Ibrutinib and Venetoclax: A New Standard for Mantle Cell Lymphoma?

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Preclinical models indicated that dual inhibition of BTK and BCL2 may be synergistic.
Preclinical models indicated that dual inhibition of BTK and BCL2 may be synergistic.

Combining two drugs, both of which are active as monotherapies in mantle cell lymphoma (MCL), yielded an overall complete response rate of 71% in a small study recently published in The New England Journal of Medicine.1 The Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, and the BCL2 inhibitor, venetoclax, historically yielded much lower compete response rates when given as long-term continuous therapy in patients with MCL.

“This study showed that the two drugs can be safely delivered together and have improved activity in terms of complete response rate and minimal residual disease clearance,” said Constantine S. Tam, MBBS, MD, of the Peter MacCallum Cancer Centre in Melbourne, Australia. “The ongoing phase 3 PCYC-1143 [study] may confirm this as a new standard of care.”

Current Standard

According to Dr Tam, the current standard of care for patients with relapsed or refractory MCL is single-agent ibrutinib. This treatment yields a median complete response rate of about 21% and a median progression-free survival of about 14 months.2 Similarly, a phase 2 study of single-agent venetoclax in relapsed or refractory disease showed a complete response rate of 21%, with a median progression-free survival of 14 months.3

Preclinical models indicated, however, that dual inhibition of BTK and BCL2 may be synergistic. The combination resulted in a complete response or complete response with incomplete hematologic recovery rate of 47% in a study of patients with chronic lymphocytic leukemia.4

To test the combination the combination in MCL, Dr Tam and colleagues conducted a single-group, phase 2 study in 23 patients with relapsed or refractory disease and 1 patient with treatment-naive disease. Patients were given ibrutinib monotherapy at 560 mg per day. After 4 weeks, venetoclax was added in a step-wise fashion up to a dose of 400 mg per day. The primary endpoint was rate of complete response at week 16.

Using computed tomography, the complete response rate at week 16 was 42%, higher than the historical result of 9% at this time point seen with single-agent ibrutinib (P < .001). Using positron-emission tomography, the complete response rate was 62% at week 16 and 71% overall. With a median follow-up of 15.9 months, median progression-free survival has not been reached. The estimated 12-month progression-free survival rate was 75%.

Minimal residual disease (MRD) was evaluated with flow cytometry in bone marrow and by allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR). Absence of MRD was confirmed using flow cytometry in 67% of patients and in 38% using ASO-PCR.

According to Dr Tam, the drug combination “opens up the possibility for improved progression-free survival and consideration for drug holidays during MRD-negative remission.” He noted, however, that researchers did not test the latter concept in a large number of patients.

“A high response rate may not result in durable responses,” added Henry C. Fung, MD, FACP, FRCPE, vice chair of the department of hematology/oncology at Fox Chase Cancer Center in Philadelphia, Pennsylvania. “A true breakthrough therapy for MCL should be well-tolerated and able to prolong survival,” he said. “Hopefully, this combination would become a breakthrough therapy.”

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