Prof John Seymour
Discussing the latest treatments in B-cell lymphomas at this year’s virtual ASCO 2021 meeting Professor John Seymour, Director of the integrated Haematology Department of the Peter MacCallum Cancer Centre & the Royal Melbourne Hospital in Melbourne, weighed up three recently FDA approved drug classes in relapsed follicular lymphoma, marginal zone lymphoma and Waldenstrom’s macroglobulinemia.
Among the three available drug classes, Professor Seymour said standard of care options included BTK inhibitors, with ibrutinib approved for other internal histologies but not follicular lymphoma; tazemetost as the first in class EZH2 inhibitor; and several PI3 kinase inhibitors.
On BTK inhibitors Professor Seymour said ibrutanib, which is approved in relapsed marginal zone lymphoma based on a phase II study showing a 50% overall response rate, demonstrated ‘only modest activity’ in relapsed follicular lymphoma.
He was referring to the DAWN study that reported an overall response rate of just 21% and a median PFS of just 4.6 months. A second study, in a ‘less biologically adverse group’ also showed ‘modest’ efficacy with an overall response rate of 38% and a median PFS of 14 months, he noted.
But Professor Seymour said more favourable efficacy has been seen among those patients with a myd88 mutation with the BTKi having ‘major activity’ in Waldenstrom’s where more than 95% of patients carry the mutation.
“There’s substantial efficacy either as a single agent or in combination with rituximab, without clear long term advantages for the combination,” he told the conference.
“Responses are durable, but almost always partial and requires ongoing indefinite treatment,” he said, adding that clinicians need to be aware of IgM rebound which can occur within days of temporary drug cessation.
The more selective BTKi, zanabrutinib, was compared directly to ibrutinib in Waldenstrom’s and appears to have equivalent efficacy but a ‘cleaner’ adverse event profile, he said.
“[There is] less atrial fibrillation and a lower rate of drug discontinuation [and] although infection rates were similar, neutropenia was more frequent with zanabrutinib”.
First in class
Meanwhile tazemetostat, the first in class EZH2 inhibiter and FDA approved based on a phase II study in relapsed refractory disease shows ‘excellent’ tolerance with low adverse events – ‘a major appealing feature’, says Professor Seymour.
In terms of its efficacy data supports its use in patients with mutated disease and particularly when tumour masses might be symptomatic, he explains.
“The median PFS has been shown to be similar between patients with mutated and non- mutated EZH2. However, the degree of cytoreduction was much greater among those carrying the mutation, with an overall objective response rate of 69% versus 35%”.
Moving to the PI3 kinase inhibitors, which include idelalisib, duvelisib, and umbralisib, Professor Seymour noted that the efficacy of these agents in follicular lymphoma appeared to be broadly similar, with overall response rates ranging 40% to 60%, although cross trial comparisons were ‘fraught’.
With similar durability of responses – median progression free survival all sit around the 9 to 12 month range – choice of agent came down to tolerability and convenience of delivery, he suggested.
According to Professor Seymour, umbrilisib had a lower rate of autoimmune adverse events and a lower rate of drug discontinuation. It was also the one PI3 kinase inhibitor approved in the setting of marginal zone lymphoma.
“Studies show an overall response rate similar to that seen in follicular lymphoma but with greater durability, such that two thirds of responses were going beyond two years,” he noted.
Also touching on the recently approved CAR T product axe-cel for relapsed follicular lymphoma – based on a phase II study showing an overall response rate of 94% and a ‘very impressive’ CR rate of 84% – Professor Seymour said the durability of its response in patients with marginal zone lymphoma was ‘disappointing’, with a median duration of 12 months.
Of more concern, he said, was the reported 60% incidence of neurologic adverse events.
“Especially the 19% rate of grade three or greater, often involving a confusional syndrome, some of which have been quite prolonged and not yet fully reversible,” he stated.
Frontline treatment
As to his own approach to sequencing the available approved targeted therapies in relapsed follicular lymphoma, Professor Seymour said chemoimmunotherapy remained the recommended frontline treatment with the choice between obinutzumab or rituximab.
At first relapse histologic transformation should also be considered, and excluded, he said, as well as the ‘prognostically adverse’ early relapse above the 24-month threshold.
For the more common late relapse of follicular histology, he says r-squared has the strongest supporting data with either tazemetostat or the PI3 kinase inhibitors. His own preference for tazemetostat prevails if EZH2 mutation is present, he adds.
“I’m not yet sure of the true place of axi-cel in follicular lymphoma, given its expense, logistic complexities, and my concern regarding neurologic toxicity,” he said in the session.
With most of the new agent responses so far appearing durable Professor Seymour is hopeful that, if sustained, there is ‘potential for long term disease control in this otherwise incurable disease context’.
Access the full presentation here.