Sonrotoclax + Zanubrutinib Study Updates as a First CLL Treatment

Sonrotoclax + Zanubrutinib: A Rising Treatment Approach

BTK with BCL-2 inhibitor combinations are gaining traction in treating chronic lymphocytic leukemia (CLL) due to their complementary mechanisms, which enhance therapy effectiveness. 

One promising combination being studied pairs the next-generation BTK inhibitor zanubrutinib with the next-generation BCL-2 inhibitor sonrotoclax. This duo has shown improved effectiveness and fewer side effects compared to its first-generation counterparts, ibrutinib and venetoclax.

A recent clinical trial reviewed the outcomes of sonrotoclax at two different doses (160 mg and 320 mg per day) when combined with zanubrutinib. The findings, presented at the ASH conference by Jacob D. Soumerai, MD, of Massachusetts General Hospital Cancer Center and Harvard Medical School, shed light on the best dosing strategy.

The trial focused on patients receiving this combination as their first treatment for CLL/SLL. Participants continued treatment until the cancer progressed, side effects outweighed the benefits, or they chose to discontinue after 22 months. 

Comparing Sonrotoclax Doses 

Remission Results

Among the 108 evaluable patients treated with zanubrutinib and sonrotoclax, 100% experienced a reduction in cancer cells. 

• Complete response:
  • 160 mg sonrotoclax group: 40% of patients
  • 320 mg sonrotoclax group: 42% of patients
  • Median time to achieve a complete response: 8.4 months 
  • A complete response means CLL was not detected, and a patient’s spleen and lymph nodes were not enlarged
    

Minimal Residual Disease (MRD) Results 

Minimal residual disease (MRD) testing detects remaining cancer cells with high sensitivity. In this trial, MRD was tested using flow cytometry at a uMRD4 level (fewer than 1 CLL cell per 10,000 white blood cells) using a blood sample.

Achieving undetectable minimal residual disease (uMRD) is significant because it may predict a longer period in remission if treatment stops. 

Another important finding was that at the median follow-up of 19.4 months since starting treatment, no patients’ cancer had progressed in the 320 mg group, and only 1 patient’s cancer had progressed in the 160 mg group. 

Side Effect Findings

The most common side effects were low neutrophils (neutropenia), bruising, contracting COVID-19 due to patients’ weakened immune systems, and diarrhea. Side effects were considered manageable with supportive therapies, dose adjustments, and temporary treatment pauses. 

A significant finding was the absence of tumor lysis syndrome (TLS), despite 34% of patients being at high risk. Unlike the rare TLS cases seen with venetoclax, no TLS cases occurred with sonrotoclax, further highlighting its advantages.

Summary 

The combination of zanubrutinib with a daily 320 mg dose of sonrotoclax showed strong treatment results:

• All individuals saw a decrease in cancer cells
• 42% of patients achieved a complete response
• 91% of individuals achieved undetectable minimal residual disease (uMRD4) after 48 weeks
• At the median follow-up of 19.4 months after starting treatment, no patients had experienced cancer progression 

These outcomes were better than those seen with the 160 mg dose of sonrotoclax. Based on the promising findings, researchers plan to continue evaluating sonrotoclax with zanubrutinib as a first treatment for people with CLL/SLL in phase 3 of the ongoing CELESTIAL-TNCLL trial. We look forward to seeing how these results may shape the future of CLL care. 

Continue Reading CLL Treatment Advancements

Sources: 

• 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
• 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Frontline Targeted Therapy Combinations