Constantine S. Tam, MBBS, MD, consulting hematologist and associate professor, Peter MacCallum Cancer Centre, discusses the superior safety and progression-free survival outcomes from the SEQUOIA phase 3 trial, which compared zanubrutinib with bendamustine and rituximab combination therapy in treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma.
Findings of the phase 3 SEQUOIA study presented at ASH 2021 showed that treatment-naive patients with chronic lymphocytic leukemia/small lymphocytic lymphoma exhibited significantly superior progression-free survival (PFS) and a favorable safety profile when given the bruton tyrosine kinase (BTK) inhibitor zanubrutinib vs bendamustine/rituximab combination therapy, said Constantine S. Tam, MBBS, MD, consulting hematologist and associate professor, Peter MacCallum Cancer Centre.
Dr Tam was the lead author of the abstract presented at ASH 2021, titled, “SEQUOIA: results of a phase 3 randomized study of zanubrutinib versus bendamustine + rituximab in patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma.”
Can you discuss the final efficacy and safety outcomes of zanubrutinib vs bendamustine and rituximab in treatment-naive patients with CLL/SLL?
So, this is a study that compared frontline patients with CLL—who are unfit for intensive chemotherapy—compared directly, head to head zanubrutinib vs bendamustine/rituximab treatment.
In all, we randomized 479 patients. These are older patients with a median age of 70. The headline results is a superior PFS in favor of the zanubrutinib arm where their PFS at 2 years is 85.5% vs 69.5% for bendamustine/rituximab—for a hazard ratio of 0.42, meaning a 58% reduction in the risk of progression, and a highly significant P-value of .0001.
Every subgroup that we examined showed a benefit to zanubrutinib over bendamustine/rituximab. The only possible subgroup where we haven't seen a statistically significant difference are those patients with IGVH-mutated CLL who we know do benefit better with bendamustine/rituximab anyway, where there is still a difference in the PFS curve, but at this short follow-up the PFS curve has not translated into a positive P-value as of yet.
How do these phase 3 results align with early findings reported for the use of BTK inhibitors in this population?
We've previously reported that zanubrutinib is effective in earlier phase 1 and 2 studies in patients with CLL, both in the frontline and the relapsed/refractory setting. And in EHA [European Hematology Association 2021 Virtual Congress], only 6 months ago, we reported a direct head-to-head study comparing zanubrutinib vs ibrutinib in relapsed CLL, showing a superior PFS and better adverse event profile in favor of zanubrutinib.
Now, what this current study does is extend the experience to the frontline, where zanubrutinib is directly compared against a standard of bendamustine/rituximab for frontline CLL. Once again, confirming good tolerance and confirming a superior PFS against an established standard-of-care. So really, what this does is extends the data of zanubrutinib from the phase 1/2 experience into the phase 3 confirmation experience, and also extends the phase 3 data from relapsed/refractory CLL to the frontline.
Far fewer patients had to stop taking zanubrutinib than the drug combination in the comparative arm. What has SEQUOIA showed about the importance of a patient’s ability to stay on a drug for a longer period of time?
When you compare the adverse events between zanubrutinib and bendamustine/rituximab in SEQUOIA, the zanubrutinib arm was associated with much better tolerance with reduced adverse events leading to dose reduction, dose interruption, or discontinuation compared with the bendamustine/rituximab arm.
I think this really confirms the highly tolerable nature of BTK inhibitors in general. And it really shows that for elderly patients with CLL, one has to choose a regimen that can be taken by the patient and completed by the patients, because if you don't finish your regimen, you're not going to get the efficacy outcome. Having said that, bendamustine/rituximab was still well tolerated, and most patients still complete the assigned chemotherapy.
I think what's really noteworthy in terms of the toxicity comparison was that there is a reduced risk of neutropenia, febrile neutropenia, or from cytopenia, in favor of zanubrutinib. And in fact, the other notable finding of the toxicity comparison was that the atrial fibrillation rate for zanubrutinib was actually identical to that of the bendamustine/rituximab arm.
As the audience would know, BTK inhibitors are associated with atrial fibrillation, and it is very reassuring to see a phase 3 study where the atrial fibrillation rates in the BTK arm is the same as a comparator arm. I think this confirms earlier data that zanubrutinib is less cardiotoxic than other BTK inhibitors, and in particular, less cardiotoxic than ibrutinib.