Shift to targeted therapies continues in relapsed/refractory indolent non-Hodgkin lymphoma
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The treatment landscape for relapsed or refractory indolent non-Hodgkin lymphoma continues to shift from chemoimmunotherapy to targeted treatments, according to a speaker at Chemotherapy Foundation Symposium.
Treatment sequencing and rational combinations remain key research areas, Lori Leslie, MD, of the lymphoma division at John Theurer Cancer Center and associate professor of medicine at Hackensack Meridian School of Medicine, said during a presentation.
Leslie described developments in follicular and marginal zone lymphoma treatment, as well as new approaches on the horizon.
Kinase inhibitors
PI3 kinase inhibitors, plagued by toxicity concerns and a lack of confirmatory data, have been removed from the treatment landscape for these subtypes, although copanlisib (Aliqopa, Bayer), administered via IV, remains available for relapsed or refractory follicular lymphoma, she said.
The immunomodulatory agent lenalidomide (Revlimid, Bristol Myers Squibb) continues to play a key role in treatment of B-cell NHL and serves as a base for combinations with newer agents in ongoing clinical trials, Leslie said. The R-squared regimen of lenalidomide and rituximab (Rituxan; Genentech, Biogen), received FDA approval in 2019 for relapsed follicular and marginal zone lymphoma.
“Since this has been formally approved, the average patient who is treated initially with chemoimmunotherapy is being strongly considered for lenalidomide-based therapy in the second-line setting, at least in my practice of follicular lymphoma,” Leslie said.
Two covalent Bruton tyrosine kinase inhibitors, ibrutinib (Imbruvica; Pharmacyclics, Janssen) and zanubrutinib (Brukinsa, BeiGene), have received FDA approval for relapsed or refractory marginal lymphoma, but none have been approved or deemed effective in follicular lymphoma.
“BTK inhibitors, including ibrutinib, are still being investigated in follicular lymphoma, mostly as part of combination therapy,” Leslie said.
Chromatin modulation and epigenetic drugs have shown activity in follicular lymphoma, Leslie noted. About 20% of patients with follicular lymphoma have activating mutations in EZH2. Tazemetostat (Tazverik, Epizyme), an EZH2 inhibitor, has been FDA approved for patients with relapsed or refractory follicular lymphoma who have EZH2-mutated disease and received two or more previous lines of therapy or no appropriate alternative treatment options.
“Considering the favorable toxicity profile, it’s an appealing medication, as well as non-cross-reactive mechanism of action to combine with other drugs,” she said.
CAR-T, bispecific antibodies
New to the landscape of FDA-approved treatments is tisagenlecleucel (Kymriah, Novartis), which in May became the second CD19-directed chimeric antigen receptor T-cell therapy to receive accelerated approval for relapsed and refractory follicular lymphoma. The first, axicabtagene ciloleucel (Yescarta; Kite Pharma, Gilead), also has been endorsed by National Comprehensive Cancer Network for patients with relapsed or refractory marginal zone lymphoma following two lines of therapy.
Toxicities associated with CAR T-cell therapy include cytokine release syndrome and neurotoxicity/immune effector cell-associated neurotoxicity syndrome, each of which can be managed.
“We have been intervening in earlier points of toxicity so that in general, in our practices, CAR-T is better tolerated than was initially demonstrated in some of the first clinical trials,” Leslie said.
The manageable toxicity profile of tisagenlecleucel allowed for outpatient infusion, which could increase access to the treatment, she noted.
T-cell engagers will be coming soon to follicular lymphoma, Leslie said. These include mosunetuzumab (Genentech), a bispecific CD20/CD3 antibody that received FDA priority review in July for adults with relapsed or refractory follicular lymphoma who received at least two prior systemic therapies.
Although bispecific antibodies have demonstrated durable responses and activity in heavily treated disease, including after CAR-T, questions remain with regard to length of therapy, resistance mechanisms, and how they can be combined with other therapies and moved into earlier lines of therapy.
“There are a lot of ongoing combinations across these T-cell engagers in patients with follicular lymphoma, including in combination with R-squared and obinutuzumab [Gazyva, Genentech],” she said.
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Leslie L. Updates in treatment options for relapsed/refractory indolent non-Hodgkin lymphoma. Presented at: 40th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow; Nov. 9-11, 2022.
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