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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)