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The State of Antibody-Drug Conjugates in 2015

TON September 2015 Vol 8 No 5 - Drug Therapies
Phoebe Starr

Antibody-drug conjugates (ADCs) offer a unique approach for the treatment of solid tumors and hematologic cancers. The idea is that a potent cytotoxic agent is linked to an antibody specifically targeted to tumor cells, and once the antibody binds to the tumor cell, the cytotoxic agent is unleashed inside the cells to attack the cancer.

However attractive this concept is, the history of bringing ADCs to the clinic has been marked by hurdles that include toxicity, explained Beverly A. Teicher, PhD, Chief of the Molecular Pharmacology Branch at the National Cancer Institute in Bethesda, MD, at an education session on “Antibody-Drug Conjugates: New Horizons to Maximize Efficacy and Minimize Toxicity” at the 2015 Annual Meeting of the American Society of Clinical Oncology.

The first ADC to be approved by the US Food and Drug Administration (FDA) in 2000 was gemtuzumab ozogamicin for acute myeloid leukemia. Gemtuzumab ozogamicin is a humanized monoclonal antibody to CD33 linked to a cytotoxic calicheamicin agent. This agent was withdrawn from the market in 2010 because of fatal toxicity events.

Two ADCs are now approved by the FDA: trastuzumab emtansine (T-DM1) for the treatment of HER2-positive (HER2+) metastatic breast cancer, and brentuximab vedotin for the treatment of refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma.

T-DM1 and Side Effects

T-DM1 links emtansine (DM-1), a potent microtubule inhibiting agent, to trastuzumab, a HER2-targeted antibody. Trastuzumab is indicted for the treatment HER2+ breast cancer, a welcome advance for patients with this heretofore untreatable type of cancer. Once T-DM1 binds to HER2, DM1 molecules are released into the cell, disrupting microtubule polymerization. This agent is cytotoxic to HER2-specific cells.

T-DM1 has been associated with off-target side effects that require careful monitoring; these include thrombocytopenia, serious hepatotoxicity, and reductions in left ventricular ejection fraction. Dose modifications or stopping therapy may be necessary when these side effects occur, said Francisco J. Esteva, MD, PhD, NYU Langone Medical Center, New York City.

T-DM1 was approved for use as second-line therapy in metastatic, HER2+ breast cancer based on superior overall survival, response rate, and time to progression compared with capecitabine/lapatinib in the large phase 3 EMILIA study. Next, the TH3RESA study found that T-DM1 was superior as a single agent in third-line or later treatment of HER2+ metastatic breast cancer versus physician’s choice of therapy.

The large, phase 3 MARIANNE trial compared T-DM1 alone or T-DM1 plus pertuzumab versus trastuzumab/taxane as first-line treatment of HER2+ metastatic breast cancer. Primary results indicated that the 2 combination arms were not significantly different.

Other trials are continuing to evaluate T-DM1 in earlier stages of HER2+ breast cancer.

Interestingly, a retrospective analysis of EMILIA showed that T-DM1 may be important for treating brain metastases in patients with metastatic HER2+ breast cancer. In that study, patients who had brain metastases at baseline achieved longer overall survival compared with capecitabine/lapatinib: median of 26.8 months versus 12.9 months, respectively (P = .0081).

Esteva believes that this evidence provides strong rationale for a study to evaluate the combination of T-DM1 with stereotactic radiosurgery and other radiation therapies.

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Last modified: April 27, 2020