What’s New with

Immunoconjugates

Louis M. Weiner, MD

Director, Georgetown Lombardi

Comprehensive Cancer Center

EMILIA

Tassel Flower (Emilia javanica)

PRESENTED BY: LOUIS M. WEINER, MD

Desdemona’s Attendant

(Othello)

Monoclonal Antibody Therapy

• Unconjugated antibodies have major roles

in the therapy of lymphomas and breast,

colorectal, head/neck cancers

• Immunoconjugates have been less

successful, though there have been some

examples of utility

PRESENTED BY: LOUIS M. WEINER, MD

Trastuzumab Emtansine (TDM-1)

An Effective New Treatment for

HER2+ Metastatic Breast Cancer

PRESENTED BY: LOUIS M. WEINER, MD

HER2

DM1

Outline

• HER2+ breast cancer treatment context

• The lessons of EMILIA

– Clinical trial results

– Clinical implications

• How immunoconjugates kill cancer cells

• How might T-DM1 work?

• Future directions

PRESENTED BY: LOUIS M. WEINER, MD

HER2+ Breast Cancer – the Context

PRESENTED BY: LOUIS M. WEINER, MD

• Pertuzumab improves the results of first-line

therapy with trastuzumab plus docetaxel in

metastatic HER2+ breast cancer (CLEOPATRA

trial; Baselga, NEJM 2012)

• Limited targeted therapy options for patients with

progressive disease

• Trastuzumab + Capecitabine TTP 8.2 mos

(Von Minckwitz, JCO 2009)

• Lapatinib + Capecitabine TTP 8.4 mos

(Geyer, NEJM 2006)

• Lapatinib + Trastuzumab PFS 12 wks

(Blackwell, JCO 2010)

EMILIA - Key Results

• Well designed, adequately powered,

appropriately randomized and stratified trial

in trastuzumab-resistant metastatic breast

cancer

• T-DM1 reasonably well tolerated

• T-DM1 PFS superior to Capecitabine +

Lapatinib

– 9.6 vs. 6.4 mos; p = .0001; HR = 0.650

– Consistent across all subgroups except > 65 yo

PRESENTED BY: LOUIS M. WEINER, MD

EMILIA - Key Results

• Interim overall survival with T-DM1 superior

to Capecitabine + Lapatinib• 65.4% vs. 47.5% at 24 mos; p = .0003; HR = 0.621

• Did not cross the efficacy stopping boundary

• T-DM1 ORR superior to Capecitabine +

Lapatinib

– 43.6% vs. 30.8%; p = .0002 with better duration

of response

PRESENTED BY: LOUIS M. WEINER, MD

Clinical Implications of EMILIA

PRESENTED BY: LOUIS M. WEINER, MD

An effective new

treatment for

Trastuzumab-

refractory HER2+

metastatic breast

cancer

New

combinations

HER2 1+/2+

Previously untreated,

HER2+ metastatic

breast cancer

Adjuvant and locally

advanced HER2+

breast cancerOther HER2+

malignancies?

Where will

Trastuzumab fit?

Paul Ehrlich (1854-1918)

PRESENTED BY: LOUIS M. WEINER, MD

• Immunologist

• 1908 Nobel Prize in Physiology or

Medicine

• Developed first effective drug for

syphilis

• Conceptualized “magic bullets”

Immunoconjugates for Cancer

PRESENTED BY: LOUIS M. WEINER, MD

T cell

Bi-specific T-Cell Engager (BiTE)(e.g., Blinatumomab)

CD19

CD3

Catalytic Immunotoxins(e.g., BL22/HA22)

CD22

Antibody-Drug Conjugates(e.g., Brentuximab vedotin)

CD30

CD20

Radioimmunotherapeutics(e.g., Ibritumomab tiuxetan)

Trastuzumab-DM1

PRESENTED BY: LOUIS M. WEINER, MD

• Internalized by HER2+ breast cancer cells

• Degradation in the lysosome results in release of DM-1 into the

cytosol

• DM-1, an extremely potent microtubule poison, binds to tubulin

leading to G2/M arrest and apoptosis

• Covalent linkage of DM1 to Trastuzumab enhances tumor-selective

cytotoxicity

• Retains effector functions of Trastuzumab

DM-1

Thioether linkage

PRESENTED BY: LOUIS M. WEINER, MD

How Does Trastuzumab Work?

Signaling Perturbation

HER2EGFR

Trastuzumab

Activation of Immune Effector Mechanisms

(e.g. ADCC)

NK Cell

HER2+

Tumor

Cell

Antibody Therapy-Induced Immunization?

PRESENTED BY: LOUIS M. WEINER, MD

ADCC

NK Cell

B cell

Antibodies

Dendritic Cell

T Cells

How Else Might T-DM1 Work?

• “Combinatorial” effects

– Trastuzumab actions (signaling effects, immune

activation)

– DM1 actions (induction of apoptosis)

• Induction of autophagy (“self eating”) to

enhance immune recognition

• Targeted HER2 antigen presentation to

induce vaccine-like effects

PRESENTED BY: LOUIS M. WEINER, MD

Tumor Cell Autophagy and Immunity

PRESENTED BY: LOUIS M. WEINER, MD

Weiner LM and Lotze MT, NEJM, 2012 Michaud et al, Science, 2011

Future Directions

• Define new clinical niches for T-DM1 in

metastatic HER2+ breast cancer

– Assess T-DM1 based combinations

• Determine the value of adjuvant T-DM1 in

HER2+ breast cancer

• Explore T-DM1 mechanisms of action

• T-DM1 lessons create opportunities for new

immunoconjugates in breast cancer and

other malignancies

PRESENTED BY: LOUIS M. WEINER, MD

Summary and Conclusions

• T-DM1 is clinically active in HER2-

overexpressing metastatic breast cancer

• T-DM1 is an important new weapon in the

therapeutic armamentarium for breast

cancer

• Future studies will define how to best use

this and related agents

• Dr. Ehrlich’s dream of “magic bullets” is

being realized

PRESENTED BY: LOUIS M. WEINER, MD

Living Dr. Ehrlich’s Dream

PRESENTED BY: LOUIS M. WEINER, MD

Living Dr. Ehrlich’s Dream

PRESENTED BY: LOUIS M. WEINER, MD

19402012 – New Constructs, Improved

Efficacy and Safety, New Indications

Hybridoma Technology

(1975)Recombinant Antibody

Technology (1980-Current)

Unconjugated Monoclonal

Antibodies (1997)

Conjugated Antibodies

(2002)