Authored by Dr. Brian Koffman
Bottom Line:
Combining the new BCL2 inhibitor sonrotoclax with the BTK inhibitor zanubrutinib produced an overall response rate of 97% in relapsed / refractory CLL / SLL.
Who Performed the Research and Where Was it Presented:
Dr. Stephen Opat from Monash University in suburban Melbourne, Australia, gave one of the rare coveted oral presentations on behalf of his international colleagues at the 2024 European Hematology Association (EHA) Annual Meeting in Madrid.
Background:
While the treatments for chronic lymphocytic leukemia / small lymphocytic leukemia (CLL / SLL) have dramatically improved lifespans for many, most patients who need treatment will eventually relapse, some repeatedly, and too many may subsequently become refractory to most if not all available therapeutic agents. Combinations are, therefore, appealing in relapsed / refractory (R/R) CLL / SLL, especially if they work in orthogonal (by independent mechanism) and are synergistic. Such is the case when combining the two classes of drugs that have revolutionized CLL / SLL treatments, namely the BTK inhibitors. This class includes ibrutinib, acalabrutinib, pirtobrutinib, and zanubrutinib, the last used in this study. Other drug classes in this therapeutic partnership are the BCL2 inhibitors, of which only venetoclax is approved, but others are in development, including sonrotoclax, the other drug used in this study. Other BTKi / BCL2i doublets have proven very effective in difficult to treat patients. The hope is this novel duo will improve on the already strong results seen in other trials of BTKi and BCL2i.
Methods and Participants:
Patients with R/R CLL / SLL were first started on zanubrutinib to decrease the risk of tumor lysis syndrome (TLS) before beginning the ramp-up of sonrotoclax. Prior BTKi was allowed if disease progression occurred on treatment.
Results:
- 45 patients with R/R CLL / SLL were enrolled across different doses of sonrotoclax (40 mg, n=4; 80 mg, n=9; 160 mg, n=6; 320 mg, n=20; 640 mg, n=6). 5 patients have not yet stated the BCL2 and are not included in the outcomes
- The median age was 65 years old.
- 28% of tested patients (11/40) had del(17p).
- 72% (13/18) had unmutated IGHV.
- The median number of prior treatments was one.
- Seven patients had prior BTKi as their last therapy.
- The median follow-up was only 17 months, so the results are preliminary.
- The recommended phase 2 dose of 320 mg of sonrotoclax, through the 640 mg, was well tolerated
Adverse Events (AEs):
- Common AEs of patients were
- COVID-19 (n=12; 27%),
- Contusion (n=12 [27%]),
- Low neutrophil count or neutropenia (n=12 [27%]),
- Diarrhea (n=11 [24%]),
- Nausea (n=11 [24%])
- fatigue (n=11 [24%]).
- Low neutrophil count was the most common serious or grade ≥3 AE (n=9 [20%]).
- No cases of tumor lysis syndrome (TLS).
- No atrial fibrillation occurred.
- No adverse event led to death, discontinuation, or dose reduction.
- Sonrotoclax was held in 14 patients for a median duration of 7 days, with half of those due to COVID-19 (n=7).
Responses:
- 32 patients across all dose levels could be evaluated.
- The ORR was an amazing 97% (31/32; 1 patient [40 mg] had stable disease.
- The complete response (CR) rate was 50% (40 mg, n=1 [25%]; 80 mg, n=4 [50%]; 160 mg, n=4 [67%]; 320 mg, n=5 [56%]; 640 mg, n=2 [40%]).
- The median time to CR was 9.8 months (range, 5.5-18.2 months).
- Of the four patients who could be assessed who had prior BTKi treatment, all responded with 3 achieving PR (n=2) or CR (n=1).
- All patients treated with sonro + zanu (160 mg, 320 mg, or 640 mg) who reached week 48 achieved uMRD-4
- Treatment is ongoing for all but 1 patient in the 40 mg cohort who progressed and stopped therapy.
Discussion and Conclusion:
All the patients who were 11 months out were uMRD-4. The combination was well tolerated with no atrial fibrillation and no TLS, problems that have caused concern with other BTKis and BCL2i.
These results are remarkable for being so early, and they are likely to improve over time. This treatment holds the promise of a safe, well-tolerated, effective, all-oral, limited-duration therapy in R/R CLL / SLL. Although not mentioned in the abstract, it is likely it works well even in patients with poor prognostic markers.
It seems to be checking all the boxes.
There is much for CLL patients to look forward to, with smart combinations of therapies allowing remissions that continue long after therapy has stopped.
Links:
Listen to my monologue below.
Read the abstract at: 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
Stay strong; we are all in this together.
Brian Koffman MDCM (retired) MS Ed (he, him, his)
Co-founder, Executive VP and Chief Medical Officer
CLL Society, Inc.
