Zanubrutinib Active in Patients with Treatment-Naive Del17p CLL/SLL

Approximately 93% of patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and del17p responded to treatment with the next-generation Bruton tyrosine kinase (BTK) inhibitor zanubrutinib, according to results from the phase III SEQUOIA trial. Its safety profile also was consistent with other BTK inhibitors, lead author Constantine S. Tam, MBBS, MD, from the Peter MacCallum Cancer Centre and the University of Melbourne in Australia, reported in his presentation at the 2019 ASH Annual Meeting.

Dr. Tam shared results from arm C of the SEQUOIA trial, a nonrandomized arm that included treatment-naïve patients with del17p CLL/SLL. “These patients are normally not suitable candidates for chemotherapy, because we know that [they] are resistant to chemotherapy,” Dr. Tam told ASH Clinical News. Zanubrutinib, which was recently approved by the FDA for the treatment of mantle cell lymphoma, was administered in twice-daily doses of 160 mg.

As of data cutoff (August 7, 2019), 109 patients (median age = 70 years; range = 42-86) were enrolled. Most patients had CLL, while 10 (9.2%) had SLL. After a median follow-up of 10 months (range = 5-18.1), 104 patients remained on study treatment. Five patients discontinued – 1 due to toxicity and 4 due to progressive disease.

Ninety-three patients (85.3%) experienced adverse events (AEs). Common any-grade AEs (reported in ≥7.5% of patients) included contusion (20.2%), rash (11.0%), upper respiratory tract infection (10.1%), and nausea (10.1%). Grade ≥3 AEs were reported in 40 patients (36.7%), including 26 patients (23.9%) with a serious AE. The most common grade ≥3 AEs included neutropenia (n=11; 10.1%), pneumonia (n=4; 3.7%), and hypertension (n=3; 2.8%). One patient died of grade 5 pneumonia 8 days after receiving the last dose of zanubrutinib, the authors noted.

“Zanubrutinib had the same side-effect profile as normal BTK inhibitors, namely bleeding, infection, and atrial fibrillation – albeit at a numerically lower rate than has been reported with ibrutinib,” Dr. Tam said.

Response rates seen with zanubrutinib treatment were high, with an overall response rate of 92.7%. This included:

  • 2 complete responses (1.9%)
  • 86 partial responses (78.9%)
  • 13 partial responses with lymphocytosis (11.9%)

The responses appeared to be durable, the researchers reported, with 95 patients experiencing remissions lasting longer than 6 months.

The next question, according to Dr. Tam, should be, “Is this response rate better than what we would expect with ibrutinib? It would be hazardous to draw comparisons between the two drugs right now, especially given that there are two phase III studies comparing them head to head.” The studies are set to report results in the next few years.

The present trial is limited by its relatively short follow-up of 10 months, he noted. “We know from ibrutinib experience that patients are going to do well in the short- to medium-term, but obviously longer follow-up will be required to confirm that these patients on zanubrutinib who are responding well at 10 months will continue to respond well at the 2-, 4-, and 5-year marks.”

Dr. Tam also noted that future research will focus on the depth of responses. “These patients are going into remission, but not into very deep remission, because, as a class, BTK inhibitors control patients’ disease but don’t get the patient to minimal residual disease–negative remissions,” he said. Planned trials are looking at whether adding venetoclax to zanubrutinib could improve responses, based on research showing improvements when venetoclax was combined with ibrutinib.

The authors report relationships with BeiGene, which sponsored the trial.

Reference

Tam CS, Robak T, Ghia P, et al. Efficacy and safety of zanubrutinib in patients with treatment-naive chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with del(17p): initial results from arm C of the Sequoia (BGB-3111-304) trial. Abstract #499. Presented at the 2019 ASH Annual Meeting, December 8, 2019; Orlando, FL.