Innovative BCL2 inhibition: indications fanning out across B-cell malignancies

Sonrotoclax in patients with CLL

The combination of the first-generation BCL2 inhibitor venetoclax and the first-in-class BTK inhibitor ibrutinib has demonstrated efficacy in patients with chronic lymphocytic leukemia (CLL) [1], although tolerability of this regimen is limited. Next-generation agents can be expected to provide optimized toxicity profiles. The second-generation BCL2 inhibitor sonrotoclax inhibits BCL2 in a more selective and pharmacologically potent manner than venetoclax, with a shorter half-life preventing drug accumulation that might contribute to toxicity [2]. Likewise, the second-generation BTK inhibitor zanubrutinib has shown superior safety and tolerability compared with ibrutinib, including fewer cardiac events, in patients with relapsed/refractory CLL [3].

BGB-11417-101, an ongoing global, phase I/IB study, is evaluating sonrotoclax as monotherapy or in combination with zanubrutinib, obinutuzumab, or both, in the setting of B-cell malignancies. At EHA 2024, Opat et al. presented updated findings for patients with relapsed/refractory CLL who received sonrotoclax plus zanubrutinib in BGB-11417-101 [4]. Treatment consisted of 8-12 weeks of zanubrutinib lead-in (320 mg QD or 160 mg BID) followed by the combination with sonrotoclax (with weekly or daily ramp-up to the target dose) until disease progression. Overall, 47 patients were treated with sonrotoclax 40 mg, 80 mg, 160 mg, 320 mg, or 640 mg. The cohorts included considerable percentages of patients with high-risk cytogenetics including del(17p), TP53 mutation and unmutated IGHV.

Deep responses at all dose levels

No dose-limiting toxicities occurred, and the maximum tolerated dose (MTD) was not reached. The sonrotoclax 320 mg dose was selected for dose expansion. Sonrotoclax plus zanubrutinib displayed a tolerable safety profile at all dose levels. At a median follow-up of 19.3 months, 46 of 47 patients remained on treatment. The analyses yielded no cardiac toxicity, including atrial fibrillation, and no tumor lysis syndrome (TLS). Adverse events (AEs) mostly comprised contusion, neutropenia, COVID-19, diarrhea, fatigue, nausea and upper respiratory tract infections, with the majority being grade 1 or 2. In the cohort receiving the recommended phase II sonrotoclax dose of 320 mg plus zanubrutinib (n = 22), neutropenia was observed in 41 %, with 36 % of patients experiencing grade ≥ 3 events. Despite the high proportion of severe neutropenia, no febrile neutropenia occurred on the study, and no deaths were reported overall. Treatment-emergent AEs (TEAEs) led to sonrotoclax discontinuation in one individual treated with the 640 mg dose. None of the patients experienced TEAEs prompting sonrotoclax dose reductions. Zanubrutinib discontinuations and dose reductions due to TEAEs were necessary in 4 % and 2 %, respectively.

Sonrotoclax plus zanubrutinib showed promising efficacy. Deep responses were obtained across all dose levels, with an overall response rate (ORR) of 97 % and a 57 % rate of complete responses (CR) plus CR with incomplete hematologic recovery (CRi) across all doses. Five of six evaluable patients with prior BTK inhibitor therapy responded to treatment. In the sonrotoclax 320 mg cohort, all patients experienced responses, and the CR/CRi rate was 73 %. Eighty-five percent of 33 minimal residual disease(MRD)-evaluable patients had undetectable MRD (uMRD) at the time of data cut-off (Figure 1). Responses deepened over time. All patients in the 160 mg, 320 mg and 640 mg cohorts who reached week 48 achieved uMRD. Only one progression-free survival event had occurred at the time of the analysis. Follow-up of this phase I/IB study is ongoing.

In addition, sonrotoclax plus zanubrutinib is currently being investigated in treatment-naïve patients with CLL. The randomized, open-label, phase III CELESTIAL-TNCLL trial is comparing the combination to the standard regimen of venetoclax plus obinutuzumab [5]. PFS has been selected as the primary endpoint.

Figure 1: Undetectable minimal residual disease in the peripheral blood of relapsed/refractory CLL patients treated with sonrotoclax plus zanubrutinib

Figure 1: Undetectable minimal residual disease in the peripheral blood of relapsed/refractory CLL patients treated with sonrotoclax plus zanubrutinib

Findings obtained for mantle cell lymphoma

Moreover, the BGB-11417-101 study contains a cohort of patients with relapsed/refractory mantle cell lymphoma (MCL). As for CLL, the combination of venetoclax and ibrutinib has proven efficacious in this setting, although the rates of toxicity were high, demonstrating a need for safer regimens [6]. Tam et al. reported results for 40 patients with relapsed/refractory MCL who received sonrotoclax 80 mg, 160 mg, 320 mg or 640 mg in addition to zanubrutinib in the BGB-11417-101 study [7]. The 160 mg and 320 mg dose levels were chosen for the expansion cohorts.

Sonrotoclax plus zanubrutinib was generally well tolerated. Dose escalation was completed without MTD being reached. No atrial fibrillation and no clinical or laboratory TLS events were observed regardless of target dose. The most common any-grade TEAEs were contusion (30 %), neutropenia (28 %), and diarrhea (28 %). Neutropenia once again constituted the most common grade ≥ 3 TEAE (18 %) but proved manageable, with no dose reductions and only one dose hold due to a concurrent COVID-19 infection. G-CSF was prescribed in 6 patients for a median treatment duration of 3.5 days. Thrombocytopenia occurred in 23 %, with 13 % of cases graded as ≥ 3. TEAEs led to sonrotoclax discontinuation in 13 %, while no dose reductions were required. For zanubrutinib, the discontinuation and dose reduction rates were 15 % and 5 %, respectively.

The combination gave rise to deep responses with ORRs of 73 % and 92 % in the 160 mg and 320 mg cohorts, respectively, and CR rates of 46 % and 83 %, respectively. Two of three response-evaluable patients with prior BTK inhibitor treatment responded, with one of them achieving CR. The 320 mg dose was selected as the recommended phase II dose for further development in future pivotal studies.

Relapsed/refractory WM: encouraging activity

Another analysis presented at EHA 2024 that is based on the BGB-11417-101 study assessed sonrotoclax monotherapy in the cohort with relapsed/refractory Waldenström macroglobulinemia (WM) [8]. Twenty individuals with a median number of prior therapies of 2.5 were treated with sonrotoclax 80 mg, 160 mg, 320 mg, or 640 mg. Twelve of them had undergone prior BTK inhibitor therapy, with 9 receiving it as their last prior systemic treatment.

The most common any-grade TEAEs across the dose cohorts included anemia (35 %), COVID-19 (30 %), and pyrexia (25 %). Anemia was the most common grade ≥ 3 event (20 %). Neutropenia and thrombocytopenia were reported in 20 % (grade ≥ 3, 5 %) and 15 % (grade ≥ 3, 10 %), respectively. One patient in the 160-mg dose cohort experienced a dose-limiting toxicity of grade 3 febrile neutropenia that resolved after 2 days without dose reduction. No laboratory or clinical TLS was observed irrespective of target dose. TEAEs led to sonrotoclax discontinuation and dose interruption in 10 % and 25 %, respectively. Dose escalation is ongoing at 640 mg, after the MTD has not been reached at data cut-off. The preliminary antitumor activity of sonrotoclax monotherapy was encouraging in this heavily pretreated population, with high and durable responses across the tested dose levels. Overall, the ORR was 79 % (Figure 2).

Sonrotoclax monotherapy is being further evaluated in patients with relapsed/refractory WM in the pivotal, phase II BGB-11417-203 study that is currently recruiting [9]. BGB-11417-203 contains three cohorts that are refractory to different drug classes. The major response rate has been defined as the primary endpoint. Patient recruitment is ongoing in Australia, the USA, China, and Europe.

Figure 2: Responses observed for sonrotoclax monotherapy in relapsed/refractory Waldenström macroglobulinemia

Figure 2: Responses observed for sonrotoclax monotherapy in relapsed/refractory Waldenström macroglobulinemia

BGB-11417-105: multiple myeloma

Sonrotoclax is also being investigated in the setting of multiple myeloma (MM). Here, no BCL2-targeted therapies have been approved to date although BCL2 is an attractive target in MM with t(11;14) and responses have been obtained with venetoclax [10]. The open-label, phase IB/II BGB-11417-105 study is testing sonrotoclax as the backbone for different combination regimens including dexamethasone, dexamethasone plus carfilzomib, daratumumab, or pomalidomide. Patients with relapsed/refractory MM harboring t(11;14) are participating in the study. Dhakal et al. presented results for 32 individuals treated with sonrotoclax 640 mg once daily, which is the recommended dose for expansion [11]. In addition, dexamethasone 40 mg was administered weekly. This group had received a median number of prior treatment lines of 3. All patients had prior proteasome inhibitor and immunomodulatory drug exposure, and most had previously received anti-CD38 antibody therapy (72 %). Many were refractory to these three drug classes. Sixty-three percent had undergone autologous stem cell transplantation.

According to the findings reported at EHA 2024, sonrotoclax plus dexamethasone was well tolerated in this heavily pretreated population. No dose-limiting toxicities occurred during dose escalation. During dose expansion, low rates of hematologic toxicities (any hematologic TEAEs, 12.5 %) and infections (21.9 %) were observed. The most common ­TEAEs were fatigue and insomnia (each 28 %), diarrhea (22 %), as well as constipation and nausea (each 16 %). TEAEs gave rise to dose interruptions of sonrotoclax in 18.8 %, while no dose reductions were necessary.

The combination provided deep and durable responses. Overall, 75 % of patients responded, with 16.7 % and 4.2 % experiencing CR and stringent CR, respectively. Very good partial responses and partial responses resulted in 29.2 % and 25.0 %, respectively. The longest duration of response was 18 months, and two patients remained on treatment for more than one year.

Tackling AML with sonrotoclax-based treatment

Venetoclax combined with the hypomethylating agent azacitidine, as compared to azacitidine alone, has improved outcomes in treatment-naïve patients with acute myeloid leukemia (AML) who were unfit for intensive chemotherapy [12]. However, there is still an unmet need as relapses are common. BGB-11417-103, an ongoing, global, phase IB/II study, is assessing sonrotoclax 40 mg, 80 mg, 160 mg, and 320 mg with or without azacitidine in patients with AML and myelo­dysplastic syndromes/myeloproliferative neoplasms. Preliminary safety and efficacy were reported at EHA 2024 for sonrotoclax plus azacitidine in 48 treatment-naïve patients with unfit AML [13].

The most common any-grade TEAEs were neutropenia (79 %), thrombocytopenia (68 %), constipation (52 %), and nausea (52 %). Grade ≥ 3 neutropenia and thrombocytopenia were observed in 77 % and 60 %, respectively, and grade ≥ 3 anemia and febrile neutropenia occurred in 38 % and 42 %, respectively. Half of patients experienced grade ≥ 3 infections and infestations. TEAEs leading to death in five patients (10 %) included pneumonia, neutropenic sepsis, bronchopulmonary aspergillosis, pulmonary sepsis and metastatic squamous cell carcinoma, although none of these were considered related to the study treatment. Three dose-limiting toxicities (i.e., grade 4 neutropenia and thrombocytopenia) were reported in two patients treated with azacitidine plus sonorotoclax 80 mg. Laboratory TLS occurred in one patient receiving azacitidine plus sonrotoclax 160 mg and resolved in 4 days without concomitant allopurinol.

Regarding antileukemic activity, the analysis revealed an ORR of 78 % and a CR rate of 54 % in the efficacy-evaluable population (n = 46; Table). CR plus CR with partial hematologic recovery was achieved in 63 % of patients, while CR plus CRi resulted in 70 %. After a median follow-up of 19.8 months, median duration of CR was 15.1 months. Thirty-seven percent of all efficacy-evaluable patients obtained MRD negativity. At the time of the analysis, the study stopping criteria had not been met in any of the dose cohorts. The safety expansion is ongoing in the 80 mg, 160 mg, and 320 mg cohorts to determine the recommended phase II dose.

Table Sonrotoclax plus azacitidine in treatment-naïve AML: disease responses

REFERENCES

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  2. Hu N et al., Preclinical characterization of BGB-11417, a potent and selective Bcl-2 inhibitor with superior antitumor activities in haematological tumor models. AACR 2020, abstract 3077
  3. Brown JR et al., Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 2023; 388(4): 319-332
  4. Opat S et al., Results from the phase 1 study of the novel BCL2 inhibitor sonrotoclax in combination with zanubrutinib for relapsed/refractory CLL/SLL show deep and durable responses. EHA 2024, abstract S156
  5. Patten P et al., CELESTIAL-TNCLL: an ongoing, open-label, multiregional, phase 3 study of sonrotoclax (BGB-11417) + zanubrutinib vs venetoclax + obinutuzumab for treatment-naïve CLL. EHA 2024, abstract PB2540
  6. Wang M et al., Ibrutinib combined with venetoclax in patients with relapsed/refractory mantle cell lymphoma: Primary analysis results from the randomized phase 3 Sympatico study. ASH 2023, abstract LBA2
  7. Tam CS et al., Combination treatment with novel BCL2 inhibitor sonrotoclax (BGB-11417) and zanubrutinib induces high rate of complete remission for patients with relapsed/refractory mantle cell lymphoma. EHA 2024, abstract P1112
  8. Cheah CY et al., Safety and efficacy results of a phase 1 study of the novel BCL2 inhibitor sonrotoclax (BGB-11417) for relapsed/refractory Waldenström macroglobulinemia. EHA 2024, abstract P1110
  9. Matous J et al., BGB-11417-203, an ongoing, phase 2 study of sonrotoclax (BGB-11417), a next-generation BCL2 inhibitor, in patients with Waldenström macroglobulinemia. EHA 2024, abstract PB2954
  10. Inam S et al., Paving the way to precision medicine in multiple myeloma. Expert Rev Hematol 2021; 14(4): 323-327
  11. Dhakal B et al., Sonrotoclax plus dexamethasone is tolerable and demonstrated antimyeloma activity in patients with relapsed/refractory multiple myeloma harboring t(11;14). EHA 2024, abstract P898
  12. DiNardo CD et al., Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med 2020; 383(7): 617-629
  13. Shortt J et al., Preliminary safety and antileukemic activity of sonrotoclax (BGB-11417), a potent and selective BCL2 inhibitor, in treatment-naïve patients with acute myeloid leukemia. EHA 2024, abstract P538

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