Authored by Dr. Brian Koffman
Bottom Line:
Epcoritamab, a bispecific antibody, shows encouraging early results in difficult-to-treat relapsed / refractory chronic lymphocytic leukemia (CLL) patients.
Who Performed the Research and Where Was it Published:
Dr. Arnon Kater from Amsterdam presented the results of an international phase I/II (dose finding / dose expansion) trial he led studying epcoritamab in relapsed / refractory (R / R) chronic lymphocytic leukemia (CLL) at the International Workshop on Chronic Lymphocytic Leukemia (iwCLL2023), October 6–9, 2023 in Boston, MA.
Background:
CLL patients who have been failed by two or more prior lines of therapy have few choices and generally poor outcomes.
While T-cell immune therapies have revolutionized the care of other lymphomas, they have been disappointing in CLL. This is because CLL cells impair the normal activity of T cells to control cancer. For example, CAR-T results in CLL, while very helpful to some, have been less successful than those of other B-cell lymphomas.
Bispecific antibodies are a different type of immunotherapy that engages the T cells without modifying them as CAR-T therapy does. Monoclonal antibodies such as rituximab or obinutuzumab work by latching onto the CD 20 protein on the surface of the cancerous CLL cells and normal B cells and labeling them for destruction by passing T cells. Bispecifics such as epcoritamab and others take this a step further. They latch on to both the CLL cells’ CD20 and CD3, a marker found on T cells. This pulls the T cell and its target B cells together, making cancer killing much more efficient.
Methods and Participants:
To be included in the trial, the 23 R / R CLL patients enrolled had to have needed therapy to have had at least two prior lines of therapies, including a BTK inhibitor (BTKi) such as ibrutinib, acalabrutinib, zanubrutinib or pirtobrutinib, be positive for CD20, a surface maker almost always seen on CLL cells, and have measurable disease. In this study cohort, all 23 patients had also received prior chemoimmunotherapy; most had failed the BTKi and venetoclax. Many were IgVH unmutated and TP53 aberrant or 17p deletion; all had bad prognostic markers. Overall, this was a very tough group of patients to treat with a poor prognosis.
The bispecific antibody epcoritamab is similar to most other large molecular antibodies, such as the COVID-19 antibodies or rituximab and obinutuzumab, in that it would be destroyed in the gut if taken orally. Therefore, it was given as a subcutaneous (under the skin, like an insulin shot) injection. The dose is stepped up very slowly at the beginning to minimize side effects. Shots started weekly, every two weeks, and every four weeks.
Results:
21 patients could be assessed at the time of the presentation.
Responses:
- 62% or 13 patients responded, with 33% or seven patients having a complete response (CR). Subsequent to this presentation, with a longer follow-up, the CR rate climbed to 50%.
- CR was similar in those with or without poor prognostic markers.
- All patients who reached a CR and approximately 50% of those with partial remission (PR) were uMRD-4 (undetectable measurable residual disease) or had less than one CLL cell in 10,000 cells in the blood. Reaching uMRD is probably a more important prognostic marker for a long remission than reaching a CR.
Adverse Events:
- All T cell therapies, including bispecific antibodies, work by activating the T cells, which can lead to cytokine release syndrome (CRS), where inflammatory cytokines or enzymes are excessively released, potentially causing adverse side effects that can be mild or even fatal.
- CRS was seen at some point in all patients but was mostly mild (fevers, chills, nausea, soreness). There were no severe CRS and no deaths from CRS.
- Another unique and troubling but fortunately rarer side effect with all T therapies is ICANS (immune effector cell-associated neurotoxicity syndrome). It was only seen in three patients and was mild.
- Infection risk due to the treatments, especially the high-dose steroids used to treat or prevent CRS, is a concern. There were two deaths from pneumonia.
- One patient died of squamous cell carcinoma of the skin. This is not usually a fatal cancer, suggesting immune suppression might have played a role in its aggressive nature.
Discussion:
These early results are promising, especially when compared to the only approved T cell therapy, CAR-T. Future considerations include:
- Using it in combination with other therapies.
- Using earlier when T cell function might be better.
- It can be used briefly as a consolidation or “mop up” therapy to deepen responses after finishing a time-limited treatment, where some residual disease remains.
Conclusions:
Although very early, the results for epcoritamab are most encouraging in difficult-to-treat CLL patients with few options. Like CAR-T, CRS, ICANS, and immune suppression leading to fatal infections and second cancers are serious risks, though preliminary results suggest better responses and milder adverse events. New trials with epcoritamab and other bispecific antibodies are being developed to maximize their efficacy and limit toxicity.
Links and Resources:
Dr. Kater shares more details in our interview.
This was only an oral presentation at iwCLL, there is no abstract. However, the presentation slide set provides excellent background material and more granularity on the study design and results.
On a personal note, I am presently on a trial of epcoritamab and am doing very well. You can read about my experience in the trial on my blog.
More information about this trial can be found on ClinicalTrials.gov: Safety and Efficacy Study of Epcoritamab in Subjects With Relapsed/ Refractory Chronic Lymphocytic Leukemia and Richter’s Syndrome (EPCORE™ CLL-1)
Stay strong; we are all in this together.
Brian Koffman, MDCM (retired), MS Ed
Co-Founder, Executive VP and Chief Medical Officer
CLL Society
