Exploring Novel Combinations in Indolent Lymphomas

Cancer cells, 3D illustration © Dr_Microbe - stock.adobe.com

The treatment of patients with indolent non-Hodgkin lymphoma (iNHL), including follicular lymphoma (FL) and marginal zone lymphoma (MZL), has significantly evolved over the past decade. Although chemotherapy has represented the standard therapeutic modality for these conditions, monoclonal antibodies, immunomodulatory agents, targeted agents, bispecific antibodies, and cellular therapies also are now available. As treatment options increase, novel combinations appear on the horizon for the management of iNHL, with a potential for toxicity mitigation and improved outcomes. These novel combinations were discussed in the presentation, “Novel Combinations in Indolent Lymphoma during the 11th Annual Meeting of the Society of Hematologic Oncology (SOHO 2023).”

The combination of lenalidomide (Revlimid®; Bristol Myers Squibb) and rituximab (Rituxan; Genentech), also referred to as R2, represents a standard treatment option for patients with relapsed FL, based on results of the randomized phase 3 trial AUGMENT trial (NCT01938001). However, despite improved progression-free survival (PFS, 39 months), as compared with single-agent rituximab (PFS, 14 months), only 30% of patients achieve a complete response (CR).¹ The use of R2 remains limited in the frontline setting, due to lack of superiority to chemoimmunotherapy, as seen in results of the randomized phase 3 trial RELEVANCE trial (NCT01650701), with a comparable CR rate of 50%.² Multiple attempts are being evaluated at improving the efficacy of R2 through its combination with novel agents targeting biologically relevant pathways.

Because of the significant role played by T cells in FL, the combination of R2 with CD3/CD20 bispecific antibodies has been investigated both in the frontline and relapsed settings. The safety and efficacy of epcoritamab-bysp (Epkinly; Genmab) a subcutaneous CD3/CD20 bispecific antibody, has been explored in combination with R2 in 66 patients with relapsed FL and 36 with previously untreated FL (grades 1 to 3A) in a phase 1/2 trial (EPCORE NHL-2; NCT04663347).³ No synergistic toxicity was observed. However, CR rates were 80% or higher, independent from the line of therapy.³ Similar data have been observed in a phase 1b study investigating the combination of mosunetuzumab-axgb (Lunsumio; Genentech), an intravenous CD3/CD30 bispecific antibody approved for the treatment of relapsed FL, with lenalidomide.⁴ This led to the ongoing randomized phase 3 CELESTIMO study (NCT04712097) comparing this combination with R2 in patients with relapsed FL, and a phase 2 study exploring this combination in the frontline setting.

As protumoral macrophages can favor FL growth and resistance to lenalidomide, the combination of R2 with agents able to interrupt the cross-talk between FL cells and macrophages is of significant interest. These include specific Bruton tyrosine kinase (BTK) inhibitors such as acalabrutinib (Calquence; AstraZeneca). The combination of the latter with R2 has been investigated in a phase 1/2 study (NCT02180711) of 29 patients with FL. Although no synergistic toxicity was observed, CR rate remained unchanged as compared with historical data with R2 at 30%.⁵ However, when used in the frontline setting and with a predose of single-agent acalabrutinib in a phase 2 study (NCT04404088) of 24 patients with FL, a CR rate higher than 90% has been reported.⁶ Of interest, the combination of a more potent BTK inhibitor, zanubrutinib (Brukinsa; BeiGene), with obinutuzumab (Gazyva; Genentech), an anti-CD20 monoclonal antibody able to better mediate antibody-dependent cellular phagocytosis than rituximab, has shown an increased CR rate, from 19% to 37%, as compared with single-agent obinutuzumab in the phase 2 ROSEWOOD trial (NCT03332017) of 217 patients with relapsed FL.⁷ These data have led to an ongoing randomized phase 3 trial (MAHOGANY, NCT05100862) comparing this combination with R2 in the relapsed setting. This adds to the long streak of success of obinutuzumab in FL, which includes a longer PFS in combination with frontline chemotherapy, as compared with rituximab combined with chemotherapy, in the randomized phase 3 trial GALLIUM trial (NCT01332968)⁸ and the high CR rates observed with its combination with lenalidomide in the phase II GALEN study (NCT01582776 ).^9,10 GALEN included relapsed patients (38%),87 and GALLIUMthose who were previously untreated (80%).¹⁰

Because of the role played by epigenetic changes in the pathophysiology of iNHL, the combination of R2 with tazemetostat (Tazverik; Epizyme), an EZH2 inhibitor approved for the treatment of relapsed FL, has also been investigated. In a phase 1b study (NCT04224493) of 44 patients with relapsed FL, a CR rate of 46% was reported in patients with wild type EZH2; 71% of those with the mutated gene11 had no increase in toxicity.¹¹ This has led to an ongoing randomized phase 3 trial (SYMPHONY-1, NCT04224493), comparing this combination with R2 in patients with relapsed iNHL.

Finally, concurrent targeting of multiple lymphomatous antigens is being considered as a combination strategy for iNHL. The safety and efficacy of adding polatuzumab vedotin (Polivy; Genentech), an antibody-drug conjugate targeting CD79b, to lenalidomide and obinutuzumab have been investigated in a phase 1/2 study (NCT02600897) of 56 patients with relapsed refractory FL.¹² In this trial, although the prespecified threshold for activity was not reached, an impressive CR rate of 63% was reported.¹² The addition of tafasitamab (Monjuvi; Incyte), an anti-CD10 monoclonal antibody, to R2 is being explored in the randomized phase 3 trial inMIND (NCT04680052), based on promising activity observed with the use of single-agent tafasitamab in patients with relapsed iNHL,¹³ and results are eagerly awaited.

As promising chemotherapy-free treatment strategies are being developed for patients with iNHL, the therapeutic landscape for these patients soon may significantly change.

References

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6. Strati P, Feng L, Westin J, et al. A phase II investigator initiated study of acalabrutinib, lenalidomide and rituximab (aR2) in patients with previously untreated high tumor burden follicular lymphoma. Hematol Oncol. 2023;41(suppl 2):13-17.

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9. Morschhauser F, Le Gouill S, Feugier P, et al. Obinutuzumab combined with lenalidomide for relapsed or refractory follicular B-cell lymphoma (GALEN): a multicentre, single-arm, phase 2 study. Lancet Haematol. 2019;6(8):e429-e437. doi: doi:10.1016/S2352-3026(19)30089-4

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11. Batlevi CL, Salles G, Park SI, et al. Tazemetostat in combination with lenalidomide and rituximab in patients with relapsed/refractory follicular lymphoma: phase 1b results of Symphony-1. Blood. 2022;140(suppl 1):2296-2298. doi: 10.1182/blood-2022-166991

12. Diefenbach C, Kahl BS, McMillan A, et al. Polatuzumab vedotin plus obinutuzumab and lenalidomide in patients with relapsed or refractory follicular lymphoma: a cohort of a multicentre, single-arm, phase 1b/2 study. Lancet Haematol. 2021;8(12):e891-e901. doi:10.1016/S2352-3026(21)00311-2

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