Could protein kinase inhibitors become a next generation pharmacotherapy for non-Hodgkin’s lymphoma?

KEYWORDS:

• B-cell lymphoma
• protein kinase
• small molecule inhibitors
• Non-Hodgkin’s

1. Introduction

Non-Hodgkin’s lymphomas (NHL) encompass a heterogeneous group of lymphoid neoplasms chiefly of B-cell origin and are diagnosed in approximately 100,000 patients in the United States annually [1]. B-NHL have been at the forefront of successful clinical translation of oncology research for decades, from the advent of radiation therapy in the early 20th century, to alkylating chemotherapies developed from nitrogen mustard following World War II, to rituximab, the first monoclonal antibody approved for cancer in 1997, and, more recently, anti-body drug conjugates, bispecific antibodies, and adoptive T-cell therapy [2]. Improved understanding of the molecular pathways supporting lymphomagenesis is paving the way for continued therapeutic advances. Essential to several of these pathways are protein kinases, and their targeted inhibition represents another fruitful and growing treatment modality for B-NHL. Here, we summarize the current and anticipated future landscape for protein kinase inhibitors (PKIs) in NHL, focusing on B-NHL and not including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) since Bruton’s tyrosine kinase inhibitors (BTKIs), a class of PKIs, are currently an established standard therapy in that space.

2. Body

2.1. Current use of PKIs in B-NHL

Key to B-NHL pathogenesis is sustained B-cell receptor (BCR) signaling [3]. Normal BCR activity begins with specific antigenic stimulation flowing to multiple downstream partners promoting cell activation and proliferation, including via mTOR and IKK/NF-κB signal transduction. Several kinases involved in BCR signaling have proven amenable to small-molecule inhibition, with targeting of BTK and phosphatidylinositol 3-kinases (PI3Ks) the most successful to date.

2.2. Bruton Tyrosine Kinases

Phosphorylation of BTK, an enzyme named for the pediatrician who described the condition X-linked congenital condition agammaglobulinemia ultimately linked to its mutation, marks an early step in BCR activation [4]. BTKIs have shown some variability of efficacy in B-NHL. In mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and lymphoplasmacytic lymphoma (LPL), the covalent inhibition of BTK, whether with the 1st-in-class agent ibrutinib or 2nd-generation agents (acalabrutinib, zanubrutinib) associated with, typically, fewer off-target effects, has led to regulatory approvals and widespread clinical adoption (Table 1). BTKIs have proven particularly valuable, to date, in settings of relapsed/refractory (R/R) disease and for frail patients in whom more intensive, conventional chemotherapy is contraindicated [5–7]. Dosed orally and indefinitely until progression or unmanageable toxicity, BTKIs are often administered for extended courses and not uncommonly cause mild but persistent side effects such as rash, gastrointestinal symptoms, or cytopenias. Less frequent but very important toxicities, including cardiac and hemorrhagic, are essential to monitor for, recognize, and mitigate promptly. While 2nd generation BTKIs are better tolerated overall than ibrutinib, important class-effect toxicities nevertheless occur. Discontinuation of BTKIs due to adverse events – which potentially compromises B-NHL outcomes – occurs in up to 50% of patients and may be avoidable in a large subset with careful monitoring and medication dose adjustments [8].

Table 1. Summary of Bruton Tyrosine Kinases in B-NHL.

	Description	B-NHL labeled indications	Key Outcomes	Key Toxicities^a	Selected Directions in B-NHL Under Investigation
Ibrutinib	1st-in class, covalent	R/R MZL (≥1 prior therapy) WM/LPL	ORR = 58%, mPFS = 15.7 mo in R/R MZL ORR 91%, 5-year mPFS = NR in R/R WM/LPL	Cardiac events	TRIANGLE: phase III, 3-arm study in 1 L MCL evaluating potential of ibrutinib to obviate need of autologous stem cell transplant consolidation.
Acalabrutinib	2^nd generation, covalent	R/R MCL (≥1 prior therapy)	ORR = 82%, mPFS = 29 mo in R/R MCL	Headache	ARCHED: phase III, 2-arm study in older adults with untreated DLBCL of R-miniCHOP with or without acalabrutinib.
Zanubrutinib	2nd generation, covalent	R/R MCL (≥1 prior therapy) R/R MZL (≥1 prior therapy) WM/LPL R/R FL (≥2 prior therapies)	ORR = 84%, mPFS = 33 mo in R/R MCL ORR = 64%, 2-yr PFS = 70% in R/R MZL VGPR = 28%, 18-mo PFS 85% in WM/LPL ORR 69%, PFS 28 mo in R/R FL in combination with obinutuzumab	Neutropenia	MAHOGANY: phase III, 2-arm study comparing zanubrutinib plus obinutuzumab against lenalidomide plus rituximab in R/R FL.
Pirtobrutinib	Noncovalent	R/R MCL (≥2 prior therapy, including a BTKI)	ORR = 58% in R/R MCL		BRUIN-MCL-321: phase 3, 2-arm study comparing pirtobrutinib with other BTKI (investigator choice) in R/R MCL

^aHemorrhage, infections, cytopenias, and cardiac arrhythmias are listed under ‘Warnings and Precautions’ for all FDA approved BTKIs. Cardiac events, headache, and neutropenia have been reported for all covalent BTKIs but may be relatively increased with specific agents. WM/LPL: Waldenstrom’s macroglobulinemia/lymphoplasmacytic lymphoma; MCL: mantle cell lymphoma; MZL: marginal zone lymphoma; ORR = overall response rate; mPFS = median progression free survival; NR = not reached; 1 L: first-line; VGPR: very good partial response.

The BTK eventually develops resistance to covalent inhibition, and in this circumstance there is no role for switching between covalent BTKIs currently on the market as their activities overlap. The 3rd generation BTKi pirtobrutinib, in contrast, binds BTK noncovalently and separately from the Cys-481 residue commonly implicated in covalent BTKI resistance [9]. Pirtobrutinib has established, albeit modest, efficacy in MCL that previously progressed on a covalent BTKI and is FDA approved for this indication [10].

The use of BTKIs in the most common B-NHLs, follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), is rapidly evolving. The single-arm phase II DAWN study in 110 patients with R/R FL reported an ORR of 20.9% and median PFS of only 4.6 months with ibrutinib monotherapy, failing to meet its primary efficacy threshold [11]. Recently, Zinzani et al. published a randomized phase II study called ROSEWOOD of the anti-CD20 antibody obinutuzumab with or without zanubrutinib in patients with FL R/R to ≥2 lines of therapy and showed superior ORR (69% to 46%) and median PFS (28.0 months to 10.4 months) with the BTKI addition [12]. The combination therapy met its primary endpoint of superior ORR, with subgroup analysis showing efficacy across age groups, rituximab refractoriness, and FL risk categorization. Interestingly, the combination was potentially relatively most efficacious in cases of early progression of disease, which is an area of unmet need in FL [13]. Treatment appeared well tolerated, with no unexpected safety signals from the combination emerging. In March 2024, the FDA granted accelerated approval to zanubrutinib with obinutuzumab for FL R/R after at least 2 lines of systemic therapy.

In DLBCL, the phase III PHOENIX study evaluated the standard chemoimmunotherapy regimen R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) with or without ibrutinib for front-line treatment of DLBCL of non-germinal center cell (GCB) of origin, as this subtype of DLBCL relies relatively heavily on BCR signaling [14]. Despite subgroup analysis showing benefit with ibrutinib in patients ≤60 years old (hazard ratio for PFS = 0.56, 95% confidence interval 0.36 to 0.86), increased toxicity in the subgroup of older patients resulted in no overall improvement in PFS or overall survival and thus no endorsement was granted by the FDA. In addition, ibrutinib has shown some efficacy as monotherapy for R/R DLBCL, particularly in non-GCB subtypes, as well as R/R DLBCL transformed from indolent B-NHL and is listed as a potentially useful drug in this space by the National Comprehensive Cancer Network (NCCN) [15,16].

2.3. Phosphatidylinositol 3-kinases

The family of PI3Ks encompasses four classes separated according to structure and function that participates in myriad roles in cellular proliferation, growth, survival, motility, and metabolism. Differential expression of PI3K isoforms across tissue types allows targeted inhibition of those most active in lymphomagenesis, such as the PI3K delta-isoform specific inhibitor idelalisib which was the first to gain approval for use in R/R FL based on promising phase II data [17]. Several additional PI3K inhibitors subsequently were shown to have significant activity across various B-NHLs. However, associated toxicities including opportunistic infections and severe autoimmune complications ultimately emerged and, in the setting of a growing array of alternative treatment options, inhibitors of PI3Ks have, as of November 2023, all been withdrawn from the B-NHL market.

3. Expert opinion

3.1. Imagining future use of PKIs in B-NHL

The future of PKIs in B-NHL is bright both in near and intermediate term horizons. The established standard treatment for fit and younger patients with MCL is multiagent chemoimmunotherapy followed by consolidation of remission with high dose therapy and autologous stem cell transplantation and subsequent maintenance anti-CD20 antibody [18,19]. At the 2022 American Society of Hematology annual meeting, Dreyling et al. presented the TRIANGLE study and showed, albeit preliminarily, that ibrutinib added to chemoimmunotherapy upfront followed by ibrutinib maintenance obviates the indication for autologous transplant consolidation in younger patients with MCL. While the publication of data in final form is awaited, the NCCN has endorsed the TRIANGLE regimen as a preferred strategy, opening the door to frontline application of BTKIs in MCL. Since ibrutinib is not approved by the FDA for use in MCL, either alternative covalent BTKI acalabrutinib or zanubrutinib could be considered.

BTKI infiltration of frontline therapy by may yet come to fruition in DLBCL, as well. Post-hoc correlative analyses of the PHOENIX study revealed patients ≤60 with one of two molecular subtypes defined by gene expression profiling, denoted MCD and N1, experienced greatly increased 3-year survival rate (100% versus 40–50%) with the addition of ibrutinib [20]. Along these lines, ESCALADE is an important ongoing phase 3 study of R-CHOP with or without acalabrutinib in younger (≤65 years) patients with untreated non-GCB type DLBCL; it has been enrolling patients since 2020 and results are eagerly awaited. Though gene expression assays are not currently routine in the workup of DLBCL, these data highlight the important biological heterogeneity of B-NHL, with each layer of biomarker-driven data contributing to refining the benefit to risk ratio and optimizing application of PKIs.

In R/R FL, how the recent accelerated approval granted by the FDA for zanubrutinib plus obinutuzumab impacts the landscape of this disease remains to be seen. The combination joins an increasingly crowded space that features bispecific antibodies, CAR-T cell therapy, and other small molecule inhibitors such as tazemetostat. Whether the superior results observed in ROSEWOOD compared to ibrutinib monotherapy in the DAWN study reflect a BTKI synergy with obinutuzumab, differences in patient selection, better efficacy of zanubrutinib, or some combination, is currently unknown. Confirmatory studies are underway, including the randomized phase III MAHOGANY trial that compares zanubrutinib and obinutuzumab to lenalidomide and obinutuzuab in R/R FL.

Lastly, resurrection of PI3K as a B-NHL target remains an active area of investigation. As these agents clearly have activity in B-NHL, the challenge has developed to deliver them with acceptable safety. Various strategies such as intermittent dosing, dynamic dose modification, and selective inhibition targeting mutated PI3K over wildtype, are actively being studied [21]. A model for such optimization may be taking place, somewhat ironically, in the application of BTKI for CLL/SLL. Since 2nd generation BTKIs supplanted ibrutinib as a favored frontline treatment in CLL/SLL based on superior tolerability, ibrutinib is now being reevaluated but in more nuanced methods than the basic full-dose, indefinite-administration schedule. Pre-emptive stepwise dose reduction of ibrutinib and also a fixed-term addition of the BCL2 inhibitor venetoclax before stopping both agents are two such methods currently under investigation in CLL/SLL. In the current landscape, PKIs have an important though somewhat peripheral role in B-NHL. Interest in evolving B-NHL therapies toward lower intensity, more sophisticated application of biomarkers, and more rationally designed dosing schedules promises an expanding footprint for BTKI in B-NHL pharmacotherapeutics.

Declaration of interests

S A Graf has received research support from BeiGene, Acerta Pharma, Janssen, Lilly/Loxo Oncology, and Genentech. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.