The Next Advancements in Cancer Drug Development: Antibody-Drug Conjugates

The annual meeting of the American Society of Clinical Oncology (ASCO) conference held June 1-5, 2012 in Chicago, IL offered a wealth of new scientific and clinical data. It is expected that this year’s event will have a significant impact on the patients treatment plans.

After reviewing this years meeting, a new type of targeted therapy was of particular interest to reviewer Daphna Halpern, Director of Oncology at Citeline, the world’s leading research authority on pharmaceutical clinical trials and drug intelligence. According to Halpern, “Antibody-Drug Conjugates (ADC’s) are looking to be one of the next advancements in cancer drug development.”

ADCTargeting cancer cells
Antibody-Drug Conjugates (ADCs) are a new type of targeted therapy composed of an antibodylinked via a biodegradable linker to a cytotoxicagent (also called “warhead”). The cytotoxic agents are designed to eliminate fast-growing cancer cells, but they can also harm healthy proliferating cells, which cause side effects. Therefore, linking an ADC with a cytotoxic agent may allow chemotherapy to directly target the cancer cell and avoid harming the health cells reducing the side effects. Based on this unique quality, it’s not surprising that drug companies are exploring this option.

MabPlex
ADC Bio
Lonza
 

Brentuximab vedotin
The U.S. Food and Drug Administration (FDA) granted accelerated approval to brentuximab vedotin (SGN-35; Adcetris™ for Injection, Seattle Genetics, Inc.) in August 2011. The approved incications include the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not candidates for ASCT and treatment of patients with systemic anaplastic large cell lymphoma (ALCL) after failure of at least one prior multi-agent chemotherapy regimen. The approval for Hodgkin lymphoma was based on a single-arm multicenter clinical trial (Trial SG035-0003) that enrolled 102 patients who had CD30-positive Hodgkin lymphoma that relapsed after ASCT.

The antibody-drug conjugate brentuximab vedotin includes the highly toxic antimicrotubule agent Monomethyl Auristatin E (MMAE), a synthetic antineoplastic agent, to human specific CD30-positive malignant cells. Because of its high toxicity MMAE, which inhibits cell division by blocking the polymerisation of tubulin, cannot be used as a single-agent chemotherapeutic drug. However, the combination of this drug with an anti-CD30 monoclonal antibody proved to be safe for anticancer therapy.

Trastuzumab emtansine
One of the most promising ADC’s that had results presented at the annual meeting of the American Society of Clinical Oncology is trastuzumab emtansine (T-DM1) by Roche/Genentech. T-DM1 comprises the antibody trastuzumab and the chemotherapy DM1 attached together using a stable linker. It is designed to target and inhibit HER2 signaling and deliver the chemotherapy directly to the HER2-positive cancer cells.

EMILIA study
The EMILIA study was the first randomized Phase III study of T-DM1. This study enrolled people with HER2-positive metastatic breast cancer who had previously received treatment with trastuzumab and a taxane chemotherapy and showed a significant and clinically meaningful improvement in PFS (progression free survival) compared with capecitabine and lapatinib. Based on the EMILIA findings, Genentech and Roche shared plans to submit applications for T-DM1 in HER2-positive metastatic breast cancer this year to the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA).

Ongoing clinical development
“Over recent years, Citeline’s product, Pipeline® has monitored 145 ADC’s; 30 of them are currently in active development,” Halpern noted. “We are also monitoring, through the product Trialtrove®, clinical trials for those ADCs that reached clinical development (Phase I-IV).” ADC’s are being developed in many types of cancers. Breast cancer has the largest number of clinical trials, and has 5 different drugs in development, followed by non-Hodgkin’s lymphoma and head and neck cancer.

Inotuzumab ozogamicin
Pfizer’s inotuzumab ozogamicin (CMC-544), the only other ADC that is currently in phase III development, also had results presented at the meeting. It is in phase III trials for relapsed or refractory acute lymphoblastic leukemia (ALL) and non-Hodgkin’s lymphoma. The interim results presented at ASCO were for an ongoing trial in refractory- relapsed ALL patients in which weekly inotuzumab ozogamicin showed activity and an overall response (OR) of 50% thus far.

Other ADC’s
There were also other ADC’s presenting data at the meeting. Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC), by Progenics Pharmaceuticals, had interim data revealed for an ongoing phase I trial for metastatic castration-resistant prostate cancer patients previously treated with a taxane.

Gemtuzumab ozogamicin
Results of two trials with gemtuzumab ozogamicin were also presented. Previously marketed for acute myeloid leukemia (AML) but withdrawn following a confirmatory post approval clinical trial that did not show improvement in clinical benefit and after a greater number of deaths occurred in the group who received it. Results were presented in a phase II study being conducted by theNational Cancer Institute (NCI) and the Southwest Oncology Group (SWOG) and showed that the combination with hydroxyurea and azacitidine is associated with a low induction mortality. A second phase II study from the MD Anderson Cancer Center concluded that the effect of fludarabine, cytarabine, filgrastim, and gemtuzumab ozogamicin (FLAG-GO) is a highly effective regimen and has resulted in high rate of relapse-free survival in patients with newly diagnosed patients with core-binding factor AML.