by Charles Bankhead, Senior Editor, MedPage Today December 5, 2022
Bruton tyrosine kinase (BTK) inhibitors continued to produce favorable results in newly diagnosed and heavily treated patients with chronic lymphocytic leukemia (CLL), the BCL2 inhibitor venetoclax (Venclexta) demonstrated durability, and the FDA flexed its regulatory muscle against a drug class used to treat CLL and other hematologic malignancies.
Zanubrutinib Wins First-Line Face-Off
Older patients with untreated CLL lived significantly longer without disease progression when they received the BTK inhibitor zanubrutinib (Brukinsa) instead of chemoimmunotherapy with rituximab (Rituxan).
The 24-month progression-free survival (PFS) rate was 85.5% with zanubrutinib and 69.5% with bendamustine-rituximab. The difference represented a 58% reduction in the hazard for disease progression or death (95% CI 0.28-0.63, P<0.00001), as reported in Lancet Oncology.
The results indicate that zanubrutinib “might be regarded as a potential standard of care for this population,” noted Constantine Tam, MD, of Alfred Hospital in Melbourne, Australia, and co-authors.
The findings compared favorably with those of two other BTK inhibitors already approved in the first-line setting: ibrutinib (Imbruvica), which achieved a 24-month PFS rate of 87% in the Alliance A041202 trial, and acalabrutinib (Calquence), which led to an identical 87% PFS rate at 24 months in the ELEVATE-TN trial.
Tam and colleagues reported findings from the phase III SEQUOIA trial involving 479 patients ages 65 and older with newly diagnosed CLL or small lymphocytic lymphoma (SLL; 92% with CLL). After a median follow-up of 26 months, the trial met the primary endpoint of PFS in favor of the BTK inhibitor.
Zanubrutinib has FDA-approved indications for relapsed/refractory marginal zone lymphoma, Waldenström macroglobulinemia, and mantle cell lymphoma. Earlier this year the agency accepted a supplemental new drug application from BeiGene to expand indications to include adults with CLL/SLL.
Pirtobrutinib Impresses in Pretreated CLL
The investigational BTK inhibitor pirtobrutinib continued a successful showing in patients with previously treated CLL/SLL, achieving an overall response rate (ORR) of 63% in patients who had received two or more prior regimens.
Patients with prior exposure to a BTK inhibitor had an ORR of 62%. Among the entire study population, the response rate increased to 86% for those who remained on the drug for at least 10 months. Responses proved durable in most cases, as the longest response was ongoing at 17.8 months, reported Anthony R. Mato, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues in an abstract presented at the European Hematology Association annual congress.
“Pirtobrutinib demonstrated promising efficacy in heavily pretreated CLL/SLL patients following multiple prior lines of therapy and in patients with BTK C481 mutations,” the investigators stated. “Pirtobrutinib was well tolerated and exhibited a wide therapeutic index.”
The data came from a phase I/II trial involving 323 patients with B-cell malignancies, 170 of whom had CLL/SLL. The updated results were consistent with those of a previous report that showed ongoing efficacy in patients with prior exposure to BTK inhibitors, BCL2 inhibitors, PI3K inhibitors, and anti-BTK/BCL2 combination therapy.
Long-Term Efficacy With Venetoclax
The BCL2 inhibitor venetoclax achieved a high response rate and prolonged PFS during long-term follow-up of patients with CLL and 17p deletions.
After a median follow-up of 70 months for 158 patients, the ORR was 77%, including complete responses in 21% of patients. Responses had a median duration of 39 months, and 28% of patients had ongoing responses at 5 years, reported Stephan Stilgenbauer, MD, of Ulm University in Germany, and colleagues in an abstract presented at the European Hematology Association annual congress.
The high-risk cohort comprised patients with previously treated or newly diagnosed CLL. The patients had received a median of two prior regimens and some had received as many as 10 prior systemic therapies for CLL. Four of five patients with untreated CLL remained disease free at the end of follow-up.
The entire cohort had a median PFS of 28.2 months, and PFS had not been reached in the patients with untreated CLL. Median overall survival was 62.5 months, and not yet reached in the small subgroup with previously untreated disease.
FDA Takes Hard Line on PI3K Inhibitors
After reviewing unfavorable survival and toxicity evidence described as “unprecedented in oncology,” the Oncologic Drugs Advisory Committee (ODAC) voted 16-0 in favor of mandating randomized controlled trials to support future approval applications for PI3K inhibitors.
Data summarized for the committee by FDA staff members showed a pattern of survival detriment, excess fatal adverse events, and high rates of severe and overall toxicity, which appeared to be class specific.
“The overall survival information is early and represents a low number of events; yet, we have the same pattern observed across multiple trials,” the authors of the FDA report noted. “Further, in each trial, there was a higher rate of death due to adverse events in the PI3K inhibitor arm, suggesting the potential detriment in overall survival may be due to toxicity.”
The FDA staff faulted sponsors’ reliance on single-arm trials powered to assess response rate, not survival. Safety data were confounded by the absence of a control group.
“I’m not a hematologist, but I would probably find it quite difficult to tell a patient that I have an agent that could reduce your tumor volume, possibly delay your progression, but at the price of significant toxicities. And oh, by the way, I can also impact your mortality in a detrimental manner,” said ODAC chair Jorge Garcia, MD, of Case Western Reserve University in Cleveland.
Since 2014, the FDA has approved four PI3K inhibitors for hematologic malignancies. Sponsors for all four drugs have subsequently withdrawn accelerated approvals or new drug applications for indolent indications.
Following the ODAC meeting, the FDA withdrew accelerated approval of umbralisib (Ukoniq) for marginal zone lymphoma and follicular lymphoma, citing safety concerns with the drug. Subsequently, ODAC recommended against approval of duvelisib (Copiktra) for CLL/SLL.
Other stories related to CLL/SLL this year included:
Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007. Follow
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