Zanubrutinib Improves PFS in Treatment-Naive CLL/SLL, Regardless of Complex Karyotypes

Paolo Ghia, MD, PhD

A progression-free survival (PFS) benefit was derived from treatment with zanubrutinib (Brukinsa) over treatment with bendamustine and rituximab (Rituxan; BR) across biomarker subgroups in patients with treatment-naive chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) without 17p deletions, according to a subgroup analysis of the phase 3 SEQUOIA trial (NCT03336333) at the 2023 ASH Annual Meeting.

Results from the subgroup analysis showed that zanubrutinib elicited better PFS outcomes when compared with bendamustine plus rituximab, regardless of genetic abnormalities. Patients with these genetic abnormalities, such as del(11q), del(13q), trisomy 12, and a complex karyotype, all experienced the PFS benefit. The median PFS was not reached in any of the patient cohorts treated with zanubrutinib vs a median PFS of 29.2 months (P < .001), 40.8 months (P < .001), 40.7 months (P < .01), and 31.1 months (P < .01) in those treated with the combination approach, respectively.

“The fact that patients with the negative progressive factors are responding better in a much more prolonged fashion compared with immuno-chemotherapy when they are treated with zanubrutinib, that helps to personalize and to individualize the treatment of our patients,” Paolo Ghia, MD, PhD, said in an interview with OncLive.

In the interview, Ghia described the various cohorts of the SEQUOIA study, expanded on outcomes from a biomarker subgroup analysis with zanubrutinib vs BR, and highlighted the importance of precision medicine in patients with treatment-naive CLL/SLL with and without 17p deletions and other genetic aberrations.

Ghia is a full professor of medical oncology, a group leader in the B-cell Neoplasia Unit, and the head of the Strategic Research Program on CLL at the Università Vita Salute San Raffaele. He is also the deputy director of the Division of Experimental Oncology in San Raffaele Scientific Institute, both in Milan, Italy.

OncLive: What was the rationale for conducting a biomarker subgroup analysis as part of SEQUOIA?

Ghia: There is another portion of the study, which is cohort 2, where patients with 17p deletions are treated with zanubrutinib only. This study presented at the 2023 ASH Annual Meeting is the biomarker analysis of the first portion of the study.

The randomization between zanubrutinib and BR was assessed because we were interested to see if and how patients with poor genetic features like mutated IGHV or complex karyotype would respond to zanubrutinib in comparison with chemoimmunotherapy. This is because we know that these patients tend to have a shorter progression-free survival and durable responses to chemoimmunotherapy.

What results from this biomarker analysis were presented at the meeting?

Our study that we presented showed that patients treated with zanubrutinib, even those with a negative genetic feature, had a better PFS compared with BR. The interesting part is also that we didn't see any difference between patients [treated with zanubrutinib, regardless if they had mutated IGHV or unmutated IGHV].

Again, this reinforces the concept that continuous BTK inhibition is benefiting all types of patients. We also have data to show that patients with complex karyotypes respond much better with zanubrutinib then with BR. Here, we presented the complex karyotype is more or equal to 3 aberrations. We know that now, following regulatory recommendations, the complex karyotypes [are defined by] 5 or more aberrations.

We will rerun again the same analysis, but at the moment, the complex karyotype is defined as 3 or more aberrations, and shows that there is no difference between patients who have complex karyotype or don't have complex karyotype, if they are treated with zanubrutinib.

We are moving towards precision medicine, and we are already assessing IGHV status and p53 aberrations to decide who should not receive chemoimmunotherapy. This study is again underscoring the relevance of such tests, so that we can really choose the best therapy and the most effective therapy for our patients.

Reference

Ramakrishnan V, Xu L, Paik JC, et al. Broad superiority of zanubrutinib (zanu) over bendamustine + rituximab (br) across multiple high-risk factors: biomarker subgroup analysis in the phase 3 SEQUOIA study in patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) without del(17p). Blood. 2023;142(suppl 1):1902. doi:10.1182/blood-2023-174543