Lenalidomide (IMiD® Agent)

Proposed Mechanism of Action

Lenalidomide is an oral, small-molecule immunomodulatory agent that directly induces tumor-cell killing and enhances immune function in preclinical studies.1,2

Lymphoma

Lenalidomide targets cereblon, a component of the E3 ubiquitin ligase complex, leading to direct tumoricidal and immunomodulatory effects.3-6 Preclinical studies have demonstrated increased activity of lenalidomide in combination with rituximab, an anti-CD20 monoclonal antibody that has been leveraged in the treatment of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia.7-12 Combinations of lenalidomide and rituximab are being investigated for the treatment of NHL subtypes, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma.13-15

Myelodysplastic Syndromes

Haploinsufficiency, caused when only 1 copy of a gene is present, is hypothesized to drive pathogenesis of del(5q) myelodysplastic syndromes (MDS)16-18 and may underlie the specific activity of lenalidomide.19 In myeloid cell lines, haploinsufficiency increases the sensitivity of del5q MDS cells to lenalidomide-mediated degradation of casein kinase 1A1 (CSNK1A1), a gene located in the deleted region of chromosome 5 in del(5q) MDS.20,21

Preclinical and correlative studies in MDS cells suggest that in non-del(5q) MDS, the effects of lenalidomide on cellular progenitors and the microenvironment work together to promote normal erythropoiesis through expansion of progenitor populations,1,22-24 reduction in proinflammatory cytokines,18 and reduction of marrow microvessel density.18

Multiple Myeloma

In preclinical studies, lenalidomide has demonstrated direct tumorcidal and immunomodulatory effects, which are mediated in both myeloma and iummune cells by targeting cereblon, a component of the E3 ubiquitin ligase complex.2-6 This interaction triggers proteasome degredation of transcription factors Ikaros and Aiolos, resulting in downregulation of myeloma survival signals, IRF4 and c-Myc, and upregulation of immunoregulatory molecule IL-2.4,6,25

Lenalidomide by Disease State

Lenalidomide in Lymphoma

  • Post Approval Research Lymphoma Mantle cell lymphoma: Relapsed/refractory (US)
  • Post Approval Research Lymphoma Mantle cell lymphoma: Relapsed/refractory (EU)
  • Phase 3 Lymphoma Diffuse large B-cell (ABC-subtype): First-line
  • Phase 3 Lymphoma Indolent lymphoma: Relapsed/refractory
  • Phase 3 Lymphoma Follicular lymphoma: First-line
  • Post Approval Research Lymphoma Adult T-cell leukemia-lymphoma (Japan)

Rationale for Clinical Development

Follicular Lymphoma

Lenalidomide exerts direct effects on FL tumors and their microenvironment in vitro.5,9,26,27 In preclinical studies, these effects on FL, T, and natural killer (NK) cells contribute to immune synapse repair and alter expression of costimulatory molecules.9,26 Immunomodulatory effects in vitro include enhanced T-cell proliferation and function and NK-cell function, including NK-cell–mediated antibody-dependent cellular cytotoxicity (ADCC) in conjunction with rituximab.5,10,27

Proposed Mechanism of Action of Lenalidomide Plus Rituximab (R2) in Follicular Lymphoma

R2 has demonstrated increased activity in preclinical studies of follicular lymphoma.

Diffuse Large B-Cell Lymphoma

Lenalidomide has direct effects in vitro on both DLBCL cells and the tumor microenvironment.5,10,27-30 In preclinical studies, direct effects using non–germinal center B cell-like (GCB) tumor cells are mediated by binding to the cereblon-containing E3 ubiquitin ligase and include inhibition of interferon regulatory factor 4 expression and nuclear factor κB activity, increased interferon-β production, inhibition of proliferation, and induction of apoptosis.28-30

Mantle Cell Lymphoma

In preclinical studies, lenalidomide increases mitochondrial release of cytochrome c and activates caspases, resulting in direct MCL tumor cell killing.11,31 In lymphoma cells, the combination of lenalidomide and rituximab increases both direct anti-tumor killing activities of lenalidomide and NK-cell–mediated killing observed with rituximab.10,11 Lenalidomide also increases rituximab-mediated activation of caspases 3, 8, and 911 and increases NK-cell killing capacity through ADCC in these cells.10

Lenalidomide in Multiple Myeloma

  • Post Approval Research Multiple Myeloma Relapsed/refractory
  • Post Approval Research Multiple Myeloma Newly diagnosed
  • Post Approval Research Multiple Myeloma Maintenance

Rationale for Clinical Development

Lenalidomide has shown direct anti-myeloma activity and direct stimulation of immune function in preclinical studies.2,32 Additional preclinical studies demonstrated increased anti-myeloma activity of lenalidomide in combination with dexamethasone and certain proteasome inhibitors and monoclonal antibodies.33-36 Celgene is currently investigating lenalidomide as a foundation for combination with other agents in multiple myeloma.

The safety and efficacy of the agents and/or uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated.

References

  1. Komrokji RS, List AF. Semin Oncol. 2011;38:648-657.
  2. Borello I. Leuk Res. 2012;36:S3-S12.
  3. Revlimid (lenalidomide) capsules, for oral use [package insert]. Summit, NJ: Celgene Corporation; 2017.
  4. Lu G, et al. Science. 2014;343:305-309.
  5. Lopez-Girona A, et al. Leukemia. 2012;26:2326-2335.
  6. Bjorklund CC, et al. Blood Cancer J. 2015;5:e354.
  7. Lagrue K, et al. Blood. 2015;126:50-60.
  8. Gribben JG, et al. J Clin Oncol. 2015;33:2803-2811.
  9. Ramsay AG, et al. Blood. 2009;114:4713-4720.
  10. Reddy N, et al. Br J Haematol. 2008;140:36-46.
  11. Zhang L, et al. Am J Hematol. 2009;84:553-559.
  12. Rituxan (rituximab) [package insert]. South San Francisco, CA: Genentech, Inc; 2016.
  13. ClinicalTrials.gov. https://clinicaltrials.gov/show/NCT01996865.
  14. ClinicalTrials.gov. https://clinicaltrials.gov/show/NCT01938001.
  15. ClinicalTrials.gov. https://clinicaltrials.gov/show/NCT02285062.
  16. Boultwood J, et al. Blood. 2002;99:4638-4641.
  17. Horrigan SK, et al. Blood. 1996;88:2665-2670.
  18. Ebert BL, et al. Nature. 2008;451:335-339.
  19. Wei S, et al. Proc Natl Acad Sci U S A. 2009;106:12974-12979.
  20. Hollenbach P, et al. Blood. 2014;124 [abstract 3606].
  21. Fink EC, et al. Blood. 2014;124 [abstract 4].
  22. List AF, et al. Cancer Control. 2006;13(suppl):4-11.
  23. Verhelle D, et al. Cancer Res. 2007;67:746-755.
  24. Mouthouh-de Parseval LA, et al. J Clin Invest. 2008;118:248-258.
  25. Krönke J, et al. Science. 2014;343:301-305.
  26. Rawal S, et al. Blood. 2012;120 [poster 2766].
  27. Haslett PAJ, et al. J Infect Dis. 2003;187:946-955.
  28. Zhang LH, et al. Br J Haematol. 2013;160:487-502.
  29. Yang Y, et al. Cancer Cell. 2012;21:727-737.
  30. Shaffer AL, et al. Clin Cancer Res. 2009;15:2954-2961.
  31. Qian Z, et al. Leuk Res. 2011;35:380-386.
  32. Borello I. Leuk Res. 2012;36:S3-S12.
  33. Gandhi AK, et al. Br J Haematol. 2014;164:811-821.
  34. Gandhi AK, et al. Curr Cancer Drug Targets. 2010;10:155-167.
  35. Celgene. Data on file (Report 8769-001).
  36. Chauhan D, et al. Blood. 2010:1164906-4915.
  37. Das DS, et al. Br J Haematol. 2015;171:798-812.