Davids Highlights Mounting Treatment Options in CLL

Matthew S. Davids, MD, MMSc

Patients with chronic lymphocytic leukemia (CLL), including those with difficult-to-treat disease classes such as double refractory, are quickly gaining more effective treatment options. As data for available agents continue to mature and promising new novel therapies emerge, Matthew S. Davids, MD, MMSc, said these treatment modalities are likely shift options.

Davids, the director of clinical research in the Division of Lymphoma at Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School in Boston, Massachusetts, presented an overview of the key updates in CLL during the 27th Annual International Congress on Hematologic Malignancies^®: Focus on Leukemias, Lymphomas, and Myeloma.¹

Novel BTK Inhibitors

Davids first talked through the latest data concerning the efficacy of pirtobrutinib (Jaypirca). The agent is currently under investigation for patients with previously treated CLL or small lymphocytic lymphoma (SLL) in the phase 1/2 BRUIN trial (NCT03740529).²

Pirtobrutinib has shown efficacy among patients who have previously received a Bruton tyrosine kinase (BTK) inhibitor; this subgroup in the BRUIN trial (n = 247) experienced an overall response rate (ORR) of 82.2% (95% CI, 76.8%-86.7%), including a 1.6% complete response (CR) rate. Additionally, in a subgroup of patients underwent prior treatment with a BTK inhibitor and a BCL2 inhibitor (n = 100) the ORR was 79.0% (95% CI, 69.7%-86.5%).

In terms of progression-free survival (PFS), at a median follow-up of 19.4 months, patients who received a prior BTK inhibitor achieved a median PFS of 19.6 months (95% CI, 16.9-22.1). In the prior BTK and BCL-2 inhibitor subgroup, the median PFS was 16.8 months (95% CI, 13.2-18.7) at a median follow-up of 18.2 months. The median lines of prior therapy were 3 and 5, respectively.

Pirtobrutinib has also shown efficacy among patients with CLL displaying a Richter Transformation, a rare complication that often leads to more aggressive disease. In another subgroup of the BRUIN trial, patients with CLL harboring a Richter Transformation (n = 75) achieved an ORR of 52.0% (95% CI, 40.2%-63.7%), including a 13.3% CR rate. Similarly, in patients with the transformation who received prior radiotherapy (n = 68) experienced an ORR of 50.0% (95% CI, 37.6%-62.4%) with a CR rate of 13.2%.³

“The durability of these responses was quite short; the median PFS was only 3.7 months [and] the median overall survival [OS] is over 1 year,” Davids said. “This is potentially a good agent to bridge patients with, but probably is not going to be sufficient on its own to provide durable response for Richter [transformation].”

Among all patients treated at every dose level in BRUIN (N = 773), treatment-emergent adverse effects (TEAEs) leading to discontinuation occurred in 2.6% of patients and dose reductions due to TEAEs occurred in 4.5%. The most common TEAEs of any grade included fatigue (28.7%), diarrhea (24.2%), and neutropenia (24.2%). Common grade 3 or greater TEAEs consisted of neutropenia (20.4%), anemia (8.8%), and COVID-19 infection (2.7%).²

Another BTK inhibitor, the non-covalent agent nemtabrutinib, is currently under investigation for patients with hematologic malignancies in the phase 1/2 Bellwave-001 study (NCT03162536). Patients with CLL/SLL who received prior treatment with BTK and BLC2 inhibitors (n = 24) achieved an ORR of 58% (95% CI, 37%-78%) with a median PFS of 10.1 months (95% CI, 7.4-15.9) and a median duration of response of 8.5 months (95% CI, 2.7-not evaluable [NE]).⁴

Notably, the benefit in terms of response rate was consist across some key subgroups. Patients with CLL/SLL with C4815-mutant BTK (n = 36), del(17p) (n = 19), or IGHV-unmutated disease (n = 30) experienced ORRs of 58% (95% CI, 41%-75%), 53% (95% CI, 29%-76%), and 50% (95% CI, 31%-69%), respectively.

The median follow-up among all CLL/SLL patients (n = 57) was 8.1 months (range, 0.1-38.8). The most common adverse effects (AEs) were dysgeusia (21%), decreased neutrophil count (20%), and fatigue (13%).

The final BTK inhibitor Davids highlighted was NX-2127, a first-in-class protein degrader of BTK.

“[There is a] unique mechanism of action here; this drug is working to target BTK and move it toward a complex with CRBN E3 ligase,” Davids said. “This then allows for ubiquitination of BTK, and it can then be destroyed by the proteasome. What’s important about this is that the degrader drug can bind to a completely different site on BTK. It’s not binding at cysteine 481. And so it doesn’t care if there’s a mutation there or some of the other common mutations that have been seen at the active site.”

NX-2127 has displayed preliminary efficacy in patients with CLL in a phase 1 trial (NCT04830137). Disease evaluable patients with CLL (n = 15) who received the agent had an ORR of 33% (95% CI, 12%-62%). Davids also added that there was a significant reduction in lymph node disease for the majority of patients, including patients who are double-exposed to BTK and BCL2 inhibitors, as well as those with BTK-resistance mutations.⁵

In terms of safety, in the overall population (N = 36), common any grade AEs consisted of fatigue (52.8%), neutropenia (38.9%), and contusion (27.8%). Serious AEs included 2 cases of atrial fibrillation/flutter, as well as single cases of contusion and anemia. For patients with CLL, there was 1 dose-limiting toxicity (DLT) and the maximum-tolerated dose was not yet reached.

Novel BCL-2 Inhibitor

Davids transitioned to discussing BCL2 inhibitors, first touching on BGB-11417. The agent is under investigation as a monotherapy and in combination with zanubrutinib (Brukinsa) for the treatment of patients with CLL/SLL in a phase 1 trial (NCT04277637).⁶

Early-stage findings from the study showed that efficacy-evaluable patients with relapsed/refractory disease (n = 6) who received monotherapy achieved an ORR of 67%, including a 33% CR rate. Efficacy-evaluable patients with relapsed/refractory disease (n = 20) and those who were treatment-naïve (n = 11) who received the combination achieved ORRs of 95% and 100%, respectively, including respective CR rates of 30% and 18%.

Regarding safety, tumor lysis syndrome (TLS) was not present clinically with 1 instance of lab TLS. Most instances of diarrhea were grade 1. Granulocyte colony-stimulating factor (G-CSF) was used in 4 of 8 patients in the monotherapy arm compared with 10 of 71 in the combination arm. Overall, 3.8% of patients used more than 1 course of G-CSF to treat neutropenia.

Another BCL2 inhibitor, lisaftoclax, is being examined as a monotherapy and as a potential component in combinations in patients with CLL/SLL in a phase 1 study (NCT04215809). As of July 4, 2022, no DLTs had been observed among the 164-patient safety population. However, there were 18 instances of dose interruption and 2 cases of dose reduction due to neutropenia.⁷

In terms of efficacy, the ORR was 67%, 79%, 98%, and 100%, among patients with relapsed/refractory disease who received lisaftoclax monotherapy (n = 43), those with relapsed/refractory disease who received lisaftoclax plus rituximab (n = 34), those with relapsed/refractory disease who received lisaftoclax plus acalabrutinib (n = 57), and those with treatment-naïve disease who received lisaftoclax plus acalabrutinib (n = 16). The median ranges of treatment duration were 16.5 months (range, 1-36), 11 months (range, 1-21), 12 months (range, 1-24), and 7 months (range, 5-11), respectively.

Immunotherapies

Davids concluded his presentation by mentioning some immunotherapies displaying efficacy in the CLL/SLL space, namely CAR T-cell therapies and bispecific antibodies.

The CAR T-cell agent lisocabtagene maraleucel (liso-cel; Breyanzi) is under investigation in patients with relapsed/refractory CLL/SLL in the phase 1/2 TRANSCEND CLL 004 trial (NCT03331198). Patients treated at all dose levels (n = 22) have experienced an ORR of 82% (95% CI, 59.7%-94.8%), and those who received 50 x 106 CAR-positive T cells (n = 9) and 100 x 106 CAR-positive T cells (n = 13) experienced ORRs of 78% (95% CI, 40.0%-97.2%) and 85% (95% CI, 54.6%-98.1%), respectively.⁸

Additionally, the CR/CR with incomplete count recovery rates were 45%, 56%, and 38%, respectively. Undetectable minimal residual disease (MRD) in the blood was present in 75% of patients in each group, and undetectable MRD in the marrow was observed in 65%, 75%, and 58% of patients, respectively. Cytokine release syndrome of any grade occurred in 74% of patients overall, with 9% of these events being grade 3.

In another trial, the phase 1 ZUMA-8 study (NCT03624036), objective responses were observed in 47% of patients with CLL/SLL who received the CAR T-cell therapy brexucabtagene autoleucel (brexu-cel; Tecartus). Patients treated with brexu-cel (n = 15) also achieved a CR rate of 13%. CRS occurred in 80% of patients, 7% of these events were grade 4, and neurologic events of any grade were reported in 73% of patients.⁹

Davids then moved into his discussion of bispecific antibodies, noting that they may eventually have a role in CLL treatment but are hampered by variable patient responses and drug resistance, underscoring the need for adjunct therapies.

In the phase 1/2 EPCORE CLL-1 trial (NCT04623541) patients with relapsed/refractory CLL with a Ritchter transformation are being treated with the investigational bispecific antibody epcoritamab. Preliminary results from the trial showed that the ORR was 60% among 10 patients, including a complete metabolic response rate of 50%. The median time to response was 1.3 months (range, 1.1-2.4) and the median time to complete response was 1.4 months (range, 1.1-2.8).¹⁰

The novel agent MS-553 is also stirring up attention in the CLL space. The agent is an inhibitor of PKCβ; inhibition of this kinase has the potential to overcome mutation-driven resistance, according to Davids.

Initial findings from a phase 1/2 study (NCT03492125) showed that patients with CLL/SLL who received MS-553 (n = 45) experienced an ORR of 48%. In terms of safety, the most common treatment-related AEs of any grade were nausea (60%), diarrhea (44%), and fatigue (28%).¹¹

Davids concluded his presentation by mentioning some other novel pathways and targets that are currently under investigation including ROR1, CD37, CDK9, CCR7, and MALT1.¹

References

1. Davids MS. New agents and approaches in CLL (focus on investigational agents). Presented at: 27th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas, and Myeloma; Miami, FL; February 24-27, 2023.
2. Mato AR, Woyach JA, Brown JR, et al. Efficacy of pirtobrutinib in covalent BTK-inhibitor pre-treated relapsed / refractory CLL/SLL: additional patients and extended follow-up from the phase 1/2 BRUIN study. Blood. 2022;140(suppl 1):2316-2320. doi:10.1182/blood-2022-159497
3. Weirda WG, Lewis DJ, Ghia P, et al. Efficacy of pirtobrutinib, a highly selective, non-covalent (Reversible) BTK inhibitor in Richter transformation: results from the phase 1/2 BRUIN study. Blood. 2022;140(suppl 1):846-849. doi:10.1182/blood-2022-157058
4. Woyach JA, Flinn IW, Awan F, et al. Efficacy and safety of nemtabrutinib, a wild-type and C481S-mutated Bruton tyrosine kinase inhibitor for B-cell malignancies: updated analysis of the open-label phase 1/2 dose-expansion Bellwave-001 study. Blood. 2022;140(suppl 1):7004-7006. doi:10.1182/blood-2022-163596
5. Mato AR, Weirda WG, Ai WZ, et al. NX-2127-001, a First-in-human trial of NX-2127, a Bruton'’ tyrosine kinase-targeted protein degrader, in patients with relapsed or refractory chronic lymphocytic leukemia and B-Cell malignancies. Blood. 2022;140(suppl 1):2329-2332. doi:10.1182/blood-2022-164772
6. Cheah CY, Tam CS, Lasica M, et al. A phase 1 study with the novel B-cell lymphoma 2 (Bcl-2) inhibitor Bgb-11417 as monotherapy or in combination with zanubrutinib (ZANU) in patients (Pts) with CLL/SLL: preliminary data. Blood. 2022;140(suppl 1):2321-2323. doi:10.1182/blood-2022-169662
7. Davids MS, Chanan-Khan A, Mudenda B, et al. Lisaftoclax (APG-2575) safety and activity as monotherapy or combined with acalabrutinib or rituximab in patients (pts) with treatment-naïve, relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (R/R CLL/SLL): initial data from a phase 2 global study. Blood. 2022;140(suppl 1):2326-2328. doi:10.1182/blood-2022-160386
8. Siddiqi T, Soumerai JD, Dorritie KA, et al. Phase 1 TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with relapsed/refractory CLL or SLL. Blood. 2022;139(12):1794-1806. doi:10.1182/blood.2021011895
9. Davids MS, Kenderian SS, Flinn IW, et al. ZUMA-8: a phase 1 study of KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory chronic lymphocytic leukemia. Blood. 2022;140(suppl 1):7454-7456. doi:10.1182/blood-2022-167868
10. Kater AP, Ye C, Sandoval-Sus J, et al. Subcutaneous epcoritamab in patients with Richter’s syndrome: early results from phase 1b/2 trial (EPCORE CLL-1). Blood. 2022;140(suppl 1):850-851. doi:10.1182/blood-2022-158298
11. Blachly JS, Stephens DM, Ye CJ, et al. Initial results from a phase 1/2 dose escalation and expansion study evaluating MS-553, a novel and selective PKCβ inhibitor, in patients with CLL/SLL. Blood. 2022;140(suppl 1):2324-2325. doi:10.1182/blood-2022-171203