CD20-Targeting Antibodies Are Shaping a New Landscape for B-Cell Cancers

OncologyLive, Vol. 22/No. 11, Volume 22, Issue 11

Among the pioneering targets for antibody therapy was CD20, the pursuit of which ultimately led to the first FDA-approved mAb for cancer therapy, rituximab, and defined a new era in the management of B-cell malignancies.

The idea of using antibodies to selectively target tumors originated over a century ago but gained traction in the 1970s with the introduction of hybridoma technology, which enabled production of monoclonal antibodies (mAbs).1 Among the pioneering targets for antibody therapy was CD20, the pursuit of which ultimately led to the first FDA-approved mAb for cancer therapy, rituximab (Rituxan), and defined a new era in the management of B-cell malignancies.2

Several CD20-targeting mAbs are now available for the treatment of both indolent and aggressive forms of B-cell non-Hodgkin lymphoma (NHL) in the front line, at relapse, and as maintenance therapy.3-7 In recent years, the clinical utility of these agents has expanded with rational combinations of CD20 mAbs plus targeted therapies (Table 13-11). The combinations pair CD20 mAbs with the Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica), the BCL2 inhibitor venetoclax (Venclexta), the PI3Kδ inhibitor idelalisib (Zydelig), or the immunomodulatory drug lenalidomide (Revlimid).8-11

Table 1. FDA-Approved Antibodies and Combinations Targeting CD203-11

The focus on combinations is continuing. TG Therapeutics is developing a novel CD20 mAb, ublituximab, which has shown promise in combination with its newly approved PI3Kδ inhibitor, umbralisib (Ukoniq), in the treatment of patients with chronic lymphocytic leukemia (CLL). The FDA is reviewing an application for this combination, dubbed U2, to which the agency previously granted a fast track designation.12,13

Meanwhile, a growing number of bispecific antibodies targeting CD20 and CD3, a second antigen expressed on T cells, are among the novel agents in development (Table 2). In a race to the finish line, Roche, Genentech, and Genmab/AbbVie have all initiated phase 3 clinical trials of their CD20 x CD3 bispecifics. At the same time, these companies and others with similar drugs in the works are having to reckon with the potential risk of toxicities that accompany the use of T-cell-engaging drugs.14

Table 2. Select Clinical Trials of Novel CD20-Directed Therapies

The Rituximab Era

Since its initial approval in 1997, rituximab has revolutionized the treatment of B-cell malignancies, which strongly express its target antigen, CD20.2,15 As a single agent and in combination with chemotherapy or, more recently, with various targeted therapies, rituximab has prolonged progression-free survival (PFS) and, in some cases, overall survival in the frontline setting and beyond.2,15,16 To address challenges with intravenous administration, the FDA has also approved a subcutaneous form of rituximab, (Rituxan Hycela),15,17 and the expiration of the rituximab patent in 2018 saw the emergence of several biosimilars in the United States and Europe.7,18

Although rituximab is highly effective, a significant number of patients relapse on or are refractory to this treatment. Development of the next-generation CD20 mAbs ofatumumab (Arzerra) and obinutuzumab (Gazyva) focused on modulating the characteristics of these antibodies to capitalize on certain antibody effector functions in an effort to improve clinical efficacy and overcome resistance.15,17,19

Ofatumumab demonstrated enhanced antitumor activity in preclinical models, including rituximab-resistant cell lines, but this did not appear to translate into clinical superiority over rituximab.15,17 Obinutuzumab, meanwhile, did demonstrate superiority over rituximab in patients with CLL and follicular lymphoma (FL) when each drug was combined with chemotherapy. Although obinutuzumab was accompanied by an increase in toxicity, the agent is a frontline treatment option in combination with targeted therapy in CLL and with chemotherapy in FL.15,20,21

The FDA also has approved 2 CD20-targeted radioimmunotherapies for use against B-cell lymphoma: iodine 131 (131I)-tositumomab (Bexxar) and yttrium 90 (90Y)-ibritumomab tiuxetan (Zevalin). However, neither has been broadly adopted into clinical practice, and Bexxar was withdrawn from the market in 2013 for commercial reasons.22,23

The Next Generation

The latest CD20 mAb in development is ublituximab, which TG Therapeutics is currently testing in combination with its recently approved PI3Kδ inhibitor umbralisib in 2 phase 3 trials. Results from the UNITYCLL trial (NCT02612311) were presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, held in December 2020.12

The U2 combination significantly prolonged PFS compared with standard-of-care chemoimmunotherapy (obinutuzumab plus chlorambucil) in patients with both treatment-naïve and relapsed/refractory CLL.12 TG Therapeutics has completed a rolling submission of a biologics license application for this combination in CLL.13

A number of ongoing clinical trials are evaluating the U2 combination, including as part of a triplet regimen with venetoclax in patients with relapsed/refractory CLL. Data from a phase 1/2 trial (NCT03379051) presented at ASH 2020 showed the triplet to be well tolerated and highly effective in this population, with an overall response rate (ORR) of 100% among the 19 patients who completed 12 cycles of therapy, and 42% of patients achieving complete remission.24 The ongoing ULTRA-V trial (NCT03801525) is studying this triplet in patients with treatment-naïve and relapsed/refractory CLL.

Ublituximab also showed significant promise in combination with ibrutinib in the phase 3 GENUINE trial (NCT02301156), the results of which have been recently published. Among 126 patients with relapsed/refractory CLL randomized to receive ublituximab plus ibrutinib (n = 64) or ibrutinib alone (n = 62), the ORR was 83% and 65%, respectively (P = .02).25

Two Targets May Be Better Than One

A major focus of ongoing clinical oncology research is bispecific antibodies, which simultaneously target 2 antigens—1 on malignant cells and 1 on T cells—in an effort to redirect the cytotoxic effects of T cells against the tumor. Although only 1 bispecific antibody, blinatumomab (Blincyto), is currently approved for cancer treatment by the FDA, hundreds of clinical trials are ongoing worldwide and analysts predict the global market will reach $12 billion by 2026.26

Among those agents in clinical trials are several targeting CD20 and a component of the T-cell receptor, CD3. Notably, these bispecifics differ from blinatumomab, a single-chain variable fragment–based agent that targets CD19 rather than CD20. The CD20 x CD3 bispecifics in development are composed of full-length antibodies in an attempt to improve pharmacokinetics and avoid the continuous intravenous infusion necessary with blinatumomab.14

The most advanced of the CD20 x CD3 bispecifics in development include mosunetuzumab (RG7828). A series of presentations at ASH 2020 highlighted the safety and efficacy of this drug in phase 1/2 clinical trials. In the ongoing GO40515 trial (NCT03677141), mosunetuzumab in combination with cyclophosphamide, hydroxydaunorubicin, vincristine (Oncovin), and prednisolone (CHOP) chemotherapy elicited ORRs of 86% in patients with relapsed/refractory NHL and 96% in patients with treatment-naïve diffuse large B-cell lymphoma (DLBCL). Investigators observed complete responses (CRs) in 71% and 85% of patients, respectively.27

Mosunetuzumab also showed promising efficacy as a frontline chemotherapy-free option for patients with DLBCL who are elderly or unfit for chemoimmunotherapy. The 19 patients in cohort B of the ongoing GO40554 trial (NCT03677154), who received intravenous mosunetuzumab monotherapy, had an ORR of 58% and a CR rate of 42%.28

In the GO29781 trial (NCT02500407), mosunetuzumab is being tested in patients with relapsed/refractory B-cell lymphomas. Among patients with FL who had received at least 2 prior systemic therapies, the ORR was 68%, with 50% of patients achieving CRs. On the basis of these results and its manageable safety profile, mosunetuzumab received a breakthrough therapy designation for this indication.29,30

Initial phase 1/2 (NCT03625037) data for epcoritamab (GEN3013), which was created using Genmab’s DuoBody technology and is being jointly developed with AbbVie, were presented at ASH 2020. Among heavily pretreated patients with B-cell NHL enrolled in the dose-escalation phase of the trial, the ORR was 66.7% for patients with DLBCL (n = 18) who received doses of 12 mg or above and 100% for the 8 patients with FL who received doses of 0.76 mg or above. Two patients with blastoid variant mantle cell lymphoma also had responses. All patients with DLBCL previously treated with chimeric antigen receptor (CAR) T-cell therapy (n = 4) achieved a response.31

Meanwhile, Roche is developing glofit-amab (CD20-TCB), a CD20 x CD3 bispecific antibody with several distinctive design features, including a 2:1 format (2 CD20-binding arms to 1 CD3-binding arm). In preclinical studies, the agent demonstrated greater potency compared with bispecifics with a 1:1 format.32

In an ongoing phase 1 clinical trial (NCT03075696) of glofitamab in patients with relapsed/refractory B-cell NHL, the ORR was 53.8% across all doses tested (0.005-30 mg), with a CR rate of 36.8%. The ORR was 65.7%, including 57.1% CRs, among patients treated with the recommended phase 2 step-up dosing schedule (2.5 mg on cycle 1 day 1; 10 mg on cycle 1 day 8; and 30 mg on cycle 2 day 1).33

Managing Toxicity

Because these bispecific antibodies engage cytotoxic T cells, a major concern is the development of T-cell–mediated toxicities, particularly cytokine release syndrome (CRS), which can be fatal. Investigators are evaluating a number of strategies to manage CRS and other toxicities, including step-up dosing, obinutuzumab pretreatment (designed to deplete peripheral and tissue-based B cells and minimize the potential for systemic activation of effector cells outside the tumor), and antibody designs that reduce the risk of T-cell overactivation.14,32

Odronextamab (REGN1979) is a first-in-class, hinge-stabilized, IgG4-based CD20 x CD3 bispecific antibody designed to have reduced effector function.34 In spite of these modifications, there have been issues with CRS in clinical trials of odronextamab, prompting the FDA to place a partial clinical hold on several ongoing studies (NCT02290951 and NCT03888105).35 In May, Regeneron Pharmaceuticals said the FDA lifted the holds after trial protocols were amended to further reduce the risk of grade 3 and higher CRS during step-up dosing and that enrollment will resume.36

In data from 1 of these studies (NCT02290951), odronextamab demonstrated promising efficacy in patients with relapsed/refractory NHL (N = 127), includ-ing those previously treated with CAR T-cell therapy. Grade 3 CRS was observed in 8 patients and grade 4 CRS in 1 patient, with most events occurring during the first 2 weeks of step-up dosing.37

Jane de Lartigue, PhD, is a freelance medical writer and editor based in Gainesville, Florida.

References

  1. Weiner LM, Surana R, Wang S. Monoclonal antibodies: versatile platforms for cancer immunotherapy. Nat Rev Immunol. 2010;10(5):317-327. doi:10.1038/nri2744
  2. Marshall MJE, Stopforth RJ, Cragg MS. Therapeutic antibodies: what have we learnt from targeting CD20 and where are we going? Front Immunol. 2017;8:1245. doi:10.3389/fimmu.2017.01245
  3. Rituxan. Prescribing information. Genentech, Inc; 2020. Accessed April 12, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/103705s5460lbl.pdf 
  4. Arzerra. Prescribing information. Novartis Pharmaceuticals Corporation; 2016. Accessed April 12, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125326s063lbl.pdf 
  5. Gazyva. Prescribing information. Genentech, Inc; 2020. Accessed April 12, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125486s025lbl.pdf 
  6. Zevalin. Prescribing information. Spectrum Pharmaceuticals, Inc; 2018. Accessed May 14, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125019s227lbl.pdf
  7. Biosimilar product information. FDA. Updated December 17, 2020. Accessed May 14, 2021. https://www.fda.gov/drugs/biosimilars/biosimilar-product-information
  8. Imbruvica. Prescribing information. Pharmacyclics LLC; 2020. Accessed April 12, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/205552s033,210563s010lbl.pdf 
  9. Zydelig. Prescribing information. Gilead Sciences, Inc; 2020. Accessed April 12, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/205858s014lbl.pdf 
  10. Venclexta. Prescribing information. AbbVie Inc; 2020. Accessed April 12, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208573s023lbl.pdf 
  11. Revlimid. Prescribing information. Celgene Corporation; 2019. Accessed April 12, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021880s060lbl.pdf 
  12. Gribben JG, Jurczak W, Jacobs RW, et al. Umbralisib plus ublituximab (U2) is superior to obinutuzumab plus chlorambucil (O+Chl) in patients with treatment naïve (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): results from the phase 3 Unity-CLL study. Blood. 2020;136(suppl 1):37-39. doi:10.1182/blood-2020-134783
  13. TG Therapeutics completes rolling submission of biologics license application to the U.S. Food and Drug Administration for ublituximab in combination with Ukoniq (umbralisib) as a treatment for patients with chronic lymphocytic leukemia. News release. TG Therapeutics, Inc. March 29, 2021. Accessed April 5, 2021. https://ir.tgtherapeutics.com/news-releases/news-release-details/tg-therapeutics-completes-rolling-submission-biologics-license 
  14. Zhu Y, Shen R, Hao R, Wang S, Ho M. Highlights of antibody engineering and therapeutics 2019 in San Diego, USA: bispecific antibody design and clinical applications. Antib Ther. 2020;3(2):146-154. doi:10.1093/abt/tbaa012
  15. Freeman CL, Sehn L. Anti-CD20 directed therapy of B cell lymphomas: are new agents really better? Curr Oncol Rep. 2018;20(12):103. doi:10.1007/s11912-018-0748-0
  16. Casan JML, Wong J, Northcott MJ, Opat S. Anti-CD20 monoclonal antibodies: reviewing a revolution. Hum Vaccin Immunother. 2018;14(12):2820-2841. doi:10.1080/21645515.2018.1508624
  17. Klein C, Jamois C, Nielsen T. Anti-CD20 treatment for B-cell malignancies: current status and future directions. Expert Opin Biol Ther. 2021;21(2):161-181. doi:10.1080/14712598.2020.1822318
  18. Nava-Parada P, Shelbaya A, Nabhan C. Rituximab biosimilars in hematologic malignancies: the need for a real-world approach. Future Oncol. 2020;16(26):2017-2027. doi:10.2217/fon-2020-0131
  19. Pavlasova G, Mraz M. The regulation and function of CD20: an “enigma” of B-cell biology and targeted therapy. Haematologica. 2020;105(6):1494-1506. doi:10.3324/haematol.2019.243543
  20. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 4.2021. Accessed May 14, 2021. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf
  21. NCCN. Clinical Practice Guidelines in Oncology. B-cell lymphomas, version 4.2021. Accessed May 14, 2021. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf
  22. Mondello P, Cuzzocrea S, Navarra M, Mian M. 90 Y-ibritumomab tiuxetan: a nearly forgotten opportunity. Oncotarget. 2016;7(7):7597-7609. doi:10.18632/oncotarget.6531
  23. Rizzieri D. Zevalin (ibritumomab tiuxetan): after more than a decade of treatment experience, what have we learned? Crit Rev Oncol Hematol. 2016;105:5-17. doi:10.1016/j.critrevonc.2016.07.008
  24. Barr P, Ma S, Zent CS, et al. A phase 1/2 study of umbralisib, ublituximab, and venetoclax (U2-Ven) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Blood. 2020;136(suppl 1):41-42. https://doi.org/10.1182/blood-2020-134818
  25. Sharman JP, Brander DM, Mato AR, et al. Ublituximab plus ibrutinib versus ibrutinib alone for patients with relapsed or refractory high-risk chronic lymphocytic leukaemia (GENUINE): a phase 3, multicentre, open-label, randomised trial. Lancet Haematol. 2021;8(4):e254-e266. doi:10.1016/S2352-3026(20)30433-6
  26. Global bispecific antibody therapeutics drug market sales size worth US$ 12 billion by 2026. News release. KuicK Research. September 23, 2020. Accessed April 6, 2021. https://www.globenewswire.com/news-release/2020/09/23/2097811/0/en/Global-Bispecific-Antibody-Therapeutics-Drug-Market-Sales-Size-Worth-US-12-Billion-By-2026.html 
  27. Phillips TJ, Olszewski AJ, Munoz J, et al. Mosunetuzumab, a novel CD20/CD3 bispecific antibody, in combination with CHOP confers high response rates in patients with diffuse large B-cell lymphoma. Blood. 2020;136(suppl 1):37-38. doi:10.1182/blood-2020-136295
  28. Olszewski AJ, Avigdor A, Babu S, et al. Single-agent mosunetuzumab is a promising safe and efficacious chemotherapy-free regimen for elderly/unfit patients with previously untreated diffuse large B‑cell lymphoma. Blood. 2020;136(suppl 1):43-45. doi:10.1182/blood-2020-136255
  29. Assouline SE, Kim WS, Sehn LH, et al. Mosunetuzumab shows promising efficacy in patients with multiply relapsed follicular lymphoma: updated clinical experience from a phase I dose-escalation trial. Blood. 2020;136(suppl 1):42-44. doi:10.1182/blood-2020-135839
  30. FDA grants breakthrough therapy designation for Roche’s CD20xCD3 bispecific cancer immunotherapy mosunetuzumab recognising its potential in follicular lymphoma. News release. Roche. July 14, 2020. Accessed April 6, 2021. https://www.roche.com/investors/updates/inv-update-2020-07-14b.htm 
  31. Hutchings M, Mous R, Clausen MR, et al. Subcutaneous epcoritamab induces complete responses with an encouraging safety profile across relapsed/refractory B-cell non-Hodgkin lymphoma subtypes, including patients with prior CAR-T therapy: updated dose escalation data. Blood. 2020;136(suppl 1):45-46. doi:10.1182/blood-2020-133820
  32. Bacac M, Colombetti S, Herter S, et al. CD20-TCB with obinutuzumab pretreatment as next-generation treatment of hematologic malignancies. Clin Cancer Res. 2018;24(19):4785-4797. doi:10.1158/1078-0432.CCR-18-0455
  33. Hutchings M, Morschhauser F, Iacoboni G, et al. Glofitamab, a novel, bivalent CD20-targeting T-cell–engaging bispecific antibody, induces durable complete remissions in relapsed or refractory B-cell lymphoma: a phase I trial. J Clin Oncol. Published online March 19, 2021. doi:10.1200/JCO.20.03175
  34. Development of novel fully human bispecific antibodies for oncology. Regeneron. April 10, 2019. Accessed April 6, 2021. https://investor.regeneron.com/static-files/2bdbbbac-f2bb-4c1f-b3be-55fac15eafca 
  35. Regeneron provides update on odronextamab clinical trials in B-cell non-Hodgkin lymphomas. News release. Regeneron. December 14, 2020. Accessed April 7, 2021. https://investor.regeneron.com/static-files/690eeaf2-643e-44eb-9c3f-baad97eb9703 
  36. Regeneron resumes enrollment of FL and DLBCL patients in odronextamab trials. News release. Regeneron. May 17, 2021. Accessed May 27, 2021. https://investor.regeneron.com/static-files/f926fedf-8c6c-4f6f-a110-f295978c0c7f
  37. Bannerji R, Allan JN, Arnason JE, et al. Odronextamab (REGN1979), a human CD20 x CD3 bispecific antibody, induces durable, complete responses in patients with highly refractory B-cell non-Hodgkin lymphoma, including patients refractory to CAR T therapy. Blood. 2020;136(suppl 1):42-43. doi:10.1182/blood-2020-136659