Phase two CD19-antibody-drug conjugate trial demonstrates promise for aggressive lymphoma

MUSC Hollings Cancer Center was one of 28 clinical sites around the world that participated in the LOTIS-2 trial to test the efficacy of Loncastuximab tesirine, a promising new treatment for aggressive B-cell lymphoma. The results of the single-arm, phase 2 trial were published online in May 2021 in Lancet Oncology.

Brian Hess, M.D., a Hollings researcher and lymphoma specialist at MUSC Health, was instrumental in bringing the phase 2 trial to Hollings. The manufacturer of Loncastuximab tesirine, ADC Therapeutics S.A., sponsored the trial.

B-cell non-Hodgkin lymphoma (NHL) is a blood cancer that begins in the lymph nodes, spleen or bone marrow. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive NHL. New treatment options are vital for patients with DLBCL. While nearly two-thirds of patients have a durable response to frontline therapy, the remaining one-third of patients relapse or are refractory to frontline treatment and typically have a poor prognosis.

The trial was open label, which means the clinician and patient were aware of the treatment that was given, and it was available to patients 18 years or older with relapsed or refractory DLBCL after two or more lines of treatment. This trial is significant because it includes a difficult-to-treat patient population, said Hess.

“Traditional chemotherapy is very unlikely to lead to a sustained response in this patient population. CD19 CAR-T cell therapy is now approved and provides hope for durable response and cure for the majority of these patients; however, not everyone is a candidate for CAR-T cell therapy. In addition, the majority of patients that receive CD19 CAR-T cell therapy eventually relapse and are in need of novel therapies such as loncastuximab,” said Hess.

The LOTIS-2 trial tested the efficacy of Loncastuximab tesirine, an antibody-drug complex that targets CD19 – the same molecule targeted on the lymphoma B-cells by CAR-T therapy. The drug complex works by attaching to CD19, widely expressed on lymphoma B cells, and delivering the drug payload into the cell, thereby minimizing systemic toxicity. Once internalized, the drug damages the DNA of the lymphoma cells, leading to cell death.

“This is a novel mechanism of action that provides potential benefit for patients who otherwise do not have a lot of options,” said Hess. “For patients who are not candidates for, not interested in, or relapse after CAR-T, this is could be a promising therapy option. Additionally, the drug is delivered intravenously every three weeks, so patient proximity to treatment centers is less critical for this therapy.”

The overall response rate in this clinical trial was 48% (70 out of 145 patients). This means that nearly 50% of relapsed DLBCL patients who had already tried two or more treatments had a complete or partial response to this new therapy.

The phase 2 trial result led to Food and Drug Administration (FDA) approval of Loncastuximab tesirine as a single agent. The next step will be to combine it with other agents to see if this improves efficacy and durability of response. This new trial is expected to be open for enrollment at MUSC in the next six months.

“I am excited that this therapy can now be given to patients who may live two to three hours away from Charleston, South Carolina, and not want or be able to travel to MUSC for treatment. We look forward to providing education on the potential efficacy and toxicity of this agent to oncology practitioners throughout the state of South Carolina so that patients can receive this therapy locally,” said Hess.

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Founded in 1824 in Charleston, MUSC is the oldest medical school in the South as well as the state’s only integrated academic health sciences center with a unique charge to serve the state through education, research and patient care. Each year, MUSC educates and trains more than 3,000 students and nearly 800 residents in six colleges: Dental Medicine, Graduate Studies, Health Professions, Medicine, Nursing and Pharmacy. The state’s leader in obtaining biomedical research funds, in fiscal year 2019, MUSC set a new high, bringing in more than $284 million. For information on academic programs, visit musc.edu.

As the clinical health system of the Medical University of South Carolina, MUSC Health is dedicated to delivering the highest quality patient care available while training generations of competent, compassionate health care providers to serve the people of South Carolina and beyond. Comprising some 1,600 beds, more than 100 outreach sites, the MUSC College of Medicine, the physicians’ practice plan and nearly 275 telehealth locations, MUSC Health owns and operates eight hospitals situated in Charleston, Chester, Florence, Lancaster and Marion counties. In 2020, for the sixth consecutive year, U.S. News & World Report named MUSC Health the No. 1 hospital in South Carolina. To learn more about clinical patient services, visit muschealth.org.

MUSC and its affiliates have collective annual budgets of $3.2 billion. The more than 17,000 MUSC team members include world-class faculty, physicians, specialty providers and scientists who deliver groundbreaking education, research, technology and patient care.

MUSC Hollings Cancer Center is a National Cancer Institute-designated cancer center and the largest academic-based cancer research program in South Carolina. The cancer center comprises more than 100 faculty cancer scientists and 20 academic departments. It has an annual research funding portfolio of more than $44 million and a dedication to reducing the cancer burden in South Carolina. Hollings offers state-of-the-art diagnostic capabilities, therapies and surgical techniques within multidisciplinary clinics that include surgeons, medical oncologists, radiation therapists, radiologists, pathologists, psychologists and other specialists equipped for the full range of cancer care, including more than 200 clinical trials. For more information, visit hollingscancercenter.musc.edu.