New DLBCL Treatments Are Poised to Fill an Unmet Need for Patients in Challenging Settings

Diffuse large B-cell lymphoma (DLBCL) is a fast-growing, aggressive disease, but it is often curable with timely and appropriate treatment. Nevertheless, approximately 25% to 33% of patients have primary refractory disease or relapse, both of which are associated with worse outcomes.^1,2 Although a curative approach may still be possible for some of these patients, the treatments required may be contraindicated in others. Recently, several effective second- and subsequent-line treatments have emerged for the population of patients who are not candidates for the intensive treatments considered necessary for cure, such as consolidation with high-dose therapy.

During a recent OncLive Peer Exchange^®, a panel of lymphoma experts discussed these therapies, including tafasitamab-cxix (Monjuvi), polatuzumab vedotin-piiq (Polivy), and selinexor (Xpovio), and how and when they use them for their patients.

“The toxicities associated with our traditional regimens have been so great,” Loretta J. Nastoupil, MD, said. “There’s probably a large number of patients who are having fewer of these intensive approaches because we make the determination that they’re not going to tolerate it.” Nastoupil noted that the newly available treatments give patients the opportunity for more effective and tolerable palliation, often with durable results.

Tafasitamab

On July 31, 2020, the FDA granted accelerated approval to tafasitamab in combination with lenalidomide (Revlimid) for the treatment of adult patients with relapsed or refractory DLBCL, including DLBCL arising from low-grade lymphoma, who are not candidates for autologous stem cell transplant.³ “Tafasitamab is a CD19 antibody,” Kami J. Maddocks, MD, said. She explained that it was initially studied as a single agent in a phase 2 study where it showed some durable complete responses, which then served as the rationale for combining it with lenalidomide.

Approval of tafasitamab in combination with lenalidomide was based on data from L-MIND (NCT02399085), an open- label, multicenter, single-arm, phase 2 trial that included 80 patients who received at least 1 dose of both tafasitamab and lenalidomide.⁴ “The first 3 months [of treatment] were pretty aggressive. They were treated with weekly infusions, then they were treated bimonthly. After a year, patients were able to go on to maintenance therapy with the antibody tafasitamab alone if they were responding,” Maddocks said.

After a median follow-up of 13.2 months, 48 patients (60%) had an objective response, of which 34 (42.5%) were complete responses (CRs) and 14 (17.5%) were partial responses (PRs).4 These findings were confirmed after more than 2 years of follow-up, with 47 patients (58.8%) having an objective response, with 33 (41.3%) being CRs and 14 (17.5%) being PRs.⁵ Additionally, 12 patients (15%) had stable disease. Responses were durable, with a median duration of response of 34.6 months. The median overall survival (OS) was 31.6 months with a median follow-up of 31.8 months, and the median progression-free survival (PFS) was 16.2 months with a median follow-up of 22.6 months.⁵

“This is a very effective regimen, especially for those patients who are not eligible for transplant, as approved based on the L-MIND study,” Amitkumar Mehta, MD, said. He indicated this also extends off-label to the frontline setting for frail, older patients who are not candidates for aggressive therapy.

A key consideration with this regimen is the management of treatment-emergent adverse effects Amitkumar Mehta, MD (TEAEs) associated with lenalidomide. In the L-MIND study, including long-term follow-up, the most common grade 3 or greater TEAEs included neutropenia, thrombocytopenia, and febrile neutropenia.^4,5 The most frequently reported serious AEs included pneumonia, febrile neutropenia, pulmonary embolism, bronchitis, atrial fibrillation, and congestive heart failure, with long-term follow-up also including lower respiratory tract infection.^4,5 To get a better sense of the burden of these AEs, their frequency and duration were calculated per patient year of exposure to the study medication (Table 1^4,5). When examining TEAE burden by treatment phase, the rate was reduced in both severity and incidence during the monotherapy maintenance phase vs the combination therapy phases.⁵

Table 1. TEAEs Per Patient Year of Exposure to L-MIND Treatment Regimen^4,5

A concern with using tafasitamab/lenalidomide in some patients has been whether it might compromise the efficacy of subsequent chimeric antigen receptor (CAR) T-cell therapy, as has been observed in cases of acute lymphoblastic leukemia. “That is not supported by any evidence [in DLBCL]. It’s theoretical…. In the small amount of data that currently exist, it does not appear that introducing tafasitamab prior to CD19directed CAR T-cell therapy is going to impact [the curative potential of the CAR T-cell therapy],” Nastoupil said, indicating that more real-world experience is needed to gain a better sense of how to optimally sequence available treatments.

Polatuzumab Vedotin

On June 10, 2019, the FDA approved polatuzumab vedotin in combination with bendamustine and rituximab for adult patients with relapsed or refractory DLBCL after at least 2 previous therapies.⁶ “Polatuzumab vedotin is an anti-CD79b antibody-drug conjugate linked to MMAE [monomethyl auristatin E], the same drug that’s in brentuximab vedotin,” John M. Burke, MD, explained.

Approval of polatuzumab vedotin was based on data from an open-label multicenter clinical trial (NCT02257567) that included 80 patients with relapsed or refractory DLBCL after at least 1 prior regimen.6 Patients were randomly assigned 1:1 to receive polatuzumab vedotin with bendamustine/rituximab or bendamustine/rituximab for 6 cycles lasting 21 days each. At the end of therapy, the CR rate was 40% in the polatuzumab vedotin combination arm vs 18% in the bendamustine/ rituximab arm. The best overall response rate (CRs and PRs) was 63% with the polatuzumab vedotin combination vs 25% with bendamustine/rituximab. Among the 25 patients who achieved PRs or CRs to the polatuzumab vedotin combination, responses lasted at least 6 months in 16 patients (64%) and at least 12 months in 12 patients (48%).⁶

Benefit with the addition of polatuzumab vedotin to bendamustine/rituximab continued to be observed after a median follow-up of almost 43 months.⁷ In the polatuzumab vedotin combination arm, 6 patients (15%) had an independent review committee (IRC)assessed duration of response greater than 24 months (range, 26.6-38.6 months) at last follow-up, with 5 receiving no new treatment and 1 undergoing an allogeneic stem cell transplant. The median IRC-assessed PFS was 9.2 months in the polatuzumab vedotin combination arm vs 3.7 months in the bendamustine/rituximab arm, whereas the median OS was 12.4 months vs 4.7 months, respectively.

The most common TEAEs in the polatuzumab vedotin arm included neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia.⁶ Serious TEAEs were reported in 64% of patients, most frequently from infection, with the most common reason for treatment discontinuation being cytopenia (18% of all patients).⁶ No new safety signals were observed during the longer follow-up period.⁷

“The FDA approval for this combination is for treatment in the third-line setting or beyond…[but] I’ve used it as either second- or third-line therapy,” Burke said. He explained that in a subset analysis the patients who received it in the second line had better outcomes than those receiving it in the third line and beyond, and that he has not had any trouble getting the regimen covered by insurance in these settings.

Burke also noted that he has used polatuzumab vedotin before CAR T-cell therapy. Moderator Ian W. Flinn, MD, PhD, agreed with that approach, adding that “it’s attractive as a bridging therapy for patients who require it,” but said he worries about using a T cell–depleting agent prior to a patient acquiring the leukapheresis product. However, he said he has been impressed overall with this agent’s efficacy and sees it as an important therapy for patients with DLBCL.

Selinexor

On June 22, 2020, the FDA granted accelerated approved to selinexor for adult patients with relapsed or refractory DLBCL, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy.⁸ Selinexor is a selective inhibitor of nuclear export. In addition to its unique mechanism action, it is novel because it is taken orally. Flinn and Maddocks both noted that its oral formulation makes it an attractive treatment option.

Approval of selinexor was based on SADAL (NCT02227251), a multicenter, single-arm, open-label, phase 2 trial that included 127 patients with DLBCL who had previously received 2 to 5 systemic regimens.⁹ Patients took 60 mg of selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The overall response rate was 28% (n = 36). There were 15 (12%) CRs and 21 (17%) PRs.

“The responses are probably less impressive than what we’ve seen with some of the other drugs that we’re mentioning that have become available in the last couple of years for relapsed disease. Moving forward, selinexor may potentially be combinable with chemotherapy or other drugs. That may really be the future of this drug—to combine it with some of the other therapies that are out there to see if they can improve efficacy,” Burke said. Multiple such studies are ongoing (Table 2).

Table 2. Clinical Trials Recruiting Patients to Assess Selinexor Combinations for Relapsed/Refractory DLBCL

The most common grade 3 to 4 TEAEs with selinexor included thrombocytopenia, neutropenia, anemia, fatigue, hyponatremia, and nausea. The most common serious AEs included pyrexia, pneumonia, and sepsis. No deaths were attributed to treatment with selinexor. Based on its safety profile, Maddocks said, “[this treatment] does require some work,” with use of various premedications needed. However, with the use of such agents, she noted that the regimen appears tolerable.

Patient selection for this treatment presents a clinical challenge, especially with other more-efficacious options available. “To me, this is something that [you can consider] if you have a patient who relapses after CAR T-cell therapy, isn’t eligible for a trial, wants to try something, or maybe if you have an older patient who is not eligible for transplant, is not eligible for CAR T, and wants to try something,” Maddocks said, noting that she has not used it for any of her patients. “I would say that in the second-line setting, for somebody who’s not going to be eligible for a curative therapy, I’m using tafasitamab-lenalidomide or, prior to that, if I could get access to it, BR [bendamustine-rituximab]–polatuzumab vedotin,” she said.

Mehta noted that several case reports of central nervous system penetration have been reported with selinexor. He said that he also has seen responses in patients with central nervous system involvement, making this a possible additional niche for this drug, although data from ongoing studies are needed to provide more definitive information.

References

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2. Freedman AS, Friedberg JW. Patient education: diffuse large B cell lymphoma in adults (beyond the basics). UpToDate. Updated August 13, 2020. Accessed May 2, 2021. bit.ly/3en27LR
3. FDA grants accelerated approval to tafasitamab-cxix for diffuse large B-cell lymphoma. FDA. Updated August 3, 2020. Accessed May 2, 2021. https://www.fda.gov/drugs/drug-approv-als-and-databases/fda-grants-accelerated-approval-tafasi-tamab-cxix-diffuse-large-b-cell-lymphoma
4. Salles G, Duell J, Barca EG, et al. Tafasitamab plus lenalido-mide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020;21(7):978-988. doi:10.1016/S1470-2045(20)30225-4
5. Salles G, Duell J, González-Barca E, et al. Long-term outcomes from the phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Presented at: 2020 European Hematology As-sociation Congress; June 11-21, 2020; virtual. Abstract EP1201. Accessed May 2, 2021. https://bit.ly/3hbJkox
6. FDA approves polatuzumab vedotin-piiq for diffuse large B-cell lymphoma. FDA. June 10, 2019. Accessed May 2, 2021. https://www.fda.gov/drugs/resources-information-ap-proved-drugs/fda-approves-polatuzumab-vedotin-piiq-dif-fuse-large-b-cell-lymphoma
7. Sehn LH, Hertzberg M, Opat S, et al. Polatuzumab vedotin plus bendamustine and rituximab in relapsed/refractory diffuse large B-cell lymphoma: updated results of a phase Ib/II randomized study and preliminary results of a single-arm extension. Blood. 2020;136(suppl 1):17-19. doi:10.1182/blood-2020-137078
8. FDA approves selinexor for relapsed/refractory diffuse large B-cell lymphoma. FDA. June 22, 2020. Accessed May 2, 2021. https://www.fda.gov/drugs/resources-information-ap-proved-drugs/fda-approves-selinexor-relapsedrefractory-dif-fuse-large-b-cell-lymphoma
9. Kalakonda N, Maerevoet M, Cavallo F, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-la-bel, phase 2 trial. Lancet Haematol. 2020;7(7):E511-E522. doi:10.1016/S2352-3026(20)30120-4