Sonrotoclax Plus Zanubrutinib Is Safe, Efficacious in Relapsed/Refractory CLL/SLL

Stephen Opat

The combination of sonrotoclax (BGB-11417) and zanubrutinib (Brukinsa) was found to have a tolerable safety profile and to induce deep and durable responses in patients with relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), according to updated findings from the phase 1 BGB-11417-101 study (NCT04277637), which were presented at the 2024 EHA Congress.

At a median follow-up of 19.3 months (range, 0.4-35.7), no dose-limiting toxicities occurred with the combination. The maximum tolerated dose (MTD) was not reached, and 320 mg was chosen as the recommended phase 2 dose (RP2D) of sonrotoclax. Furthermore, the combination elicited a 97% overall response rate (ORR), with a complete response (CR)/CR with incomplete hematologic recovery (CRi) rate of 57% across all dose levels. In the 320-mg cohort, the ORR was 100%, and the CR/CRi rate was 73%.

“CLL/SLL remains incurable as many treated patients experience relapse, necessitating further treatment with novel agents,” Stephen Opat, lead study author and the director of Clinical Haematology at Monash Health in Melbourne, Australia, said in the presentation. “Sonrotoclax, a next-generation BCL-2 inhibitor, is a more selective and pharmacologically potent inhibitor of BCL-2 than venetoclax [Venclexta] with a shorter-half-life and no drug accumulation. Zanubrutinib is a next-generation BTK inhibitor approved globally for 5 indications, including CLL.”

The ongoing, global BGB-11417-101 trial is evaluating sonrotoclax as monotherapy or in combination with zanubrutinib and/or obinutuzumab (Gazyva) in patients with B-cell malignancies, including relapsed/refractory CLL/SLL, relapsed/refractory mantle cell lymphoma, or treatment-naive CLL/SLL.

The primary end points of the trial are safety per CTCAE v5.0 criteria, as well as the determination of the MTD and RP2D.

In the sonrotoclax plus zanubrutinib dose-finding arm, patients with relapsed/refractory CLL/SLL (n = 47) received 8 to 12 weeks of zanubrutinib lead-in therapy at 320 mg daily or 160 mg twice daily, then zanubrutinib in combination with sonrotoclax with weekly ramp-up to the target dose until disease progression. In the dose-expansion phase, patients received daily or weekly ramp-up to the target sonrotoclax dose of 320 mg. In total, 4, 9, 6, 22, and 6 patients received sonrotoclax at 40 mg, 80 mg, 160 mg, 320 mg, and 640 mg throughout the dose-finding and dose-expansion phases.

Among all patients, the median age was 65 years (range, 36-76), most (75%) were male, and had an ECOG performance status (PS) of 0 (60%). Twenty-six percent of evaluable patients had 17p deletions, and 53% had 17p deletions and/or TP53 mutations. Most patients (68%) had unmutated IGHV. Patients had received a median of 1 prior line of therapy (range, 1-3), 15% had received prior BTK inhibitors, and the median duration of prior BTK inhibition was 34.2 months (range, 1.6-86.6).

Among patients who received sonrotoclax at the target dose of 320 mg, the median follow-up was 6.8 months (range, 0.4-26.9), the median age was 67 years (range, 36-76), most were male (82%), and 50% had an ECOG PS of 0. Seventeen percent of evaluable patients had 17p deletions, and 59% had 17p deletions and/or TP53 mutations. Most patients (75%) had unmutated IGHV. Patients had received a median of 1 prior line of therapy (range, 1-3), 14% had received prior BTK inhibitors, and the median duration of prior BTK inhibition was 38.1 months (range, 34.2-49.1).

Among all patients, any-grade treatment-emergent adverse effects (TEAEs) occurred in 94%, grade 3 or higher TEAEs occurred in 51%, and serious TEAEs occurred in 28%. Two patients had TEAEs leading to zanubrutinib discontinuation, and 1 patient had TEAEs leading to zanubrutinib dose reduction. In total, 94% of patients received treatment with sonrotoclax. Among these patients, 1 had TEAEs leading to discontinuation of the drug. No patients had TEAEs leading to sonrotoclax dose reduction, and no deaths were observed.

Among the patients who received sonrotoclax at 320 mg, any-grade TEAEs occurred in 91%, grade 3 or higher TEAEs occurred in 59%, and serious TEAEs occurred in 32%. No patients had TEAEs leading to zanubrutinib discontinuation, and 1 patient had TEAEs leading to zanubrutinib dose reduction. In total, 86% of patients received treatment with sonrotoclax at this dose level. Among these patients, none had TEAEs leading to sonrotoclax discontinuation or dose reduction.

The most common TEAEs observed in the entire patient population were contusion (grade 1/2, 32%; grade ≥3, 0%), neutropenia (6%; 21%), COVID-19 (26%; 2%), diarrhea (28%; 0%), fatigue (26%; 0%), nausea (23%; 0%), upper respiratory tract infection (23%; 0%), cough (21%; 0%), constipation (15%; 2%), headache (17%; 0%), hypertension (4%; 9%), back pain (13%; 0%), sinusitis (11%; 0%), thrombocytopenia (11%; 0%). Among the patients who received sonrotoclax at 320 mg, the most common TEAEs were neutropenia (grade 1/2, 5%; grade ≥3, 36%), upper respiratory tract infection (32%; 0%), contusion (23%; 0%), diarrhea (23%; 0%), and constipation (18%; 5%). Overall, no cases of tumor lysis syndrome, atrial fibrillation, febrile neutropenia, or dose reductions due to diarrhea were observed.

Among 33 patients evaluable for minimal residual disease (MRD) status, 85% had undetectable MRD at data cutoff. Opat noted that responses with the combination deepened over time. Among evaluable patients in the 160-mg cohort (n = 6), the best MRD outcomes by week 24 were MRD4-positive (17%), undetectable MRD4 (50%), and not available (NA; 33%). Among evaluable patients in the 320-mg cohort (n = 9), the best MRD outcomes by week 24 of treatment were MRD4-positive (22%), undetectable MRD4 (44%), and not available (NA; 33%). However, by week 48, all patients who received sonrotoclax at 160 mg, 320 mg, and 640 mg who reached week 48 (160-mg cohort, n = 6; 320-mg cohort, n = 5) achieved undetectable MRD.

Overall, 1 progression-free survival event was observed, which occurred in the 40-mg cohort.

Forty-six patients remain on study treatment.

“This phase 1/1b study demonstrated the safety and tolerability of the combination of sonrotoclax and zanubrutinib in patients with relapsed/refractory CLL/SLL with 46 of 47 patients remaining on study treatment at a median follow-up of 19.3 months,” Opat summarized in an email to OncLive^®. “The majority of adverse events were mild with neutropenia being the only significant adverse event of grade 3 or higher occurring in 21% [of patients]. The treatment was highly efficacious with an ORR of 97%, with a 57% CR/CRi rate across all doses, and an ORR of 100%, with a 73% CR/CRi rate at the 320mg recommended phase 2 dose of sonrotoclax. High levels of MRD negativity were observed with 28 of 33 patients having undetectable levels of MRD at the time of data cutoff.”

“Follow-up is ongoing with this promising combination therapy,” Opat concluded in the presentation.

Reference

Opat S, Anderson MA, Tedeschi A, et al. Results from the phase 1 study of the novel BCL2 inhibitor sonrotoclax (sonro) in combination with zanubrutinib (zanu) for relapsed/refractory (R/R) CLL/SLL show deep and durable responses. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract S156.