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Antibody-based therapies add weight to immunotherapy concepts for R/R DLBCL

Oct 1, 2020
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At the European School of Haematology (ESH) conference, How to Diagnose and Treat Lymphoma, the Lymphoma Hub will hold a virtual Satellite Symposium (Sunday November 8, 2020, at 15:50–16:50 CET) providing expert opinions on how to treat patients with relapsed/refractory (R/R) lymphoma. The international experts, Marie José Kersten, Kieron Dunleavy, Francesc Bosch, Astrid Pavlovsky, and the Lymphoma Hub Chair, Gilles Salles, will give an overview of the existing and emerging treatment approaches for patients with R/R disease, and the efforts being made to improve patient outcome in this setting.

Chimeric antigen receptor (CAR) T-cell therapy is one of the most recent advances in the treatment of R/R lymphoma, demonstrating particularly good outcomes in patients with diffuse large B-cell lymphoma (DLBCL). Even so, a proportion of patients do not respond to CAR T-cell therapy, or eventually relapse, and the Lymphoma Hub previously published an outline on how to manage patients with DLBCL who relapse following CAR T-cell therapy. Additionally, CAR T-cell therapy may not be available due to patient- or region-specific factors, and so alternative therapies are needed.1

Patients with R/R DLBCL who relapse following third-line therapy have limited treatment options, but there have been some studies reporting promising results with antibody-based therapies. Here we provide an overview of emerging antibodies under investigation for the treatment of R/R DLBCL, summarized in Table 1, where CAR T-cell therapy has been unsuccessful or is not feasible.

Table 1. Antibody-based therapeutics under investigation for the treatment of R/R DLBCL1-3

ADC, antibody-drug conjugates; Benda, bendamustine; BiTE, bispecific T-cell engaging antibody; CR, complete response; CVP, cyclophosphamide + vincristine + prednisolone; DHAP, dexamethasone + high dose cytarabine + cisplatin; GDP, gemcitabine + dexamethasone + cisplatin; ICE, ifosfamide + carboplatin + etoposide phosphate; LEN, lenalidomide; mAb, monoclonal antibody; ORR, overall response rate; PD-1, programmed cell death receptor 1; R, rituximab

Class

Molecular target

Agent

Phase

ORR, %

CR, %

mAb

CD20

Obinutuzumab

II

20

Ofatumumab-DHAP

II

38

15

CD19

Tafasitamab (MOR208)

II

26

Tafasitamab + LEN

II

58

33

CD40

Dacetuzumab

II

9

Dacetuzumab/R-ICE

IIb

36

PD-1

Nivolumab

II

10

PD-L1

Durvalumab

I/II

18

8

ADC

CD30

Brentuximab vedotin

II

44

17

CD22

Inotuzumab ozogamicin + R

III

41

Inotuzumab ozogamicin + R-CVP /

Inotuzumab ozogamicin + R + R-GDP

I

57/33

CD79b

Polatuzumab vedotin

I

56

Polatuzumab vedotin + R-Benda

I/II

70

58

CD19

Coltuximab ravtansine + R

II

44/31

Denintuzumab mafodotin

I

33

22

Loncastuximab tesirine

I

40

22

BiTE

CD3/CD19

Blinatumomab

II

43

19

CD20/CD3

RG6026

I

33

Mosunetuzumab

I

37.1

19.4

Monoclonal antibodies

CD20

The anti-CD20 monoclonal antibody (mAb), rituximab (R), has revolutionized the treatment of B-cell malignancies and improved patient prognosis in the DLBCL setting. Despite an established efficacy and a well-defined safety profile, patients can develop resistance to treatment with R. In a pledge to overcome this, several mAbs have been designed to refine CD20-targeted therapy. Obinutuzumab was engineered with the aim of enhancing antibody-dependent cellular cytotoxicity, but the single-agent outcomes of patients with R/R DLBCL have been poor.1 At this year’s American Society of Clinical Oncology (ASCO) Annual Meeting, the primary safety and efficacy data from a phase II study evaluating obinutuzumab in combination with the anti-programmed death ligand 1 (PD-L1) mAb, atezolizumab, and venetoclax in patients with R/R DLBCL was presented. These initial results were encouraging, and the combination was particularly effective in patients with a low tumor burden; watch the video below for more information.

Atezolizumab + obinutuzumab + venetoclax in patients with R/R DLBCL

Another anti-CD20 mAb, ofatumumab, targets a different CD20 epitope to R. Nevertheless, when evaluated in a randomized phase II trial, there was no significant difference in clinical efficacy between patients treated with ofatumumab-dexamethasone + high dose cytarabine + cisplatin (DHAP) vs R-DHAP.

CD19

The major target of CAR T-cell therapy, CD19, provides an alternative antigen for mAbs. The anti-CD19 mAb, tafasitamab (MOR208), achieved limited single-agent efficacy in patients with R/R DLBCL.1 However, the combination of tafasitamab with lenalidomide demonstrated favorable efficacy and safety profiles in patients with R/R DLBCL, and the combination is now U.S. Food and Drug Administration (FDA)-approved as second-line treatment for adult patients with R/R DLBCL. The Lymphoma Hub also published a summary of the phase II L-MIND study, which led to the approval of tafasitamab plus lenalidomide.

Immune checkpoints

Targets of mAb-based therapies are not limited to those found on lymphoma cells. Malignant cells manipulate immune checkpoint pathways, including the programmed cell death receptor 1 (PD-1)/PD-L1 axis, resulting in suppressed T-cell-mediated tumor destruction.

Anti-PD-1 mAbs have been successful in treating a variety of malignancies such as Hodgkin lymphoma, but their effectiveness in the DLBCL setting is poorly defined. A phase II trial evaluated the PD-1 inhibitor, pidilizumab, in patients with R/R DLBCL who achieved a partial response or better following salvage therapy, prior to autologous stem cell transplantation (ASCT). The 16-month progression-free survival rate of patients treated with pidilizumab was 76% and the study met its primary endpoint. Outcomes with an alternative anti-PD-1 mAb, nivolumab, have been less encouraging.

PD-L1 upregulation and subsequent T-cell exhaustion have been observed in patients following treatment with CAR T-cell therapy. The phase I/II ALEXANDER trial investigated whether pre-conditioning with the anti-PD-1 mAb, pembrolizumab, prior to anti-CD19/CD22-directed CAR-T therapy, could alleviate T-cell exhaustion and increase long-term responses in patients with R/R DLBCL. Read the results of the study, as presented at the ASCO 2020 Virtual Annual Meeting, here.

Case study4

A case report recently published in Biology of Blood and Marrow Transplantation by Noa G. Holtzman and colleagues, outlined the successful treatment of a patient with R/R DLBCL with the anti-PD-1 mAb, pembrolizumab, following unsuccessful treatment with allogeneic CAR T-cell therapy. The 26-year-old male had received treatment with autologous CD19-targeted CAR-T with CTL019 (CD3ζ/4-1BB) and axicabtagene ciloleucel (CD3ζ/CD28). Following confirmed relapse in the cerebellum, the patient was treated with focal radiation and pembrolizumab (200 mg IV, every 3 weeks) and remains in complete metabolic response 3 months into treatment, with no treatment-related toxicities or graft-versus-host disease.

Durvalumab is an anti-PD-L1 mAb, which was evaluated both as monotherapy and in combination in the phase I/II FUSION NHL 001 study. Durvalumab was well tolerated but seemed to add limited benefit to conventional therapy in patients with R/R DLBCL.2

Overall, mAbs have demonstrated limited single-agent efficacy in patients with R/R DLBCL, but favorable safety profiles support the further investigation of mAbs in combination with other targeted agents.

Antibody-drug conjugates

Antibody-drug conjugates (ADCs) comprise a mAb linked to a small-molecule agent to facilitate on-target cytotoxic effects.

Brentuximab vedotin (BV) is an anti-CD30 mAb linked to the antimicrotubule agent, monomethyl auristatin E (MMAE), and is FDA and European Medicines Agency (EMA)-approved for several lymphoma subtypes. A phase II study (NCT01421667), evaluating the efficacy of BV in patients with B-cell non-Hodgkin lymphomas, highlighted the clinical activity of BV in patients with R/R DLBCL, both as a single agent, and in combination with R, irrespective of CD30 expression. Results from this study support further investigation of BV in the R/R setting, and combination strategies are also being considered for first-line treatment of DLBCL.5

Polatuzumab vedotin, an anti-CD79b mAb conjugated with MMAE, is a newly available treatment option that has exhibited encouraging safety and efficacy outcomes in comparative trials evaluating patients with R/R DLBCL.1 In the GO29365 study, polatuzumab vedotin demonstrated synergy with bendamustine and R, and became the first immunochemotherapy to be FDA and EU-approved for the treatment of patients with R/R DLBCL who are not eligible for transplant.

Bispecific antibodies

Bispecific antibodies are designed to simultaneously bind two distinct epitopes. In lymphoma treatment, bispecific T-cell engaging (BiTE) antibodies facilitate the ligation of T cells with lymphoma cells, resulting in a heightened T-cell-mediated antitumor response.1

Blinatumomab is a first-in-class BiTE that brings together CD3+ T cells and CD19+ B cells, augmenting T-cell mediated lysis of malignant cells. Blinatumomab is FDA-approved for the treatment of Philadelphia chromosome-negative R/R B-cell acute lymphoblastic leukemia (ALL), and a phase II study (NCT01741792) reported encouraging response rates and tolerability in patients with R/R DLBCL treated with blinatumomab.

The CD20/CD3-directed bispecific antibodies, mosunetuzumab and RG6026, have also exhibited promising overall response rates in patients with R/R DLBCL. Results from the ongoing phase I/Ib dose-escalation and expansion study (GO29781) of mosunetuzumab for R/R B-cell non-Hodgkin lymphoma were presented at the 61st American Society of Hematology (ASH) Annual Meeting & Exposition; read a summary of the data here.

Treatment with bispecific antibodies does not come without limitations, including unreliable efficacy and cytokine release syndrome. Nevertheless, novel bispecific antibodies have demonstrated favorable clinical efficacy and tolerability in patients with R/R DLBCL, making them a promising immunotherapy in patients with otherwise limited treatment options.

For more information on the status of bispecific antibodies in the treatment of hematological malignancies, read the Lymphoma Hub article here.

Conclusion

Although CAR T-cell therapy has undoubtedly improved outcomes for patients with R/R DLBCL, a proportion of patients relapse, do not respond to treatment, or may not have access to CAR T-cell therapy. Antibody-based therapeutics generally offer a manageable safety profile, but clinical efficacy has been varied. Results from studies evaluating these novel agents support the further investigation of combination therapies to improve the clinical outlook for patients with R/R DLBCL and may complement the armamentarium of immunotherapies beyond CAR T-cell therapy.

  1. Sarkozy C and Sehn LH. New drugs for the management of relapsed or refractory diffuse large B-cell lymphoma. Ann Lymphoma. 2019;3:10. DOI: 21037/aol.2019.09.01
  2. Casulo C, Santoro A, Ando K, et al. Durvalumab (anti PD-L1) as monotherapy or in combination therapy for relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL): A subgroup analysis from the phase 1/2 Fusion NHL-001 global multicenter trial. Blood. 2019;134(1):5320. DOI: 10.1182/blood-2019-124102
  3. Schuster SJ, Bartlett NL, Assouline S, et al. Mosunetuzumab induces complete remissions in poor prognosis non-Hodgkin lymphoma patients, including those who are resistant to or relapsing after chimeric antigen receptor T-cell (CAR-T) therapies, and is active in treatment through multiple lines. 2019;134(1):6. DOI: 10.1182/blood-2019-123742
  4. Holtzman NG, El Chaer F, Mohindra P, et al. Relapsed diffuse large B-cell lymphoma after allogeneic CAR T-cell therapy successfully treated with PD1 inhibition. Biol Blood Marrow Transplant. 2019;25(3):S182-S183. DOI: 10.1016/j.bbmt.2018.12.328
  5. Jacobsen ED, Sharman JP, Oki Y, et al. Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression. 2015;125(9):1394-1402. DOI: 10.1182/blood-2014-09-598763

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