Blood cancers

Professor Andrew Roberts: How far can venetoclax take us beyond CLL?

Professor Andrew Roberts

A highlight at the ASH Annual Meetings is the prestigious Ham-Wasserman lecture – named in honour of two distinguished past presidents of the Society.

This year the 2020 Ham-Wasserman lecture was delivered by Australian Professor Andrew Roberts.

Professor Roberts presented a history of the development of BCL-2 inhibition from the 1980s through to the breakthrough of the first BH3-mimetic venetoclax – initially as a treatment for CLL, and its current and future use.

He told the virtual meeting that BCL2 overexpression was a common theme in blood cancers and from early after its discovery, BCL-2 was recognised as an attractive target.

He said the reward of some three decades of research had been that venetoclax had established the paradigm that apoptosis can now be directly triggered as a cancer therapy.

“I think we’re really at the beginning of the dawn of BH3 mimetic treatment,” he said.

“These are cytotoxic drugs that are generally well tolerated, and they show a real capacity to improve outcomes for at least some groups of patients, but there’s plenty more to be done.”

“We’re going to find out more about this because there’s over 230 trials using this drug going on worldwide, most in haematological malignancies, and other companies are bringing BCL-2 inhibitors to compete with venetoclax.”

He said all the data with venetoclax-based treatments shows that CR and, ideally, MRD-negativity were the best indicators of whether patients would do well long term.

“So the goal of treatment, at least using surrogate markers, should be to try to eliminate disease and achieve those two statuses.”

Professor Robert said combination therapy will be the norm – rational combinations of drugs based on preclinical and clinical evaluation.

“There’s significant trials trying to enhance TP53 activity and by adding cytotoxics to increase the signal through TP53. And there’s the addition of other BH3 mimetics that target either MCL1 or BCL-xL that are also being explored. So watch this space.”

Key clinical questions yet to be answered included:

  • How to integrate biomarkers for response and resistance?
  • What was the optimal duration of venetoclax-based therapy?
  • What about long-term safety issues with prolonged BCL-2 inhibition?

Beyond CLL

He said he was looking forward to the results of a UK study that will inform whether duration of venetoclax therapy for any individual can be optimised by monitoring serial MRD.

“In AML, we need to know whether venetoclax can be added safely and is an advantage, if added to standard induction therapy, for fit patients. And can it be combined with other targeted agents to reduce the risk of subclonal resistance?”

“In myeloma, we’re looking forward to the formal outcomes of a randomised trial that hasn’t been fully reported as yet. And we want to know if there’s a selective benefit in the t(11;14) and other biomarker-selected subgroups. And, of course, can the drug be combined safely with other targeted agents?”

Professor Roberts said that in lymphoma the key questions include whether a venetoclax/ibrutinib combination is superior to ibrutinib monotherapy in relapsed mantle cell lymphoma, with two trials underway.

“And, in diffuse large B-cell lymphoma, does venetoclax add efficacy to R-CHOP? Expect to see early-phase results in acute lymphoblastic leukemia, myelodysplasia, and other diseases in the near future.”

In summing up, he acknowledged the huge number of scientists and clinical teams, colleagues and collaborators around the world that had brought this class of anti-cancer treatment forward from the bench to the clinic.

Professor Roberts is Research and Education Lead for Haematology across the Victorian Comprehensive Cancer Centre, holds joint appointments with the Walter and Eliza Hall Institute (WEHI) and the University of Melbourne, and practices at the Royal Melbourne Hospital and Peter MacCallum Cancer Centre.

Disclosure statement: Professor Roberts receives a share of milestone and royalty payments related to venetoclax paid by Genentech and AbbVie to WEHI.

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