Pirtobrutinib shows evidence to inaugurate a third generation of BTK inhibitors
The Bruton’s tyrosine kinase (BTK) protein is a crucial component of antigen-dependent B-cell receptor signalling that regulates B-cell development and maturation. BTK is also implicated in major processes of malignant B non-Hodgkin lymphoma (NHL-B) and chronic lymphocytic leukaemia (CLL) cells such as proliferation, survival, and trafficking. BTK inhibition has a profound effect on malignant cell survival.¹
BTK inhibitors have been a considerable therapeutic advance in the treatment of NHL-B and CLL. The three BTK inhibitors approved to date, namely ibrutinib, acalabrutinib, and zanubrutinib, are all covalent and irreversible inhibitors at an energetically important area of the protein—the C481 binding site.¹ Ibrutinib was the
first approved drug.² The second-generation inhibitors, acalabrutinib and zanubrutinib, were designed to be more BTK selective.³,⁴ Covalency and irreversibility are therapeutics strengths for these drugs; however, this covalency bond had induced resistance mutations occurring at the covalent binding site C481, rendering the drugs inactive.1,5
In The Lancet, Anthony Mato and colleagues6 report the results of a phase 1/2 study with pirtobrutinib (working name; formerly known as LOXO-305), as part of a new BTK inhibitor class via non-covalent and reversible inhibition, in patients with relapsed or refractory B-cell malignancies. The study included 109 (34%) women and 214 (66%) men, with a median age 68 years
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(IQR 62–74). From a pharmacological point of view, two advantages of this new drug class are highlighted. First, the selectivity of the drug on BTK appears to be increased; however, full pharmacological data would be interesting for the detailed kinase activities. Second, this class does not bind BTK to the C481 residue, and the efficacy of the drug is therefore not affected by mutations in the BTK binding site.7 These two properties offer additional potential therapeutic activity and avoid off-target toxicities.¹,⁷
Safety data are presented on all 323 patients treated.6 The safety profile appears particularly promising, as suggested by the absence of dose-limiting toxicity, and thus maximum tolerated dose level was not reached. Based on the pharmacokinetic profile, a 200 mg daily dose will be retained for the phase 2 and 3 trials. The most common adverse events were fatigue (65 [20%]), diarrhoea (55 [17%]), contusion
(42 [13%]), and neutropenia (41 [13%]). Other side- effects of the BTK inhibitor reported with pirtobrutinib were arthralgia (16 [5%]), hypertension (15 [5%]),
haemorrhage (15 [5%]), and atrial fibrillation (2 [1%]). Few adverse events were of grade 3 or higher severity.
Pirtobrutinib appears to be attractive for a secure use alone or in combination with other drugs. First, the frequency of haemorrhage is low (4·6% for adverse events of any grade), as compared with other BTK inhibitors (50·4% with ibrutinib,8 39·1% with acalabrutinib,³ and 48·5% with zanubrutinib4). Second, the frequency of atrial fibrillation with pirtobrutinib (1%) is also favourably low (16·2% with ibrutinib,2 3·9% with acalabrutinib,3 and 2·0% with zanubrutinib4). However, the duration of follow-up (6 months) is insufficient to draw conclusions for long-term safety. Because side- effects of tyrosine kinase inhibitors, whether on target or off target, could eventually be cumulative, Mato and colleagues conclude longer follow-up is needed to better understand the pirtobrutinib safety profile associated with long-term administration.
The pirtobrutinib study contributes to the fine-tuning of the knowledge of the balance of on-target effects (here on the targeted BTK, with expected side-effects) and off-target effects (outside of the intended BTK target, with unexpected side-effects). For example, the low frequency of atrial fibrillation with pirtobrutinib suggests atrial fibrillation is an off-target effect of the BTK inhibitor.
Few infections (mild severity upper respiratory tract infection in 7% of patients) occurred in the pirtobrutinib study and no severe infection occurred. As a powerful inhibition of BTK could theoretically affect the anti- infectious defences in humans,9 the results of a prolonged follow-up will be interesting to scrutinise, specifically in terms of the effects on the immune system and infection. The previously reported infectious toxicities of BTK and PI3K inhibitors—with opportunistic fungal and viral cytomegalovirus infections—must be kept in mind, and patients must be carefully monitored, especially when exposed to prolonged treatment.1,10 Safety data on chronic use of these inhibitors will inform future combination therapy and optimal treatment duration modality (ie, fixed, continuous, or sequential).
The pirtobrutinib study6 shows promising efficacy data, which is even more remarkable when considering the population was heavily pretreated, with a median of three previous lines of systemic therapy. The efficacy in patients with CLL setting (n=139 evaluable patients) is interesting, with an overall response rate (ORR) of 63%. This ORR was the same, irrespective of whether patients were treated with BTK inhibitor, presented a BTK C481 mutation, or previous treatments. In patients with mantle cell lymphoma (n=56 evaluable patients), Waldenström macroglobulinaemia (n=19 evaluable patients), and other B-cell lymphomas (n=55 evaluable patients), efficacy data were observed in many histological types, including mantle cell lymphoma (ORR 52%), Waldenström macroglobulinaemia (ORR 68%), and diffuse large B-cell lymphoma (ORR 24%).
The diversity of the antitumour activity of pirtobrutinib observed on several histological types is attractive for effective use in several B-cell malignancies, in which a common source of pathology would be overactivated B-cell receptor signalling. The identification of a specific patient population with tumours overactivated by abnormal BCR signalling and presumed to respond to therapy should be difficult. Despite dramatic advances in biology in the past 30 years, the effect on a molecular medicine personalised with therapeutic decision remains meagre in the field of NHL-B or CLL. Apart from the activating EZH2 mutation in lymphoma druggable with the EZH2 inhibitor,11 few reliable molecular alterations are recognised as druggable. The pirtobrutinib study, by opening the way for a third generation of BTK
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inhibitors, could improve such a personalised molecular approach in the treatment of B-cell malignancies.
J-MM reports non-financial support from Mylan, Celgene, Bristol-Myers Squibb, and Roche; personal fees from Bristol-Myers Squibb and AstraZeneca; and funding for clinical trials from AbbVie, Agios, Amgen, Argen-X, Debio Pharma, Eisai, Forma therapeutics, Genentech, Loxo, Lilly, Medimmune, Roche, Sanofi, Xencor, GlaxoSmithKline, Astex, and Seattle Genetics, all outside the area of work commented on here. VR reports non-financial support from Mylan, Celgene, Bristol-Myers Squibb, and Roche; personal fees from Bristol-Myers Squibb and AstraZeneca, and funding for clinical trials from AbbVie, Agios, Amgen, Argen-X, Debio Pharma, Eisai, Forma therapeutics, Genentech, Loxo, Lilly, Medimmune, Roche, Sanofi, and Xencor; and grants from Argen-X, GlaxoSmithKline, Astex,
and Seattle Genetics, all outside the area of work commented on here.
*Jean-Marie Michot, Vincent Ribrag
[email protected]
Département des Innovations Thérapeutiques et Essais Précoces (J-MM) and Department of Hematology (VR), Gustave Roussy, Université Paris-Saclay, Villejuif F-94500, France
1 Wen T, Wang J, Shi Y, Qian H, Liu P. Inhibitors targeting Bruton’s tyrosine kinase in cancers: drug development advances. Leukemia 2020; published online Oct 29. https://doi.org/10.1038/s41375–020–01072–6.
2 Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia 2020; 34: 787–98.
3 Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet 2020; 395: 1278–91.
4 Tam CS, Opat S, D’Sa S, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood 2020; 136: 2038–50.
5 Woyach JA, Furman RR, Liu T-M, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med 2014;
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6 Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory
B-cell malignancies (BRUIN): a phase 1/2 study. Lancet 2021; 397: 892–901.
7 Johnson AR, Kohli PB, Katewa A, et al. Battling BTK mutants with noncovalent inhibitors that overcome Cys481 and Thr474 mutations. ACS Chem Biol 2016; 11: 2897–907.
8 Wang ML, Blum KA, Martin P, et al. Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results. Blood 2015; 126: 739–45.
9 Burger JA, Wiestner A. Targeting B cell receptor signalling in cancer: preclinical and clinical advances. Nat Rev Cancer 2018; 18: 148–67.
10 Ghez D, Calleja A, Protin C, et al. Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib. Blood 2018;
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11 Italiano A, Soria J-C, Toulmonde M, et al. Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study. Lancet Oncol 2018; 19: 649–59.
Adopting an intersectionality framework to address power and equity in medicine
Responses to police brutality and the disproportionate effects of COVID-19 among ethnic minority populations have widened realisations about racism, and social and health inequities.1 Typically, medical institutions such as the Association of American Medical Colleges outline their position against racism1 separately from their mis- sion for achieving gender equity.2 However, in western settings, the downstream effects of medical education on doctors and patients is shaped by patriarchal and colonial histories and values.3,4 Patriarchal cultures in medicine constrain women doctors’ career choices and progression internationally.5 Medical textbooks reinforce norms based on Whiteness by under-representing racial and ethnic minorities—eg, different presentations and clinical signs for patients with darker skin tones.6 Exporting western biomedical knowledge to other global settings reinforces inequality.3 Dismantling the power structures in medicine, however, requires complex thinking that goes beyond focusing on one dimension at a time—eg, patriarchy or racism. This requirement is also relevant to the decolonising global health movement.
Medical institutions need to turn their lens towards intersectionality—the inextricable way that factors such
as race, class, gender, disability, and sexuality intersect to shape each other within broader structures and processes of power.7 Intersectionality has its roots in Black feminist scholarship8 and its transformative potential has been recognised in the context of global health7 and in medicine.4 However, as Sharma has argued: “to be truly transformative, any intersectional approach must grapple with the issue of power and privilege within medicine
Published Online December 21, 2020 https://doi.org/10.1016/ S0140-6736(20)32513-7