‘Set and forget’ combination of ibrutinib and venetoclax effective in frontline CLL

Blood cancers

By Mardi Chapman

8 Mar 2022

Professor Constantine Tam

Professor Con Tam

Australian-led research has shown that fixed-duration ibrutinib plus venetoclax achieves deep, durable responses, clinically meaningful PFS and treatment-free remissions in CLL, including in patients with high-risk features.

The international phase 2 CAPTIVATE study enrolled 159 patients 18-70 years with previously untreated CLL/SLL to receive three cycles of ibrutinib monotherapy followed by 12 cycles of combined ibrutinib plus venetoclax.

The fixed duration of treatment study follows an initial CAPTIVATE cohort in which treatment discontinuation was guided by minimal residual disease (MRD) after a pre-randomisation regimen of ibrutinib plus the ibrutinib-venetoclax combination.

Senior investigator on the study Professor Con Tam, from the Peter MacCallum Cancer Centre, told the limbic that the positive findings pre-randomisation – including undetectable MRD achieved by 75% of patients in peripheral blood and 68% in bone marrow – gave them pause to think.

“As it turned out, the response was so good on the MRD cohort that the question then arose, that in real life … isn’t it easier to give a set-and-forget regimen?”

The current fixed-duration study, published in Blood, found a complete response rate of 56% – higher than the 40% observed in a historical FCR comparator.

CR rates were higher in patients without del(17p) than those with del(17p)/mutated TP53 (61% v 56%); those without bulky disease versus those with bulky disease (66% v 31%); and in those with unmutated versus mutated IGHV (62% v 47%).

Best uMRD rates were 77% in peripheral blood (PB) and 60% in bone marrow (BM) in the all-treated population.

“In patients without del(17p), uMRD rates were 76% (95% CI, 69-84) in PB and 62% (95% CI, 54-70) in BM. uMRD rates for patients with del(17p)/mutated TP53 were 81% (95% CI, 67-96) in PB and 41% (95% CI, 22-59) in BM.”

In patients with the best response of CR, uMRD rates were 90% in PB and 72% in BM.

“With median follow-up of 27.9 months, estimated 24-month PFS rates by investigator assessment were 95% (95% CI, 90-97) in the all-treated population, 96% (95% CI, 91-98) in patients without del(17p), and 84% (95% CI, 63-94) in patients with del(17p)/mutated TP53,” the study said.

In nine patients who progressed and were retreated with ibrutinib monotherapy, seven had a partial response while two had still to be evaluated.

‘User-friendly’ regimen

Professor Tam, lead author on the fixed-duration cohort study, said the new findings confirmed the earlier CAPTIVATE cohort.

“The MRD-guided cohort showed MRD clearance of about 75% and for those patients randomised to stop, they seemed to have durable responses. What this separate cohort shows is that we can recruit a whole new group of patients and still get exactly the same results.”

“We also showed that patients are staying in remission. They are not relapsing when we stop this treatment. But in those patients who do relapse if they are retreated with ibrutinib as a single agent, they do respond. This is a highly effective, all oral, fixed duration regimen which produces very good results.”

Professor Tam said a fixed-duration regimen was a lot more user-friendly than a MRD-guided strategy which requires testing that is not available to most clinicians.

However Australian clinicians won’t have early access to the combination treatment.

“We don’t even have ibrutinib frontline. We will probably end up getting ibrutinib …frontline, as monotherapy, through the PBS in the next two years. For the combinations to get up? It will be a while.”

The study also found that ibrutinib plus venetoclax had a favourable safety profile with 92% of patients able to complete all planned treatment.

“Tumour debulking with the 3 cycles of ibrutinib lead-in reduced tumor burden category for tumour lysis syndrome monitoring and prophylaxis for 94% of patients with high tumour burden at baseline,” it said.

“With reduced need for intensive monitoring and hospitalisation, and no risk of infusion-related reactions, the all-oral, fixed-duration regimen of ibrutinib plus venetoclax offers improved patient convenience and ease of administration.”

The study was supported by Pharmacyclics LLC, an AbbVie Company.

Disclosures: Australian investigators Professor Con Tam, Professor Stephen Opat and Associate Professor Bryone Kuss report honoraria and/or research funding from a number of pharmaceutical companies including AbbVie.

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