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ASH 2022 | Efficacy of pirtobrutinib in patients with R/R MCL previously treated with a covalent BTKi

In this video, Michael Wang, MD, The University of Texas MD Anderson Cancer Center, Houston, TX, discusses the efficacy of pirtobrutinib in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) previously treated with a covalent Bruton’s tyrosine kinase (BTK) inhibitor. Pirtobrutinib is currently being investigated in the BRUIN study (NCT03740529), and Prof. Wang presents updated results from this trial, commenting on the response rates observed in patients with MCL and the mechanism of action of this agent. This interview took place at the 64th ASH Annual Meeting and Exposition congress held in New Orleans, LA.

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Transcript (edited for clarity)

The second abstract I presented is on pirtobrutinib in relapsed/refractory mantle cell lymphoma. Among 90 primary analysis patients with relapsed mantle cell lymphoma, the overall response rate was 58% and CR was very reasonable.

What is astonishing is that in BTK-naive patients, those with mantle cell lymphoma relapse, never received a prior covalent BTK inhibitor, the response rate among 15 patients was 85%...

The second abstract I presented is on pirtobrutinib in relapsed/refractory mantle cell lymphoma. Among 90 primary analysis patients with relapsed mantle cell lymphoma, the overall response rate was 58% and CR was very reasonable.

What is astonishing is that in BTK-naive patients, those with mantle cell lymphoma relapse, never received a prior covalent BTK inhibitor, the response rate among 15 patients was 85%. So, let me explain the significance of this: all the FDA approved covalent irreversible BTK binders and inhibitors, they cause around a similar overall response rate between 70 to 90%, the CR is about half of that, maybe a little more. But, because the three agents bind to the same epitope on the ATP binding site of the Bruton’s tyrosine kinase protein, and so if the patient is treated with one covalent BTK inhibitor and becomes resistant, this same patient will be resistant to the other two.

As we all know, the three approved agents, covalent BTK inhibitors include ibrutinib, acalabrutinib, and zanubrutinib. But pirtobrutinib binds very differently from the three covalent BTK inhibitors: it binds to the BTK protein also in the HP binding site, but in a non-covalent, reversible fashion. So even new proteins, new BTK proteins, are made, and because it’s constantly binding on and off, it can inhibit the newly formed BTK proteins. So this way, the effect of pirtobrutinib is very impressive and it can overcome prior covalent BTK inhibitor resistance and it is even more effective in prior BTK now exposed to patients with mantle cell lymphoma.

 

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Disclosures

Deciphera: Consultancy; BioInvent: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Research Funding; IDEOlogy Health: Honoraria; Celgene: Research Funding; VelosBio: Consultancy, Research Funding; Molecular Templates: Research Funding; Loxo Oncology: Research Funding; Dava Oncology: Honoraria; Oncternal: Consultancy, Research Funding; Genmab: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Leukemia & Lymphoma Society: Consultancy, Honoraria; MJH Life Sciences: Honoraria; Medscape: Honoraria; Pepromene Bio: Consultancy; Eastern Virginia Medical School: Honoraria; LLC TS Oncology: Honoraria; Studio ER Congressi: Honoraria; Oncology Specialty Group: Honoraria; Moffit Cancer Center: Honoraria; OncLive: Honoraria; Physicians Education Resources (PER): Honoraria; Practice Point Communications (PPC): Honoraria; Meeting Minds Experts: Honoraria; Genentech: Consultancy, Research Funding; Milken Institute: Consultancy; Merck: Honoraria; Lilly: Consultancy, Research Funding; Kite Pharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; InnoCare: Consultancy, Research Funding; Vinverx: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Acerta Pharma: Honoraria, Research Funding; AbbVie: Consultancy.