NcXHF

ANTIBODY-DRUG CONJUGATES AND T-DM1
objective response rates and progression-free survival in patients
with advanced disease. 54,55 The ADAPT HER2/
HR trial compared T-DM1 monotherapy to T-DM1 plus
endocrine therapy (premenopausal patients: tamoxifen;
postmenopausal patients: aromatase inhibitor or trastuzumab
plus endocrine therapy as neoadjuvant therapy).
The treatment with T-DM1 plus endocrine therapy resulted
in a greater median fractional decrease in proliferation
(Ki67) after 3 weeks of therapy (40% in the T-DM1/
endocrine therapy arm vs. 14% and 25% in the T-DM1
monotherapy and trastuzumab/endocrine therapy arms,
respectively). 56
T-DM1 is an ideal candidate to combine with agents that
have been diffıcult to combine with chemotherapy because of
overlapping toxicities. Ongoing trials combine T-DM1 with
a variety of downstream signaling inhibitors and other molecular
pathways, including inhibitors of heat shock proteins,
cyclin-dependent kinases, PI3K/AKT, and mammalian target
of rapamycin (mTOR).
Importantly, T-DM1 may be considered a prototype and is
almost certainly just the fırst ADC for the treatment of HER2-
expressing breast cancer. The potential to use HER2 as a molecular
address also may increase the proportion of patients who
could benefıt from HER2-targeted agents. For example,
SYD985 is an HER2-targeting ADC that combines trastuzumab
and a duocarmycin payload with a cleavable linker. In cell lines
with low HER2 expression (i.e., HER2 2 and 1), SYD985
had both in vitro and in vivo activity. 57 If confırmed in the clinic,
this could extend the target population of patients with breast
and gastric cancers who may respond to this treatment modality
to include those with fluorescence in situ–negative or
immunohistochemistry-negative HER2 2 and 1 disease.
Disclosures of Potential Conflicts of Interest
Relationships are considered self-held and compensated unless otherwise noted. Relationships marked “L” indicate leadership positions. Relationships marked “I” are those held by an immediate
family member; those marked “B” are held by the author and an immediate family member. Institutional relationships are marked “Inst.” Relationships marked “U” are uncompensated.
Employment: None. Leadership Position: Francisco J. Esteva, Viatar CTC Solutions, Inc. Stock or Other Ownership Interests: None. Honoraria: None.
Consulting or Advisory Role: Francisco J. Esteva, Genentech/Roche, GSK, Novartis. Kathy Miller, Clovis Oncology, Imclone, Nektar. Speakers’ Bureau: None.
Research Funding: Kathy Miller, AVEO (Inst), BiPar Sciences (Inst), Eli Lilly (Inst), EntreMed (Inst), Genentech (Inst), Geron (Inst), ImClone Systems (Inst),
Macrogenics (Inst), Medivation (Inst), Medivation (Inst), Merrimack (Inst), Novartis (Inst), Pfizer (Inst), Seattle Genetics (Inst), Taiho Pharmaceutical (Inst).
Patents, Royalties, or Other Intellectual Property: Francisco J. Esteva, Myriad Genetics (royalties). Expert Testimony: None. Travel, Accommodations,
Expenses: Francisco J. Esteva, Novartis. Other Relationships: None.
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