The development of new KIT inhibitors like bezuclastinib is largely fueled by the need for alternatives to high-dose avapritinib in advanced SM. Concerns about cognitive effects and rare intracranial hemorrhage with avapritinib create an opportunity for agents with less blood-brain barrier penetration.
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While pirtobrutinib works after covalent BTK inhibitors, no data shows covalent inhibitors work after pirtobrutinib failure. This uncertainty about future options makes clinicians cautious about using it as an initial therapy, especially for younger CLL patients who will need multiple treatments over their lifetime.
Non-covalent BTK inhibitors like pirtobrutinib are currently approved for use after covalent BTK inhibitors fail. Moving them to the frontline setting, as studied in BRUIN-313, disrupts the established treatment pathway and creates uncertainty for managing relapsed disease, as the standard 'next step' is removed.
The GSK3 inhibitor was developed for CNS diseases, requiring high specificity and the ability to cross the blood-brain barrier. These same pharmaceutical characteristics—potency and lipophilicity—proved highly advantageous for treating cancer, demonstrating an unexpected but effective therapeutic pivot from neuroscience to oncology.
Pathways like integrins have long been of interest but lacked effective therapeutic approaches. The advent of new technologies, such as antibody-drug conjugates and checkpoint inhibitors, has created opportunities to re-explore these older targets with potent, modern drugs, breathing new life into decades-old research.
The DAYBREAK pivotal study focuses on third-line plus patients who have already failed both BTK and BCL2 inhibitors. By enrolling this high unmet need population, particularly those resistant to the newest non-covalent inhibitors, Neurix aims for an accelerated regulatory approval to get its drug to market faster.
Avapritinib is dosed at 200mg for advanced systemic mastocytosis (SM) but only 25mg for indolent SM. This tenfold difference is not based on tolerance but on the goal of therapy: extending survival in advanced SM versus improving quality of life without significant toxicity in indolent SM, where survival is near-normal.
Despite strong single-agent trial results, experts believe the field is shifting away from continuous monotherapy. The most significant future impact for pirtobrutinib will likely be as a backbone of fixed-duration combination therapies with drugs like venetoclax, aiming for deeper remissions without indefinite treatment.
While pirtobrutinib is effective after covalent BTK inhibitors, the reverse is unproven. Starting with pirtobrutinib frontline raises a critical unanswered question about whether patients will still respond to older covalent inhibitors, complicating sequencing decisions, especially for younger patients.
Recurrent non-melanoma skin cancers in patients on ruxolitinib may be attributable to its JAK1 inhibition. In such cases, a viable strategy is to switch the patient to a more JAK2-selective inhibitor, such as pacritinib or fedratinib, to potentially mitigate this specific side effect while maintaining disease control.
Clinicians are hesitant to use newer, potentially safer non-covalent BTK inhibitors before established covalent inhibitors. While it's known that non-covalents work after covalents fail, the reverse is unproven, creating a one-way treatment path that reserves these newer agents for later lines of therapy.
