Piecing Together the Proper BTK Usage in CLL

Chronic Lymphocytic Leukemia

An emerging need in the chronic lymphocytic leukemia (CLL) population is the progression observed with covalent BTK inhibitors and venetoclax (Venclexta), according to a presentation given by Nicole Lamanna, MD, during the 42nd Annual Chemotherapy Symposium Foundation, an event held by Physicians’ Education Resource, LLC.

Lamanna highlighted various treatment options available for patients with CLL who have relapsed multiple times. The presentation focused on a number of emerging and established clinical trials, while also discussing the use of CAR T-cell therapy in this population.

“Our patients who have relapsed multiple times are becoming a new clinically unmet need. With the covalent and the venetoclax- based therapies, patients can be bridged to a non-covalent, like ibrutinib [Imbruvica]. These patients are not going to last that long, so they need to get on a clinical trial or bridge or receive CAR T-cell therapy if they’re eligible,” said Lamanna, an associate clinical professor of medicine in the Hematologic Malignancies Section of the Hematology/Oncology Division at Columbia University Herbert Irving Comprehensive Cancer Center in New York, New York.

How to Optimally Sequence CLL Treatment

Lamanna began by discussing sequencing options that were historically used and explored what is now being considered for these patients with CLL.

Prior to the first-line approval of ibrutinib, frontline options included chemoimmunotherapy followed by covalent BTK inhibitors; the third-line setting comprised a venetoclax-containing regimen. After ibrutinib was approved in the frontline setting, second-line setting included a venetoclax-containing regimen.¹

With the 2019 approval of venetoclax plus obinutuzumab (Gazyva) in the frontline setting, the second-line setting then had limited data; however, treatment with venetoclax-containing regimens or a BTK inhibitor were likely to be effective, she explained.

Lamanna highlighted a trial evaluating patients with CLL who were treated with venetoclax or a BTK inhibitor.² In the study, 42 patients were double exposed and 18 were double refractory. Results showed that the median overall survival (OS) was 5.3 months in the whole cohort, with patients in the progressive CLL cohort showed a median OS of 11.3 months, compared with 3.4 months in the Richter transformation cohort.

Potential Treatment Options of Patients With Double-Exposed CLL

Results from the phase 1/2 TRANSCEND CLL 004 trial (NCT03331198) explored the use of lisocabtagene ciloleucel (liso-cel; Breyanzi). Patients were enrolled if they were ineligible for a BTK inhibitor; had high-risk disease, or 2 prior therapies had failed them; or had standard-risk disease, and 3 prior therapies had failed them.³

Results showed that the primary end point, which was complete response/complete hematologic recovery (CR/CRi) by an independent review committee, was met. The CR/CRi rate in the full population was 19.3% (95% CI, 11.7%-29.1%). A total of 18.4% of patients experienced a CR/CRi after progression on a BTK inhibitor and venetoclax treatment failure.

Results from this trial led to the FDA approval of liso-cel in March 2024 for patients with CLL who have received 2 or more lines of therapy.⁴

The Investigation With BTK Degraders in CLL

Emerging therapies are being developed to help with the unmet need for continued progression after multiple lines of therapy. In the phase 1/2 CaDAnCE-101 trial (NCT05006716), investigators evaluated BGB-16673 for patients with relapsed/refractory B-cell malignancies.⁵ Specifically, 49 patients with relapsed/refractory CLL/ small lymphocytic lymphoma (SLL) were enrolled in the part 1a/1b portion of the trial.

The median follow-up was 4.60 months (range, 0.3-19.8) and 82% of patients remained on treatment. The median lines of prior therapy was 4. Of the available data, 82% of patients had unmutated IGHV disease, 60% had del(17p) or TP53 mutations, and 47% had complex karyotype.

Results showed that of the response-evaluable patients with CLL/SLL, the overall response rate was 72% (n = 31/43). The disease control rate was 88%, and the time to first response was 2.8 months (range, 2.6-6.2).

The most common grade 3 or higher adverse effects included neutropenia/neutrophil count decrease (20%), pneumonia (12%), fatigue (2%), anemia (2%), and lipase increase (2%). No cases of atrial fibrillation of grade 3 or higher hypertension were reported.

ORRs were similar for patients who had previously received covalent BTK plus BCL2 inhibitors (70%), del(17p) or TP53 mutation (68%), or complex karyotype (67%). The study also reported responses in patients with C481S, T474I, and/or L528S BTK mutations, plus PLCG2 mutations.

Another study discussed included the phase 1a/b NX-5948-301 trial (NCT05131022), of which up to 66 patients with CLL/SLL were enrolled, with 31 continued on step-up dosing of NX-5984.⁶ Currently, 27 patients are on treatment.

Results showed that the objective response rate was 69.2% (95% CI, 48.2%-85.7%) with no CRs, a 69.2% partial response (PR) rate, 23.1% having stable disease, and 7.7% having progressive disease. The median duration of treatment was 2.8 months.

Based on mutation status, BTK degradation on this trial showed robust responses and degradation of wild-type and mutant BTK. Overall, 43.3% had BTK mutations, including C4815 (23.3%), L528 (6.7%), T474 (10.0%), V416 (3.3%), and G541V (3.3%).

The most common grade 3 or higher AEs included neutropenia (15.2%) and thrombocytopenia (8.9%).

Do the Next Steps for CLL Include Bispecific Antibodies?

Lamanna presented information regarding what might be next steps for improving CLL treatment and outcomes. For example, phase 1b/2 EPCOR trial (NCT04623541), specifically that of the relapsed/refractory CLL-1 expansion cohort.⁷ Patients were given epcoritamab-bysp (Epkinly) with 23 patients fully enrolled through step-up dosing.

The trial included 70% of patients who had IGHV-unmutated CLL and 65% who had TP53 aberrations. The median number of lines of therapy was 4 (range, 2-10), with 65% of patients having 4 or more lines of treatment. Overall, 100% of patients had a small molecule inhibitor, 100% had a BTK inhibitor, and 83% had a BCL2 inhibitor.

The ORR in the total efficacy evaluable group (n = 21) was 62%, 33% had CRs, 29% had PRs, 19% had stable disease, and 5% had progressive disease. Responses occurred early and appeared durable.

Treatment-emergent AEs remained low-grade, with the most common grade 2 AEs being cytokine release syndrome (73.9%), peripheral edema (17.4%), and constipation (17.4%).

References

1. FDA approves ibrutinib plus rituximab for chronic lymphocytic leukemia. News release. FDA. April 21, 2020. Accessed November 13, 2024. https://shorturl.at/DwYjh
2. Lew TE, Lin VS, Cliff ER, et al. Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition. Blood Adv. 2021;5(20):4054-4058. doi:10.1182/bloodadvances.2021005083
3. Siddiqi T, Maloney DG, Kenderian SS, et al. Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Lancet. 2023;402(10402):641-654. doi:10.1016/S0140-6736(23)01052-8
4. U.S. FDA approves Bristol Myers Squibb’s Breyanzi® as the first and only CAR T cell therapy for adults with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). News release. Bristol Myers Squibb. March 14, 2024. Accessed November 13, 2024. https://shorturl.at/C31Qo
5. Parrondo RD, Thomspon MC, Frustaci AM, et al. Preliminary efficacy and safety of the Bruton tyrosine kinase pegrader BGB-16673 in patients with relapsed or refractory CLL/SLL: results from the phase 1 BGB-16673-101 study. Presented at the 2024 European Hematology Association Congress; June 13-16, 2024; Madrid, Spain. Abstract S157.
6. Searle E, Forconi F, Linton K, et al. Initial findings from a first-in-human phase 1a/b trial of NX-5948, a selective Bruton’s tyrosine kinase (BTK) degrader, in patients with relapsed/refractory B cell malignancies. Blood. 2023;142(suppl 1):4473. doi:10.1182/blood-2023-179508
7. Kater AP, Eradat H, Niemann CU, et al. Epcoritamab in patients with relapsed or refractory chronic lymphocytic leukemia: results from the phase 1b/2 EPCORE CLL-1 trial expansion cohort. Presented at: 2023 International Workshop on CLL; October 6-9, 2023; Boston, MA. Abstract 1546171.