Antibody-drug conjugates (ADCs) offer a unique therapeutic approach for the treatment of solid and hematologic malignancies. ADCs deliver a potent cytotoxic agent on the backbone of an antibody specifically targeted to malignant cells. This two-pronged approach is predicted to destroy tumor cells in a more efficient manner while sparing normal tissues.
The road of ADCs into clinical practice has not been easy; however, recent developments in the treatment of breast cancer and lymphoma have been positive. The future of ADCs is likely bright.
The Education Session “Antibody-Drug Conjugates: New Horizons to Maximize Efficacy and Minimize Toxicity” (from Monday, June 1, 8:00 AM-9:15 AM, in room S406) will look at the past, present, and future of ADCs in the clinical management of solid cancers.
History of ADCs and How They Act
Session chair Beverly A. Teicher, PhD, chief of the molecular pharmacology branch of the National Cancer Institute, will provide a historic perspective on ADCs.
Dr. Teicher will show how murine antibodies were typically bound to chemotherapeutic agents such as doxorubicin, vinblastine, and methotrexate in the early development of ADCs. The failure of these early ADCs in clinical trials was attributed to the immunogenicity of murine antibodies, lack of potency of the cytotoxic agents, and poor selectivity of the early antibody targets between tumor and normal tissue, among other factors.
“The history of antibody conjugates has been marked by hurdles identified and overcome,” Dr.Teicher said.
She will discuss how gemtuzumab ozogamicin overcame some of these issues. Gemtuzumab ozogamicin is a humanized monoclonal antibody to CD33 linked to a cytotoxic agent, which belongs to the class of calicheamicins. The humanized monoclonal antibody was less immunogenic, the CD33 target more tumor selective (expressed predominantly on leukemic cells), and the cytotoxic agent had more potency.
In 2000, the U.S. Food and Drug Administration (FDA) granted accelerated approval to gemtuzumab ozogamicin for the treatment of acute myeloid leukemia. Gemtuzumab ozogamicin was withdrawn from the market in 2010 because of fatal toxicity events seen in significantly more patients on gemtuzumab ozogamicin compared with those who did not receive gemtuzumab ozogamicin observed in a post-marketing SWOG S0106 study.
Currently, two ADCs have been approved by the FDA: trastuzumab emtansine (T-DM1) was approved for the treatment of metastatic breast cancer, and brentuximab vedotin was approved for the treatment of refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma.
Dr. Teicher will highlight the significance of target selection and drugs of choice. Most of the potent cytotoxic drugs selected for application in ADCs target tubulin or DNA. She will discuss why these drugs, which were tested in clinical trials as free small molecules in the early 1990s, failed because of toxicity, poor bioavailability, or limited therapeutic index.
T-DM1 emerged as one of the two success stories of ADCs to date. Dr. Teicher will use T-DM1 to explain how ADCs work. In T-DM1, DM1—a microtubule inhibiting agent—is physically linked to trastuzumab, a HER2-targeted antibody. Trastuzumab is indicated for the treatment of HER2-positive breast cancer—a well-established target.
Dr. Teicher will further explain how T-DM1 works after binding to HER2 on tumor cells. The complex of HER2 and T-DM1 is internalized into the cell where it undergoes lysosomal degradation. In the process, DM1-containing molecules, which bind to cellular tubulin, are released into the cells. By disrupting microtubule polymerization, T-DM1 is cytotoxic to HER2-specific cells. In addition, by binding to HER2, trastuzumab inhibits downstream proliferative signals.
Integrating T-DM1 in Clinical Practice
In discussing the integration of ADCs into clinical practice, Francisco J. Esteva, MD, PhD, of the NYU Langone Medical Center, will focus on the safety and efficacy of T-DM1 in the treatment of metastatic breast cancer. He will also discuss how it is being advanced into the treatment of early-stage breast cancer.
Dr. Esteva will highlight the prevalence of toxicities seen in clinical studies with respect to its safety.1 In particular, he will focus on safety of the off-target toxicity of thrombocytopenia seen with T-DM1. This unexpected T-DM1 side effect is explained by its impairing megakaryocyte differentiation but not mature platelet destruction.
Serious hepatotoxicity is also seen with T-DM1, making it important to monitor serum transaminases and bilirubin in patients receiving T-DM1. Finally, he will emphasize the importance of monitoring patients for reductions in left ventricular ejection fraction—another side effect seen with T-DM1.
Dr. Esteva will stress the importance of monitoring these side effects and instituting dose modification or stopping therapy, as appropriate.
In his discussion on the efficacy of T-DM1, Dr. Esteva will share data from the pivotal trials that brought T-DM1 into clinical practice. Patients enrolled across all trials that evaluated or will evaluate T-DM1 are required to have HER2-positive tumors.
In the EMILIA phase III study, women with HER2-positive, unresectable, locally-advanced or metastatic breast cancer who had prior therapy with trastuzumab, and whom taxane therapy failed, were randomly assigned to receive T-DM1 or the combination of capecitabine and lapatinib.2 Clinical efficacy data on overall survival, response rate, and time to progression will be highlighted—all were significantly higher for patients receiving T-DM1, which led to the approval of T-DM1 for the second-line treatment of metastatic breast cancer.
In the third-line or latter treatment of metastatic breast cancer, the TH3RESA study provided compelling evidence that single-agent T-DM1 was better than the oncologist’s choice of therapy.Progression-free survival, which was almost double with T-DM1, provides a place for T-DM1 in later-line settings for the treatment of metastatic breast cancer.
Although data from the large, phase III MARIANNE trial (which enrolled 1,095 patients) have not been released as of this writing, a December 2014 press release from Roche/Genentech indicated that T-DM1 alone or the combination of T-DM1 and pertuzumab was not significantly better than the combination of trastuzumab and a taxane in the first-line treatment of patients with metastatic breast cancer.
Given its lower toxicity profile, can T-DM1 still be used off label? Dr. Esteva will share his own views on the matter.
Other trials are evaluating T-DM1 in the early-stage setting of HER2-positive breast cancer. Dr. Esteva will highlight key features of the ADAPT (NCT01745965), ATEMPT NCT01853748), KAITLIN (NCT01966471), KATHERINE (NCT01772472), and KRISTIN studies.
Finally, Dr. Esteva will share insights on how a retrospective analysis of the EMILIA study indicated that T-DM1 may be important for treating brain metastases.3 Because the prognosis of HER2-positive breast cancer with brain metastases is poor, Dr. Esteva will provide data for a low incidence of brain metastases in patients treated with T-DM1. In addition, for patients with brain metastases at baseline, T-DM1 is also associated with a significantly higher overall survival compared with patients receiving lapatinib and capecitabine (26.8 vs. 12.9 months; hazard ratio, 0.382; p = 0.0081). Dr. Esteva will argue this provides strong rationale for a study to evaluate T-DM1 in combination with stereotactic radiosurgery and other radiation therapy modalities.
The Future of ADCs and Rational Combinations
In the concluding presentation, Kathy Miller, MD, of the Indiana University Melvin and Bren Simon Cancer Center, will provide insight into the future of ADCs and what rational combinations can be evaluated in clinical studies.
There is currently a paucity of data on ongoing studies evaluating ADCs. Dr. Miller will indicate that, conceptually, potential combinations can fall into the broad categories of anti-HER2 agents, cytotoxics, inhibitors of downstream signaling molecules, and inhibitors of parallel pathways implicating other growth factors.
With xenograft models indicating that tumor inhibition was enhanced with T-DM1 and pertuzumab compared with T-DM1 or pertuzumab alone, Dr. Miller will argue that the combination can be used at full doses. She will show that the combination of T-DM1 plus pertuzumab in patients who were previously treated (objective response rate: 33% and progression-free survival: 5.5 months) was similar to those observed with single-agent T-DM1 or with the combination of pertuzumab and trastuzumab.
When providing therapy with T-DM1 and pertuzumab, Dr. Miller will draw on preclinical models that suggest that the order the two drugs are given in may dictate clinical outcome. Results suggest that providing T-DM1 before pertuzumab may provide optimum clinical outcomes. She will also highlight studies that are ongoing, which combine T-DM1 with lapatinib or other novel HER2-targeted agents.
Dr. Miller will then discuss the possibility of combining T-DM1 with other cytotoxics. Although it may appear that adding a cytotoxic to another cytotoxic may not be desirable, it could still be an option for patients who experience aggressive, high-risk disease. That is why trials are evaluating T-DM1 in combination with other cytotoxics such as paclitaxel, docetaxel, and capecitabine.
She will also provide insights into the treatment of HER2-positive and ER-positive breast cancer, diseases that typically have a low response to standard chemotherapy. Will the combination of T-DM1 and endocrine therapy provide clinical benefits better than either agent alone? Proliferative markers such as Ki67 suggest they will.
Finally, Dr. Miller will highlight other rational combinations of T-DM1 and inhibitors that target other parallel pathways, especially those associated with cellular proliferation. In addition, she will indicate that the success of T-DM1 has paved the way to evaluate other molecules such as SYD985—a HER2-targeting ADC. SYD985 uses the trastuzumab backbone to target tumors expressing low levels of HER2. However, in SYD985, duocarmycin—a DNA-binding molecule—is used instead of the microtubule agent, DM1. This approach may expand the target population to include patients whose tumors express low levels of HER2, Dr. Miller will indicate.