From Lymphomas to Myeloma, Bispecific Antibodies Make a Big Splash at ASH

For several years, chimeric antigen receptor (CAR) T-cell therapies took center stage during the annual meeting of the American Society of Hematology (ASH). Despite their cost, CAR T-cell therapies are no longer treatments of last resort; at ASH 2021 in Atlanta, Georgia, news on the first day focused on bringing rival therapies for diffuse large B-cell lymphoma (DLBCL), axicabtagene ciloleucel (axi-cel, Yescarta), and lisocabtagene maraleucel (liso-cel, Breyanzi), into second-line treatment. During 2022, both were approved for this use.^1,2

There’s still plenty of excitement about CAR T, but as seen at ASH 2022 in New Orleans, Louisiana, these customized treatments now share the limelight with bispecific antibodies, which made news across disease states from large B-cell lymphoma (LBCL) to follicular lymphoma (FL) to multiple myeloma (MM). As their name suggests, these treatments aim at 2 targets, increasing their potency against cancer. And for those wondering, yes, there are trispecific antibodies in the works.³

As speakers noted during ASH, bispecifics have pluses and minuses compared with CAR T-cell therapy, which many say is becoming the treatment of choice, especially in second-line DLBCL. But bispecific antibodies are crucial in 2 ways: first, some patients who receive CAR T-cell treatment later progress and need other options. Second, as off-the-shelf products, bispecific antibodies don’t require the multistep process of collecting T cells and waiting for an engineering process that can take up to 6 weeks. For frail patients or those with rapidly progressing disease, a bispecific antibody may be a good option, as Nancy L. Bartlett, MD, wrote in an editorial in the New England Journal of Medicine to accompany papers released during ASH.⁴

“Many of the logistic limitations of CAR T cells may be addressed by an emerging class of off-the-shelf T-cell–engaging bispecific antibodies,” she wrote. As Bartlett explained, the cancer-killing qualities of these agents results from simultaneous binding of a tumor-associated antigen and endogenous T cells, which triggers T-cell activation.

Although toxicity with these agents varies, Bartlett noted that bispecifics are needed and useful for the 60% of patients who ultimately relapse after CAR T-cell therapy. Experts say they still have much to learn about sequencing the different therapeutic classes, especially as they navigate availability issues in CAR T, which seem particularly acute in MM.⁵

During ASH, new data involving bispecific antibodies included presentations on glofitamab in LBCL, mosunetuzumab in FL and epcoritamab in B-cell lymphomas. New data was also presented for teclistamab (Tecvayli), which in October 2022 became the first FDA-approved bispecific B-call maturation antigen (BCMA)-directed CD3 T-cell engager for use in relapsed or refractory (R/R) MM.⁶

Updated Phase 2 Data for Glofitamab in LBCL

Glofitamab is a CD20 x CD3 T-cell-engager with a unique 2:1 configuration, with bivalency for CD20—meaning it redirects T cells to eliminate normal and malignant B cells. The treatment is administered intravenously (IV) for 12 cycles. Data presented at the American Society of Clinical Oncology in June from an ongoing pivotal phase 1/2 study (NCT03075696) showed a median complete response (CR) of 39.4% (61 of 155 patients) and an overall response rate (ORR) of 51.5% (80 of 155 patients).7 In data presented in New Orleans, patients were pretreated with obinutuzumab to mitigate cytokine release syndrome (CRS) and the option of retreatment was available if patients experienced disease progression. The median number of prior treatments was 3, including 19.6 with prior CAR T-cell therapy (30 of 155 patients); of these, 7 patients achieved CR.⁸

At ASH 2022, Martin Hutchings, MD, PhD, of Copenhagen University Hospital presented data in an oral session that focused on duration of CRs in patients with R/R LBCL after the end of treatment. Hutchings offered updated data from the abstract, showing that 12 months after the end of treatment, 61% of patients (n=37/61) maintained a CR, 92.6% remained progression-free, and 1 patient (n=1/44) experienced disease progression. The estimated rate of patients with a CR lasting 24 months is 79%, and the median PFS (in months) for those achieving CR is not evaluable (NE) (95% CI, 27.5-NE).

During the session, Hutchings was asked if glofitamab was a cure. While more follow-up was needed, he said, “I do believe there is a curative potential.” A subcutaneous version of glofitamab is being developed, he said.

A paper based on earlier data from the phase 2 study in R/R DLBCL was published online in NEJM during the conference.9 According to a statement from the drug’s sponsor, Genentech, data the pivotal phase 2 study have been submitted for review to the European Medicines Agency, and submissions to FDA are ongoing.¹⁰

Mosunetuzumab in Follicular Lymphoma

In July 2022, Genentech reported that FDA had granted priority review to mosunetuzumab for patients with R/R FL, saying the therapy could be the first CD20 x CD3 T-cell engaging bispecific antibody approved “for the treatment of any type” of non-Hodgkin lymphoma.¹¹ The European Commission authorized marketing in June 2022; in December 2022, approved the therapy for adults after 2 or more lines of systemic therapy.¹²

Longer-term data presented at ASH 2022 showed that after a median of 28.3 months of follow-up, mosunetuzumab continued to produce durable responses in patients with FL. In this part of the pivotal phase 2 study (NCT02500407) 60% of patients with 2 or more prior therapies experienced a CR of 60% (54 of 90 patients; 95% CI, 49.1-70.2) and 77.8% achieved an objective response, which incluses CR plus partial responses (95% CI, 67.8-85.9).¹³

Among those who achieved CR, after 24 months 62.7% of patients were still in remission (95% CI: 37.7–87.7). Overall, 48.3% remained progression-free (95% CI: 36.2-60.3), and the median duration of response and duration of CR, as well as median PFS were not reached. No new CRS events or adverse events of grade 3 or higher were reported.

Epcoritamab in B-cell Lymphomas

Other presentations at ASH 2022 offered new data on epcoritamab, an investigational therapy known as a DuoBody-CD3xCD20 bispecific antibody. As described in 2018, this platform “induced potent activation, proliferation and cytotoxic activity of both CD4+ and CD8+ T cells in the presence of CD20-expressing cells.”¹⁴ Epcoritamab, developed by AbbVie and Genmab, is being studied in multiple B-cell malignancies, including DLBCL and FL. FDA accepted the therapy for priority review for patients with R/R LBCL after at least 2 prior treatments, with a target action date of May 21, 2023.¹⁵

Results presented included updated phase 1/2 data from EPCORE NHL-2 for non-Hodgkin lymphoma, which combines subcutaneous epcoritamab with rituximab, dexamethasone and chemotherapy. Pau Abrisqueta, MD, PhD, of Hospital Universitario Vall dHebron in Barcelona, Spain, outlined data for patients with R/R DLBCL who were eligible for autologous stem cell transplant (ASCT). He explained that these patients were all high-risk and highly refractory; under current standard of care, not all patients will make it to ASCT and about half will not have long-term remission. For the 27 evaluable patients in this arm, results showed an 85% ORR (23 of 27 patients) and a 67% (18 of 27 patients) with a complete metabolic response rate. Median time to response was 1.4 months. After a median follow-up of 12.6 months, 16 patients proceeded to ASCT and of this group, “there is no sign of progression,” Abrisqueta said. Median PFS and median OS were not reached; an estimated 90% of patients were alive at 12 months.¹⁶

Common treatment emergent adverse events (TEAEs) in this study arm that affected at least a quarter of patients were thrombocytopenia (69%), anemia (51%), neutropenia (44%), CRS (41%), and nausea (31%), and fatigue (28%).

In other results, high response rates for epcoritamab were seen in chronic lymphocytic leukemia with Richter’s Syndrome17 and in follicular lymphoma, both in R/R patients and those previously untreated.^18,19

Teclistamab With Daratumumab, Lenalidomide in MM

More than 90% of patient with R/RMM showed strong responses when treated with a combination of the bispecific antibody teclistamab (Tecvayli) and daratumumab (Darzalex), a monoclonal antibody studied in combination with classic triplet therapy. Teclistamab is a subcutaneous treatment.²⁰

Results from MajesTEC-1 presented at ASH 2021 led to the fall approval of teclistamab.^6,21 Data from 32 patients the phase 1b MajesTEC-2 study (NCT04722146), presented December 10, 2022, represent the first results from a triplet regimen using the bispecific antibody. In an interview with Evidence-Based Oncology™ (EBO), Emma Searle, MD, PhD, of The Christie Hospital and the University of Manchester, explained, “The patient population in MajesTEC-2 was less heavily pretreated than the patient population in MajesTEC-1, and we're seeing very high overall response rates in this combination of near to 94% across the 2 different dosing schedules. Those responses appear to deepen over time.”

At a median follow-up of 8.4 months (1.1 to 12.9 months range), the ORR was 93.5%. Among all patients in the trial, very good partial responses or better were seen by 90.3% of the patients, and 54.8% achieved a CR or better. Median time to response was 1 month. At the time of data cut off, 80.6% of patients were on treatment and did not have disease progression. Median duration of response had not been reached.²⁰

Common AEs were neutropenia (84.4% of any grade, 78.1% grade 3/4) and thrombocytopenia (25% any grade, 15.6% grade 3/4), and CRS (81.3% all grade 1/2); 97% of CRS occurred in cycle 1.

According to Janssen, the MajesTEC-7 study (NCT05552222) will evaluate this triplet regimen in patients with newly diagnosed MM.²²

Hayden E. Klein contributed to this report.

References

1. FDA approves axicabtagene ciloleucel for second-line treatment of large B-cell lymphoma. FDA. Updated April 1, 2022. Accessed December 17, 2022. https://bit.ly/3RqnXzB

2. U.S. FDA approves Bristol Myers Squibb’s CAR T cell therapy Breyanzi for relapsed or refractory large B-cell lymphoma after one prior therapy. News release. Bristol Myers Squibb. June 24, 2022. Accessed December 17, 2022. https://bit.ly/3W45UAY

3. Kuchnio A, Yang D, Vloemans N, et al. Characterization of JNJ-80948543, a novel CD79bxCD20xCD3 trispecific T-cell redirecting antibody for the treatment of B-cell non-Hodgkin lymphoma. Presented at: 64th American Society of Hematology Annual Meeting and Exposition, December 10-13, 2022; New Orleans, LA: Abstract 1342. Accessed December 18, 2022. https://ash.confex.com/ash/2022/webprogram/Paper168739.html

4. Bartlett NL. Bispecific antibodies in lymphoma—another win for T cells. N Engl J Med. 2022; 387:2285-2286. doi: 10.1056/NEJMe2212732

5. Astor L. Bispecifics vs CAR T-cell therapy: Which is better in relapsed/refractory multiple myeloma? Targeted Oncology. Published October 1, 2022. Accessed December 18, 2022. https://bit.ly/3HO58DO

6. FDA approves teclistamab-cqyv in relapsed or refractory multiple myeloma. News release. FDA website. October 25, 2022. Accessed December 18, 2022. https://bit.ly/3jhKC4r

7. Dickinson M, Carlo-Stella C, Morschhauser F, et al. Glofitamab in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and ≥ 2 prior therapies: Pivotal phase 2 expansion results. J Clin Oncol 2022; 40(suppl 16):Abstract 7500. doi: 10.1200/JCO.2022.40.16_suppl.7500

8. Hutchings M, Carol-Stella C, Morschhauser F, et al. Relapse is uncommon in patients with large B-cell lymphoma who are in complete remission at the end of fixed-course glofitamab treatment. Presented at: 64th American Society of Hematology Annual Meeting and Exposition, December 10-13, 2022; New Orleans, LA: Abstract 441. Accessed December 19, 2022. https://ash.confex.com/ash/2022/webprogram/Paper157554.html

9. Dickinson MJ, Carlo-Stella C, Morschhauser F, et al. Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2022;387:2220-2231.

doi: 10.1056/NEJMoa2206913

10. Genetech presents new data demonstrating the potential of glofitamab and mosunetuzumab as fixed duration, off-the-shelf treatment options for lymphoma. News release. BusinessWire. December 12, 2022. Accessed December 18, 2022. https://bwnews.pr/3VetVEa

11. FDA grants priority review to Genetech’s mosunetuzumab for people with relapsed or refractory multiple myeloma. News release. July 5, 2022. Accessed December 18, 2022. https://bit.ly/3BR2l9d

12. FDA approves Genentech’s Lunsumio, a first-in-class bispecific antibody, to treat people with relapsed or refractory follicular lymphoma. News release. December 22, 2022. Accessed December 23, 2022. https://bit.ly/3XdCvFg

13. Budde E, Bartlett NL, Giri P, et al. Subcutaneous mosunetuzumab is active with a manageable safety profile in patients (pts) with relapsed/refractory B-cell non-Hodgkin lymphomas (B-NHLs): updated results from a phase 1/2 study. Abstracat 1628. Accessed December 18, 2022. https://ash.confex.com/ash/2022/webprogram/Paper157729.html

14. Hiemstra IH, Engelberts PJ, Jong B, et al. Duobody-CD3xCD20 shows unique and potent preclinical anti-tumor activity in Vitro and In Vivo, and is being evaluated clinically in patients with B-cell malignancies. Blood. 2018; Blood (2018) 132 (suppl 1): 1664. https://doi.org/10.1182/blood-2018-99-115957

15. Genmab announces US Food and Drug Administration accepts for priority review biologics license application (BLA) for epcoritamab (DuoBody-CD3xCD20) for the treatment of relapsed/refractory large B-cell lymphoma (LBCL). News release. Business Wire. November 21, 2022. Accessed December 18, 2022. https://bit.ly/3PHQ1hu

16. Abrisqueta P, Cordoba R, Falchi L, et al. Subcutaneous epcoritamab + R-Dhax/c in patients with relapsed or refractory diffuse large B-cell lymphoma eligible for autologous stem cell transplant: updated phase 1/2 results. Presented at: 64th American Society of Hematology Annual Meeting and Exposition, December 10-13, 2022; New Orleans, LA: Abstract 443. Accessed December 18, 2022. https://ash.confex.com/ash/2022/webprogram/Paper158278.html

17. Kater AP, Ye JC, Sandoval-Sus J, et al. Subcutaneous epcoritamab in patients with Richter’s Syndrome: early results from phase 1b/2 trial (EPCORE CLL-1). Presented at: 64th American Society of Hematology Annual Meeting and Exposition, December 10-13, 2022; New Orleans, LA: Abstract 348. Accessed December 18, 2022. https://ash.confex.com/ash/2022/webprogram/Paper158298.html

18. Falchi L, Abrisqueta P, Nijland M, et al. Subcutaneous epcoritamab with rituximab + lenalidomide in patients with relapsed or refractory follicular lymphoma: phase 1/2 trial update. Presented at: 64th American Society of Hematology Annual Meeting and Exposition, December 10-13, 2022; New Orleans, LA: Abstract 609. Accessed December 18, 2022. https://ash.confex.com/ash/2022/webprogram/Paper158203.html

19. Falchi L, Leslie LA, Belada D, et al. Subcutaneous Epcoritamab in combination with rituximab + lenalidomide (R2) for first-line treatment of follicular lymphoma: initial results from phase 1/2 trial. Presented at: 64th American Society of Hematology Annual Meeting and Exposition, December 10-13, 2022; New Orleans, LA: Abstract 611. December 18, 2022. https://ash.confex.com/ash/2022/webprogram/Paper158232.html

20. Searle E, Quach H, Wong SW, et al. Teclistamab in combination with subcutaneous daratumumab and lenalidomide in patients with multiple myeloma: results from one cohort of MajesTEC-2, a phase 1b, multicohort study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition, December 10-13, 2022; New Orleans, LA: Abstract 160. Accessed December 18, 2022. https://ash.confex.com/ash/2022/webprogram/Paper159711.html

21. Melillo G. Phase 1/2 trial results underscore teclistamab’s efficacy in RRMM. The American Journal of Managed Care®. Published December 22, 2021. Accessed December 18, 2022. https://bit.ly/3FIfUck

22. Janssen presents first data from MajesTEC-2 trial of TECVAYLI (teclistamab) in combination with Darzalex (daratumumab) subcutaneous (SC) formulation and lenalidomide in relapsed or refractory multiple myeloma. News release. GlobeNewswire. December 10, 2022. Accessed December 18, 2022. https://bit.ly/3YypgzT