13 July 2022

Zanubrutinib makes it onto PBS for WM

Haematology Leukaemia Medical oncology PBS Rare cancers

Zanubrutinib, a next generation selective bruton tyrosine kinase (BTK) inhibitor, is now available on the PBS to patients with Waldenstrom’s macroglobulinemia (WM) who relapse, or for whom chemotherapy is unsuitable as a first line treatment.

Up until now, Australians with WM, a rare type of slow-growing non-Hodgkins Lymphoma, have been unable to access BTK inhibitors after receiving frontline immune-chemotherapy, either with rituximab and bendamustine (R-Benda), or rituximab with dexamethasone, rituximab and cyclophosphamide (oral) (DRC).

The PBS never listed the first generation BTK, ibrutinib, despite its proven effectiveness against WM in relapsed patients.

“The reality is, most people with WM in Australia, about 60-70%, were actually on clinical trials with either ibrutinib or zanubrutinib,” said zanubrutinib global lead Professor Constantine Tam from the Peter MacCallum Cancer Centre.

But others were missing out, he said, especially those in rural areas.

Professor Tan said patients who previously had chemotherapy now had another option for second line treatment, thereby avoiding the risk of secondary cancers and other possible chemotherapy complications.

“The other group the drug is funded for, which was a bit of a surprise, is frontline treatment for those less suitable for chemotherapy on the basis of comorbidities,” said Professor Tam.

“Ibrutinib is quite dirty. It hits a number of different enzymes which accounts for side-effects including atrial fibrillation and bleeding. With zanubrutinab, those side-effects are still present, but at a much lower level.”

Professor Constantine Tan

Zanubrutinib (commercially known as Brukinsa) was developed after the use of ibrutinib, the first BTK inhibitor, became the standard of care in Europe and America, explained Professor Tan.

The drug is made by Chinese company BeiGene, but Professor Tan has been involved since designing the first trial in all lymphomas in 2014, recruiting the first 25 patients in the world in Melbourne and showing the drug was very effective.

“The main advantage is that it’s a lot cleaner than ibrutinib,” he said.

“Ibrutinib is quite dirty. It hits a number of different enzymes which accounts for side-effects including atrial fibrillation and bleeding. With zanubrutinab, those side-effects are still present, but at a much lower level.”

In head-to-head studies with ibrutinib, Professor Tan said zanubrutinib clearly demonstrated better efficacy in CLL.

“In the head-to-head study on Waldenstrom’s, zanubrutinab response rates were higher but didn’t meet the P value, although they came very, very close,” said Professor Tam.

The original 2014 cohort included some with Waldenstrom’s, he said. “So we’ve got as much as eight years’ follow up on those patients. Some have relapsed, and some are doing fine.

“In the randomised study, there is a trend to improved progression-free survival with zanubrutinib, but that’s not statistically significant just yet. We think it’s at least as good as ibrutinib. Only time will tell. It’s certainly less toxic.”

Professor Judith Trotman, head of haematology at Concord Repatriation General Hospital in Sydney, told Oncology Republic that zanubrutinib was a “life-saving and life-changing” therapy for people with WM.

“It’s thrilling that this medication, which is so well tolerated, is now PBS-approved for this rare patient population.”

Professor Trotman said immuno-chemotherapy continues to be the best first line treatment for most people with WM.

“WM is generally a very indolent, very slowly progressing lymphoma. With close monitoring, most people are usually well enough to tolerate gentle immuno-chemotherapy and that’s time limited. They can save their zanubrutinib for use when they relapse in later years.”

Zanubrutinib is an immunosuppressive therapy that needs to be taken continuously and indefinitely, as opposed to a finite course of chemotherapy, but it was so well tolerated that patients did not have a problem with that, said Professor Trotman.

“People get into the habit of taking it and they know if they don’t, their symptoms will come back.”

Furthermore, she said it didn’t matter if people forgot the occasional dose or didn’t take their dose at the same time each day. “It’s very straightforward for most patients,” she said.

“Unfortunately in our COVAX-lymphoma study we found that patients on BTK inhibitors mount a very poor antibody response to covid vaccination. “Patients need to be aware that just like rituximab and chemotherapy suppresses B cell response to vaccination, so do these BTK inhibitors. They’re generally quite familiar with that concept,” said Professor Trotman.