Authored by Brian Koffman, MDCM (retired), MSEd
The Bottom Line:
Epcoritamab, a novel bispecific antibody monotherapy, showed strong results in relapsed / refractory high-risk CLL patients running out of options.
Who Performed the Research and Where Was it Presented:
Dr. Alexey Danilov of City of Hope Medical Center, Duarte, CA, shared the results in an oral presentation at the American Society for Hematology (ASH) Annual Meeting in 2024 on behalf of a multicenter group of researchers.
Background:
Monoclonal antibodies are potent immunotherapy drugs that are millions of copies of identical (monoclonal) Y-shaped proteins. Examples include rituximab and obinutuzumab, where both arms on the Y attach to a surface protein (CD20) found on chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) B cells, tagging them for destruction by the immune system, specifically any nearby T cells. Bispecific monoclonal antibodies go a step further. One arm of the Y attaches to CD20 on the cancer. At the same time, the other arm has been engineered to attach to CD3, a surface protein found on T cells, the soldiers of the immune system, grabbing and juxtaposing them next to the CLL cells, ensuring the destruction of the cancer cells. Several bispecific antibodies have been successfully used and approved to treat other lymphomas, but their use in CLL / SLL is still experimental.
There is a significant unmet need for CLL patients who have poor prognostic markers and have relapsed after multiple therapies, including a Bruton tyrosine kinase inhibitor (BTKi) and venetoclax. That is why epcoritamab is being studied in this population.
Methods and Participants:
This multicenter open-label Phase 1 trial enrolled CLL / SLL patients with two or less prior lines of therapy, including a BTKi. Most had progressed on the BTKi and venetoclax. Patients received subcutaneous (a tiny shot under the skin in the abdomen) epcoritamab 48 mg once every 28 days, but only after slow weekly increases of the dose over several weeks with aggressive treatments with fluids and medication to reduce the risks from cytokine release syndrome (CRS). In the latest cohort, an extra step in the dose ramp-up and stronger measures were added to further mitigate CRS.
Results:
- A total of 40 patients. The average age was 71.5 years old.
- The median number of prior lines of therapy was four, with a range of 2-10 lines of therapy. Eighty-eight percent had prior chemoimmunotherapy, and 85% had received BTKi and venetoclax (double exposed).
- Sixty-three percent had TP53 aberrations, while 70% had unmutated IGHV, so overall, this was a high-risk, difficult-to-treat group.
Responses:
- The overall response rate (ORR) was 61%.
- The complete response (CR) rate was 39%.
- Responses were quick, averaging two months to the first response and 5.6 months to CR.
- ORR/CR rate was 67%/33% among those with TP53 aberrations (n=15), 63%/44% in IGHV-unmutated disease (n=16), and 53%/37% in those double-exposed (n=19).
- Results are early, but the median progression-free survival (PFS was 12.8 months, and the median overall survival (OS) has not been reached,
- In the 12 responders tested for measurable residual disease (MRD) by next-generation sequencing in peripheral blood, nine (75%) had undetectable MRD (uMRD) at 10−4, and eight (67%) had uMRD at 10−6.
Adverse Events:
- The most common side effect was CRS, which was seen in almost all patients (96%). No one quit the trial due to CRS. There was no neurotoxicity or tumor lysis syndrome in the slower ramp-up cohort.
- Other common nonblood-related side effects were diarrhea (48%), peripheral edema or swelling (48%), fatigue (43%), and injection-site reaction (43%).
- Low blood counts were common, but many of these were present at the start of the trial, suggesting they were caused by the disease and not the treatment.
- Four patients died, three from infections and one from skin cancer.
Conclusions:
Epcoritamab is a potent immune therapy, with better early results than published with CAR-T, another immunotherapy used in CLL / SLL. While cytokine release syndrome was almost universal, it was generally low grade, especially with the newer protocol, which has a slower ramp-up and more efforts at mitigation. With the possibility of higher response rates and fewer adverse events than CAR-T, there are many questions yet to be answered.
- Does it offer more durable responses?
- Would adding a targeted agent, such as a BTKi that doubles CAR-T response rates, help bispecifics too? There is reason to believe it would.
- Would moving it up as an earlier line of treatment when the immune system is more robust lead to deeper and longer responses?
We are very early in the process with much to learn, but the news so far is encouraging for this whole new way of treating CLL / SLL.
Links and Resources:
Watch the interview on the abstract here:
Read the ASH 2024 abstract: Epcoritamab Monotherapy in Patients (Pts) with Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia (CLL): Results from CLL Expansion and Optimization Cohorts of Epcore CLL-1
Read more about epcoritamab for relapsed / refractory CLL: Solid Results for Epcoritimab for Relapsed / Refractory CLL
On a personal note, I am participating in this trial with Dr. Danilov caring for me. Check out my epcoritamab blog to learn about all my early trial challenges and my good news.
