A Review of Selected Presentations From ASH 2024
December 7-10, 2024 • San Diego, California
Fixed-Duration Acalabrutinib + Venetoclax With or Without Obinutuzumab vs Chemoimmunotherapy for First-Line Treatment of CLL: Interim Analysis of the Multicenter, Open-Label, Randomized, Phase 3 AMPLIFY Trial
Fixed-duration venetoclax plus ibrutinib is a first-line treatment option for patients with chronic lymphocytic leukemia (CLL). Although the regimen is associated with durable responses, cardiac toxicity is a concern, especially in older patients.1,2 Acalabrutinib is associated with improved safety and tolerability over ibrutinib.3
At ASH 2024, Jennifer R. Brown, MD, PhD, presented results from the prespecified interim analysis of the randomized, open-label, phase 3 AMPLIFY trial comparing fixed-duration acalabrutinib plus venetoclax (with or without obinutuzumab) vs investigator’s choice of chemoimmunotherapy in fit patients with treatment-naive CLL (Figure 1).4 A total of 867 patients with treatment-naive CLL were randomly assigned to receive acalabrutinib 100 mg orally twice daily (cycles 1-14) plus venetoclax 400 mg orally once daily (cycles 3-14) (AV; n=291); acalabrutinib 100 mg orally twice daily (cycles 1-14), venetoclax 400 mg orally once daily (cycles 3-14), and obinutuzumab 1000 mg (cycles 2-7) (AVO; n=286); or chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine and rituximab (BR) for 6 cycles (n=290).
After a median follow-up of 40.8 months, the trial met its primary endpoint, demonstrating a significant improvement in independent review committee (IRC)–assessed progression-free survival (PFS) with AV vs FCR/BR (median, not reached vs 47.6 months; hazard ratio [HR], 0.65; P=.0038). IRC-assessed PFS was also significantly longer with AVO vs FCR/BR (median, not reached vs 47.6 months; HR, 0.42; P<.0001). The 3-year PFS rates with AV, AVO, and FCR/BR were 76.5%, 83.1%, and 66.5%, respectively. The PFS benefit of AV and AVO over FCR/BR was maintained in the subset of patients with unmutated immunoglobulin heavy chain variable region (uIGHV), with 3-year PFS rates of 68.9%, 82.8%, and 56.8%, respectively, but not in the mutated IGHV subgroup.
Rates of undetectable minimal residual disease (uMRD) (<10-4) in peripheral blood at the end of treatment were higher with AVO than with AV or FCR/BR in the intent-to-treat (ITT) populations (67.1%, 34.4%, and 45.5%, respectively) and the evaluable populations (95.0%, 45.0%, and 72.9%, respectively). The acalabrutinib-containing regimens continued to show a PFS benefit over FCR/BR in the subset of patients with uMRD at end of treatment, whether comparing AV with FCR/BR (median, not reached vs 49.2 months; HR, 0.43; 95% CI, 0.24-0.76) or comparing AVO with FCR/BR (median, not reached vs 49.2 months; HR, 0.27; 95% CI, 0.16-0.46).
In the overall population, overall survival (OS) was longer with AV vs FCR/BR (HR, 0.33; 95% CI, 0.18-0.56; P<.001) but not with AVO vs FCR/BR. After censoring for deaths due to COVID-19 (10 with AV, 25 with AVO, and 21 with FCR/BR), OS was longer with either AV or AVO vs FCR/BR.
The incidence of serious adverse events (SAEs) with AV, AVO, and FCR/BR was 24.7%, 38.4%, and 27.4%, respectively. The incidence of SAEs leading to death was 3.4%, 6.0%, and 3.5%, respectively, and AEs led to treatment discontinuation in 7.9%, 20.1%, and 10.8% of patients, respectively. The most frequent grade 3 or higher AE was neutropenia. Safety analyses showed a low rate of cardiac AEs with AV (9.3%; 1.7% grade ≥3) and AVO (12.0%; 2.5% grade ≥3).
References
1. Kater AP, Owen C, Moreno C, et al. Fixed-duration ibrutinib-venetoclax in patients with chronic lymphocytic leukemia and comorbidities. NEJM Evid. 2022;1(7):EVIDoa2200006.
2. Brown JR, Moslehi J, O’Brien S, et al. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Haematologica. 2017;102(10):1796-1805.
3. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452.
4. Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib plus venetoclax with or without obinutuzumab vs chemoimmunotherapy for first-line treatment of CLL: interim analysis of the multicenter, open-label, randomized, phase 3 AMPLIFY trial. Presented at: 66th ASH Annual Meeting and Exposition; December 7-10, 2024; San Diego, California, USA. Abstract 1009.
Combined Pirtobrutinib, Venetoclax, and Obinutuzumab as First-Line Treatment of Patients With CLL
The combination of a covalent Bruton tyrosine kinase inhibitor (cBTKi) with a BCL2 inhibitor (BCL2i), with or without an anti-CD20 monoclonal antibody, is associated with high rates of uMRD in patients with CLL.1 The noncovalent BTKi pirtobrutinib is approved by the US Food and Drug Administration (FDA) for patients with relapsed/refractory (R/R) CLL who have received at least 2 prior lines of therapy including a BTKi and a BCL2i.2 At ASH 2024, Nitin Jain, MD, presented results of an investigator-initiated phase 2 trial evaluating a time-limited triplet regimen of pirtobrutinib, venetoclax, and obinutuzumab as first-line therapy in patients with CLL (Figure 2).3
The trial enrolled 80 patients with treatment-naive CLL with a median age of 63 years (range, 38-78 years); del(17p) was present in 9% of patients, del(11q) was present in 29%, and TP53 mutations were detected in 13%.
Patients received pirtobrutinib 200 mg daily starting at day 1 of cycle 1 and through cycle 13, obinutuzumab for 6 cycles starting on day 1 of cycle 1, and venetoclax starting on day 1 of cycle 2 and ramping up to a target dose of 400 mg daily that was continued through cycle 13. Downgrading of tumor lysis syndrome (TLS) risk category after 1 cycle of pirtobrutinib and obinutuzumab occurred in 19 of 21 patients (90%) with a high risk of TLS at baseline and in 42 of 49 patients (86%) with a medium risk of TLS at baseline.
At the end of cycle 7, the proportion of evaluable patients with uMRD at 10-4 (uMRD4) was 93% in the blood (n=66) and 91% in the bone marrow (n=66). At the end of cycle 13, uMRD4 rates in the blood and bone marrow were 100% and 98%, respectively. Rates of uMRD at 10-6 (uMRD6) in the bone marrow and blood were 64% and 79%, respectively, at 6 months, and 80% and 85%, respectively, at 12 months. Investigators noted that these uMRD rates exceeded previous reports with ibrutinib and venetoclax in previously untreated CLL.1
Investigators noted that the safety profile was similar to prior studies with combination treatment in first-line CLL. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 60% and 14% of patients, respectively, and 58% of patients required granulocyte colony-stimulating factor. Neutropenic fever developed in 4 patients. Reduction of pirtobrutinib dose occurred in 21% of patients and reduction of venetoclax dose in 31% of patients; neutropenia was the most common reason for dose reductions. Two patients developed atrial fibrillation, including 1 in the setting of COVID-19 infection. After a median follow-up of 11.9 months, PFS and OS remained at 100%.
References
1. Jain N, Keating MJ, Thompson PA, et al. Combined ibrutinib and venetoclax for first-line treatment of patients with chronic lymphocytic leukemia (CLL): 5-year follow-up data. Blood. 2023;142(suppl 1):4635.
2. U.S. Food & Drug Administration. FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic. Accessed January 6, 2025.
3. Jain N, Ferrajoli A, Swaminathan M, et al. Combined pirtobrutinib, venetoclax, and obinutuzumab as first-line treatment of patients with CLL. Presented at: 66th ASH Annual Meeting and Exposition; December 7-10, 2024; San Diego, California, USA. Abstract 1011.
Sonrotoclax and Zanubrutinib as Frontline Treatment for CLL Demonstrates High MRD Clearance Rates With Good Tolerability: Data From an Ongoing Phase 1/1b Study BGB-11417-101
Sonrotoclax is a novel next-generation BCL2i designed to have greater selectivity and potency against BCL2 than venetoclax, plus a shorter half-life and without drug accumulation.1 The BTKi zanubrutinib is effective in treatment-naive and R/R CLL and has demonstrated more favorable safety than ibrutinib.2
At ASH 2024, Jacob D. Soumerai, MD, presented updated results from the phase 1/1b BGB-11417-101 trial evaluating sonrotoclax plus zanubrutinib in patients with treatment-naive CLL/small lymphocytic lymphoma (SLL) (Figure 3).3 A total of 137 patients received 8 to 12 weeks of zanubrutinib lead-in (320 mg once daily or 160 mg twice daily) followed by zanubrutinib plus sonrotoclax at 160 mg (n=51) or 320 mg (n=86) until disease progression or intolerance.
The median age of enrolled patients was 62 years (range, 32-84 years); 9.0% of patients had del(17p), 22.0% had a TP53 mutation, and 17.2% had del(11q). IGHV was unmutated in 59.8% of patients.
The rate of grade 3 or higher treatment-emergent adverse events (TEAEs) was 59.9% with sonrotoclax 160 mg plus zanubrutinib and 45.3% with sonrotoclax 320 mg plus zanubrutinib. The rate of serious TEAEs was 25.5% and 23.3%, respectively. TEAEs led to discontinuation of zanubrutinib in 1 patient at the 160 mg dose (2%) and 4 patients at the 320 mg dose (4.7%). No fatal TEAEs occurred. No cases of laboratory or clinical TLS occurred. The most frequent TEAE was neutropenia, occurring in 50% of patients (24% grade 3/4) in the 160 mg cohort and in 29% of patients in the 320 mg cohort (23% grade 3/4). Neutropenia was transient and did not lead to increased rates of grade 3 or higher infections. Gastrointestinal TEAEs included diarrhea, reported in 32% of patients (4% grade 3/4) in the 160 mg group and 21% of patients (0% grade 3/4) in the 320 mg group.
At week 24, sonrotoclax plus zanubrutinib was associated with an overall response rate (ORR) of 100% in the 320 mg cohort; uMRD4 in the blood was attained in 59% of patients in the 160 mg cohort and 78% in the 320 mg cohort. By week 48, uMRD rates had increased to 82% and 91%, respectively. No patients progressed from uMRD4 to detectable MRD. After a median follow-up of 19.4 months, no progression was observed in the 320 mg cohort and there was 1 primary progression event of Richter transformation in the 160 mg cohort. The combination of sonrotoclax 320 mg and zanubrutinib is currently being evaluated in patients with treatment-naive CLL in the phase 3 CELESTIAL-TNCLL trial (NCT06073821).
References
1. Guo Y, Xue H, Hu N, et al. Discovery of the clinical candidate sonrotoclax (BGB-11417), a highly potent and selective inhibitor for both WT and G101V mutant BCL2. J Med Chem. 2024;67(10):7836-7858.
2. Molica S, Tam C, Allsup D, Polliack A. Advancements in the treatment of CLL: the rise of zanubrutinib as a preferred therapeutic option. Cancers (Basel). 2023;15(14):3737.
3. Soumerai JD, Cheah CY, Anderson MA, et al. Sonrotoclax and zanubrutinib as frontline treatment for CLL demonstrates high MRD clearance rates with good tolerability: data from an ongoing phase 1/1b study BGB-11417-101. Presented at: 66th ASH Annual Meeting and Exposition; December 7-10, 2024; San Diego, California, USA. Abstract 1012.
BRUIN CLL-321: Randomized Phase 3 Trial of Pirtobrutinib vs Idelalisib + Rituximab or Bendamustine + Rituximab in BTK Inhibitor–Pretreated CLL/Small Lymphocytic Lymphoma
Outcomes are poor in patients with CLL with progression on a cBTKi.1 Thus there is a need for effective treatments after cBTKi use. The randomized, phase 3 BRUIN CLL-321 trial was undertaken to compare single-agent pirtobrutinib against idelalisib plus rituximab (IdelaR) or BR in patients with CLL/SLL previously treated with a cBTKi. At ASH 2024, Jeff P. Sharman, MD, presented results from the BRUIN CLL-321 trial after a median follow-up of 17.2 months (Figure 4).2
The trial enrolled 238 patients with CLL/SLL previously treated with a cBTKi, including ibrutinib (87%), acalabrutinib (16%), zanubrutinib (7%), or another cBTKi (3%). About one-half of patients (51%) had received a BCL2i.
Patients were stratified based on del(17p) status and prior venetoclax, and randomly assigned to pirtobrutinib 200 mg orally once daily (n=119) or IdelaR/BR (n=119). Optional crossover from the control group to the pirtobrutinib group was allowed upon progressive disease. Many patients had high-risk features, including del(17p) and/or TP53 mutations (54%) or a complex karyotype (65%). The population was heavily pretreated, with a median of 3 prior regimens (range, 1-13).
After a median follow-up of 7.5 months, the trial met its primary endpoint, demonstrating a significant improvement in IRC-assessed PFS with pirtobrutinib vs IdelaR/BR (HR, 0.58; 95% CI, 0.38-0.89; P=.01). In a subsequent analysis, after a median follow-up of 17.2 months, the PFS benefit of pirtobrutinib over IdelaR/BR was maintained, with a median PFS of 14.0 months and 8.7 months, respectively (HR, 0.54; 95% CI, 0.39-0.75; P=.0002). The PFS benefit of pirtobrutinib was consistent across clinical and genetic subgroups. Investigator-assessed PFS showed similar findings, with a median PFS of 15.3 months with pirtobrutinib and 9.2 months with IdelaR/BR (HR, 0.48; 95% CI, 0.34-0.67; P<.0001).
Other efficacy outcomes were also improved with pirtobrutinib over IdelaR/BR, including event-free survival (EFS; median, 14.1 vs 7.6 months; HR, 0.39; 95% CI, 0.28-0.53; P<.0001) and time to next treatment or death (TTNT; median, 24.0 vs 10.9 months; HR, 0.37; 95% CI, 0.25-0.52; P<.0001). The TTNT benefit with pirtobrutinib over IdelaR/BR was observed in both venetoclax-naive patients (median, 29.5 vs 12.5 months; HR, 0.36; 95% CI, 0.21-0.61; P=.0001) and venetoclax-treated patients (median, 20.0 vs 8.7 months; HR, 0.37; 95% CI, 0.23-0.60; P<.0001).
No significant difference was observed in OS between groups; the 18-month OS rate was 73.4% with pirtobrutinib and 70.8% with IdelaR/BR (HR, 1.09; 95% CI, 0.68-1.75). However, 76% of patients in the IdelaR/BR arm crossed over to pirtobrutinib upon progression. In an inverse probability-of-censoring weighting crossover-adjusted OS analysis, the HR was 0.87 (95% CI, 0.51-1.5).
Regarding safety, the most common grade 3 or higher TEAEs with pirtobrutinib and IdelaR/BR were infections (29.3% vs 23.9%), neutropenia (20.7% vs 27.5%), anemia (11.2% vs 7.3%), and increased alanine aminotransferase (0.9% vs 9.2%). Rates of drug-related discontinuation were 5.2% and 21.1%, respectively. Richter transformation was not observed in the pirtobrutinib group and developed in 3 patients in the IdelaR/BR group.
After adjusting for the longer median treatment exposure with pirtobrutinib (15.1 months) compared with IdelaR/BR (7.1 months/4.7 months), incidence rates of most TEAEs were significantly lower with pirtobrutinib than with IdelaR/BR. Notable grade 3 or higher AEs of interest with pirtobrutinib included infection (29.3%), neutropenia (20.7%), anemia (11.2%), thrombocytopenia (7.8%), bleeding (3.4%), hypertension (2.6%), and atrial fibrillation or flutter (1.7%).
Investigators concluded that BRUIN CLL-321, the first randomized, phase 3 trial to be conducted entirely in patients previously treated with a cBTKi, demonstrated superior PFS with pirtobrutinib compared with IdelaR/BR in this population of heavily pretreated patients. Pirtobrutinib was also associated with an approximately 2-year delay in the TTNT and was well tolerated with low rates of treatment discontinuation.
References
1. Mato AR, Hess LM, Chen Y, et al. Outcomes for patients with chronic lymphocytic leukemia (CLL) previously treated with both a covalent BTK and BCL2 inhibitor in the United States: a real-world database study. Clin Lymphoma Myeloma Leuk. 2023;23(1):57-67.
2. Sharman JP, Munir T, Grosicki S, et al. BRUIN CLL-321: randomized phase 3 trial of pirtobrutinib vs idelalisib + rituximab or bendamustine + rituximab in BTK inhibitor pretreated CLL/small lymphocytic lymphoma. Presented at: 66th ASH Annual Meeting and Exposition; December 7-10, 2024; San Diego, California, USA. Abstract 886.
Epcoritamab Monotherapy in Patients With R/R CLL: Results From CLL Expansion and Optimization Cohorts of EPCORE CLL-1
Epcoritamab is a bispecific CD20-directed CD3 T-cell engager that received FDA approval for the treatment of adults with different types of R/R large B-cell lymphoma and follicular lymphoma after at least 2 lines of systemic therapy, based on results of the phase 1/2 EPCORE NHL-1 trial.1,2
The phase 1/2 EPCORE CLL-1 trial is evaluating epcoritamab monotherapy in patients with R/R CLL. As previously reported, EPCORE CLL-1 showed encouraging activity in patients with CLL and Richter transformation (Table 1).3,4 Although toxicities with epcoritamab were generally manageable, efforts are ongoing to reduce the incidence and severity of cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) with epcoritamab.
At ASH 2024, Alexey Danilov, MD, PhD, presented results from the CLL expansion cohort of the EPCORE CLL-1 trial and preliminary results from a cycle 1 optimization.5 EPCORE CLL-1 enrolled patients with CD20-positive R/R CLL who had received at least 2 prior lines of systemic therapy; the expansion phase required measurable disease with at least 5 × 109/L B lymphocytes. Prior allogeneic stem cell transplantation was not allowed.
The expansion phase included 23 patients who received CRS prophylaxis with prednisone; epcoritamab was administered via step-up dosing of 0.16 mg on day 1 of cycle 1, 0.8 mg on day 8 of cycle 1, and the first full dose of 48 mg on day 15 of cycle 1. The cycle 1 optimization phase enrolled 17 patients who received CRS prophylaxis with dexamethasone and adequate hydration; step-up dosing included 0.16 mg on day 1 of cycle 1, 0.8 mg on day 8 of cycle 1, 3 mg on day 15 of cycle 1, and the first full dose of 48 mg on day 22 of cycle 1. Median follow-up was 22.8 months for the expansion phase and 2.9 months for the cycle 1 optimization.
The median age of enrolled patients was 72 years (range, 55-83 years) for the expansion cohort and 68 years (range, 56-81 years) for the cycle 1 optimization cohort. IGHV was unmutated in 70% and 71% of patients, respectively, and TP53 aberrations were present in 65% and 59%, respectively. Patients had received a median of 4 prior lines of therapy (range, 2-10); 90% were refractory to a BTKi and 50% had discontinued a BCL2i due to progression.
TEAEs were primarily low grade. The most frequent TEAEs were CRS (96%; 17% grade 3), anemia (65%; 61% grade 3), thrombocytopenia (65%; all grade 3/4), diarrhea (48%; 4% grade 3), neutropenia (48%; all grade 3/4), and peripheral edema (48%; all grade 1/2). TEAEs led to treatment discontinuation in 5 patients in the expansion phase and in 1 patient in the cycle 1 optimization. There were 4 fatal TEAEs in the expansion phase and none in the cycle 1 optimization.
The cycle 1 optimization appeared to mitigate the development of both ICANS and clinical TLS. ICANS occurred in 3 patients in the expansion cohort (3%; 1 grade 1, and 2 grade 2) compared with no patients in the cycle 1 optimization. Grade 2 clinical TLS occurred in 1 patient in the expansion phase and no patients in the cycle 1 optimization. The overall incidence of CRS in the expansion phase was 96% (n=22) and was grade 1 in 9% of patients, grade 2 in 70%, and grade 3 in 17%. The overall incidence of CRS in the cycle 1 optimization was 82% (n=14) and was grade 1 in 71% and grade 2 in 12%. The majority of CRS events occurred in the first full dose. All events resolved after a median of 3 to 3.5 days.
The primary endpoint was ORR, attained in 61% (39% complete response [CR]) in the expansion cohort (n=23; median follow-up, 22.8 months) and 60% (10% CR) in the cycle 1 optimization cohort (n=10; median follow-up, 2.9 months). Most responding patients attained uMRD4 in the blood, including all evaluable patients with CR. The median time to response was 2.0 months (range, 1.6-3.8 months) and median time to complete response was 5.6 months (range, 1.6-11.1 months).
After a median follow-up of 22.8 months in the expansion phase, median PFS was 12.8 months and median OS was not reached; 12-month PFS and OS rates were 52% and 70%, respectively. Interleukin 6 induction after the first full dose was significantly lower in the cycle 1 optimization group vs the expansion group. CD8 T-cell activation was comparable in the expansion and cycle 1 optimization cohorts, but late activation was higher in the cycle 1 optimization group.
Investigators concluded that the cycle 1 optimization measures of an additional step-up dose, use of dexamethasone, and adequate hydration decreased the risk and severity of CRS and ICANS. The trial is continuing to enroll and evaluate epcoritamab as a single agent and in combination regimens for patients with CLL.
References
1. EPKINLY® (epcoritamab-bysp) prescribing information. Plainsboro, NJ: Genmab US, Inc. Revised August 2024.
2. Kater AP, Christensen JH, Bentzen HH, et al. Subcutaneous epcoritamab in patients with relapsed/refractory chronic lymphocytic leukemia: preliminary results from the EPCORE CLL-1 Trial. Blood. 2021;138(suppl 1):2627.
3. 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.
4. Danilov A, Fakhri B, Awan FT, et al. Epcoritamab monotherapy in patients with R/R CLL: results from CLL expansion and optimization cohorts of EPCORE CLL-1. Presented at: 66th ASH Annual Meeting and Exposition; December 7-10, 2024; San Diego, California, USA. Abstract 883.
Efficacy and Safety of the BTK Degrader NX-5948 in Patients With R/R CLL: Updated Results From an Ongoing Phase 1a/b Study
The development of BTKi resistance mutations is a challenge in the treatment of patients with CLL. One of the mechanisms through which BTK mutations can sustain intact B-cell receptor signaling in the context of BTK inhibition is through BTK scaffolding.1 The novel BTK degrader NX-5948 has been shown to overcome BTKi resistance mutations and disrupt BTK scaffolding and is now being evaluated in the phase 1a/b NX-5948-301 trial in patients with R/R B-cell malignancies.1
The study is enrolling patients at least 18 years of age with R/R B-cell malignancies who have received at least 2 prior lines of therapy (at least 1 for primary central nervous system [CNS] lymphoma). The phase 1a dose escalation is evaluating NX-5948 once daily in patients with CLL/SLL (up to 66 patients) and non-Hodgkin lymphoma (NHL)/Waldenström macroglobulinemia (up to 66 patients). The phase 1b dose expansion plans to enroll up to 160 patients with R/R B-cell malignancies to evaluate NX-5948 at 2 dosages (200 mg and 600 mg once daily).
At ASH 2024, Nirav N. Shah, MD, presented results from the phase 1a/b study in patients with CLL/SLL (Table 2).2 A total of 60 patients with CLL/SLL enrolled, with a median age of 67.0 years (range, 35-88 years); 63.3% were male, 6.7% were Hispanic or Latino, and 85% were White. Patients had received a median of 4 prior lines of therapy (range, 1-12). All but 1 patient had received a prior BTKi, and 28.3% had also received a noncovalent BTKi. Other prior therapies included a BCL2i in 83.3% of patients, BTKi and BCL2i in 81.7%, chimeric antigen receptor T-cell therapy in 5.0%, a bispecific antibody in 6.7%, a PI3K inhibitor in 30.0%, and chemotherapy or chemoimmunotherapy in 71.7%. Genetic alterations, assessed in 57 patients, included mutations in TP53 (40.4%), BTK (38.6%), PLCG2 (12.3%), and BCL2 (10.5%).
Patients received NX-5948 dosed at 50 to 600 mg once daily. As of the data cutoff, 46 patients were continuing to receive treatment and 14 patients had discontinued treatment due to radiologic progression (n=5), clinical progression (n=4), death (n=2), physician decision (n=2), or an AE (n=1).
The most frequent TEAEs of any grade were purpura/contusion (36.7%), fatigue (26.7%), petechiae (26.7%), rash (23.3%), neutropenia (23.3%), and diarrhea (20.0%). One case of grade 1 atrial fibrillation was reported in a patient with preexisting atrial fibrillation. Grade 3 or higher AEs included neutropenia (18.3%), anemia (6.7%), and pneumonia (3.3%). In the overall population of 125 patients with B-cell malignancies, there were 6 TEAEs that resulted in drug discontinuation, including 1 in a patient with CLL and 5 in patients with NHL. Two grade 5 AEs were reported, including 1 pulmonary embolism and 1 case pending; these were deemed not related to NX-5948.
Investigators measured BTK degradation over the first 29 days of treatment and found that NX-5948 degrades both wild-type and mutated BTK, including BTK C481R/S, T474F/I, L528W/S, and V416L/M.
In the primary ORR analysis, which included 49 patients with CLL with at least 1 response assessment at 8 weeks, NX-5948 was associated with an ORR of 75.5% (all partial responses [PR] plus 1 PR with rebound lymphocytosis). In an exploratory analysis of 38 patients with at least 2 response assessments at 16 weeks, the ORR was 84.2% (all PR). Clinical activity was observed in patients with baseline mutations and with CNS involvement.
The median duration of treatment was 3.9 months (range, 0.1-21.0 months); the median duration of response was not reached (95% CI, 6.9 months–not reached) and 13 patients (26.5%) had a response duration exceeding 6 months. Investigators concluded that NX-5948 demonstrated an encouraging clinical profile in this heavily pretreated population of patients with CLL and was well tolerated across B-cell malignancies.
References
1. Montoya S, Bourcier J, Noviski M, et al. Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127. Science. 2024;383(6682):eadi5798.
2. Shah NN, Omer Z, Collins G, et al. Efficacy and safety of the BTK degrader NX-5948 in patients with R/R CLL: updated results from an ongoing phase 1a/b study. Presented at: 66th ASH Annual Meeting and Exposition; December 7-10, 2024; San Diego, California, USA. Abstract 884.
Preliminary Efficacy and Safety of the BTK Degrader BGB-16673 in Patients With R/R CLL/Small Lymphocytic Lymphoma: Results From the Phase 1 CaDAnCe-101 Study
BGB-16673 is a novel chimeric degradation-activating compound that degrades wild-type and mutated forms of BTK, including BTK associated with resistance to covalent and noncovalent BTKi, and reduces BTK levels even in the context of clinically relevant resistance mutations.1,2 The phase 1/2 open-label dose-escalation/expansion CaDAnCe-101 study is evaluating BGB-16673 in patients with selected R/R B-cell malignancies (NCT05006716). At ASH 2024, Meghan C. Thompson, MD, presented results from CaDAnCe-101, focusing on patients with CLL (Table 3).3
The study enrolled a total of 60 patients with CLL/SLL who had received at least 2 prior therapies, including a cBTKi if approved for disease. Patients received escalating doses of oral BGB-16673 (50-600 mg) once daily. The median age was 70 years (range, 50-90 years); risk characteristics included uIGHV in 82.6% of patients, del(17p) and/or TP53 mutations in 66.7%, and complex karyotype in 50%. Patients had received a median of 4 prior lines of therapy (range, 2-10); 93.3% of patients had received a prior cBTKi, 21.7% had received a noncovalent BTKi, and 83.3% had received a BCL2i.
The 1 dose-limiting toxicity observed was a grade 3 maculopapular rash with the 200 mg dose; the patient continued treatment after a 5-day hold. No treatment-related AEs led to death. No cases of atrial fibrillation or pancreatitis occurred; 2 patients (3.3%) had a major hemorrhage and 1 patient developed febrile neutropenia in the context of COVID-19 pneumonia and norovirus diarrhea. Grade 3 or higher TEAEs occurring in more than 1 patient included neutropenia (21.7%), pneumonia (8.3%), lipase increase (3.3%), and thrombocytopenia (3.3%). Investigators noted rapid and significant improvements in cytopenia in patients with a response to treatment.
The ORR was 77.6% across all 49 evaluable patients and 93.8% with the 200 mg dose. Responses were observed across biologic subsets, including in patients previously treated with a cBTKi and a BCL2i (26/30; 86.7%), patients who additionally received a noncovalent BTKi (7/12; 58.3%), and in patients with del(17p) and/or TP53 mutations (23/31; 74.2%), complex karyotype (11/15; 73.3%), BTK mutations (10/16; 62.5%), and PLCG2 mutations (4/6; 66.7%). After a median follow-up of 10.2 months, median PFS had not been reached.
Activity was also observed in patients with Richter transformation, with an ORR of 58.3% (7/12), including a CR rate of 8.3% (1/12). A phase 2 cohort is currently enrolling patients with CLL/SLL who had previously received a BTKi and a BCL2i.
References
1. Feng X, Wang Y, Long T, et al. P1239: Bruton tyrosine kinase (BTK) protein degrader BGB-16673 is less apt to cause, and able to overcome variable BTK resistance mutations compared to other BTK inhibitors (BTKi). Hemasphere. 2023;7(suppl):e368855c.
2. Wang H, Hou X, Zhang W, et al. P1219: BGB-16673, a BTK degrader, overcomes on-target resistance from BTK inhibitors and presents sustainable long-term tumor regression in lymphoma xenograft models. Hemasphere. 2023;7(suppl):e24358c2.
3. Thompson MC, Parrondo RD, Frustaci AM, et al. Preliminary efficacy and safety of the BTK degrader BGB-16673 in patients with R/R CLL/small lymphocytic lymphoma: results from the phase 1 CaDAnCe-101 Study. Presented at: 66th ASH Annual Meeting and Exposition; December 7-10, 2024; San Diego, California, USA. Abstract 885.