily P.O Placebo daily P.O

1 year

3144A2-3004-WW: A Randomized Double-Blind Placebo-Controlled Trial of Neratinib (HKI-272) After Trastuzumab in Women with Early-Stage HER-2/neu Overexpressed/Amplified Breast Cancer (ExNET study)

NSABP B-47 Adjuvant Trastuzumab in HER2 Low EBC

Primary Breast Cancer

IHC 1+ or 2+ for HER2 and FISH Negative

Docetaxel 75mg/m2 + CTX 600mg/m2 Q3wk x 6

orACx4 Paclitaxel Qwk x 12

Std or DD AC

RandomizationRandomization

Docetaxel 75mg/m2 + CTX 600mg/m2 Q3wk x 6

orACx4Paclitaxel Qwk x 12

Std or DD AC + Trastuzumab x 1 yr beginning with TC or

WP

Thank you for your attention

• T-DM1 (Antibody drug conjugate)

• Pertuzumab (HER2 dimerisation inhibitor)

• Neratinib (pan-ErbB receptor tyrosine kinase inhibitor of ErbB-1,-2,-4)