Considerations for CAR T-Cell Therapy Vs Bispecific Antibodies in Relapsed/Refractory Follicular Lymphoma

Caron A. Jacobson, MD, MMSc

Patient preferences should be considered when selecting the optimal treatment regimen for patients with relapsed/refractory (R/R) follicular lymphoma (FL), as both CD19-directed CAR T-cell therapies and CD20-targeted bispecific antibodies can be efficacious in this population, according to a presentation by Caron A. Jacobson, MD, MMSc, at the 2023 SOHO Annual Meeting.

“What it comes down to is that ultimately this is a discussion to have with the patient,” Jacobson, medical director, Immune Effector Cell Therapy Program, Dana-Farber Cancer Institute, said during her presentation at SOHO 2023. “You’ll have patients who prefer a 1-time, 1 and done therapy, and are able to uproot their lives and move to a CAR T-cell treatment center. And you’ll have others who prefer a more modulated approach and would accept a shorter progression-free survival [PFS] for the ease of administration.”

CAR T Cells

The phase 2 ZUMA-5 study (NCT03105336) explored the anti-CD19 CAR T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta®, Kite/Gilead) as a treatment for patients with R/R indolent non-Hodgkin lymphoma (iNHL). This agent has a CD28 costimulatory domain. Of those enrolled, the majority had FL (n = 127) with the remainder having marginal zone lymphoma (MZL, n = 28).

After a median follow-up of 40.5 months,² median PFS with axi-cel was 40.2 months for those with FL and was not yet reached in those with MZL. The 36-month PFS rates were 54.4% and 56.2% for those with FL and MZL, respectively. The median overall survival (OS) was not reached in any group. The 36-month OS rate was 75.5% for those with FL and 73.0% for those with MZL. Activity with axi-cel was also observed in those with progression less than 24 months after initial chemoimmunotherapy (POD24). For those with POD24 (n = 70) the median PFS was 40.2 months with axi-cel. The median PFS was not yet reached in those without POD24 (n = 41).

CAR T cells are associated with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). In the primary analysis of the ZUMA-5 trial,³ grade 3 or greater CRS was observed in 6% of patients with FL (n = 124) and grade 3 or greater neurologic events were observed in 15%.

Axi-cel was initially approved in 2017 and has since gained an accelerated approval for relapsed/refractory adult patients with FL after 2 or more lines of systemic therapy. Given its time on the market, Jacobson noted, there is now real-world data available on its use, with new findings recently presented at the 2023 European Hematology Association (EHA) meeting.⁴

In the real-world setting,⁴ among efficacy evaluable patients with FL (n = 148), the objective response rate (ORR) was 93% (95% CI, 88%-97%) with 84% of patients achieving a complete response (CR; 95% CI, 77%-89%). Similar responses were seen across groups, based on age, prior exposure to bendamustine, and the number of prior lines of therapy, Jacobson noted.

“The disadvantages are that it obviously requires referral to a specialized center for at least 1 month around the time of infusion,” said Jacobson. “The risk profile does remain considerable and requires a motivated patient.”

Other anti-CD19 CAR T-cell therapies are also available for patients with iNHL, including tisagenlecleucel (tisa-cel; Kymriah®, Novartis), which received FDA approval for relapsed/refractory FL in 2022 based on findings from the ELARA trial (NCT03568461). This agent has a 4-1BB costimulatory domain.

Among the 94 patients in the primary efficacy analysis,⁵ the median PFS was not yet reached with tisa-cel, with a 24-month PFS rate of 57.4% (95% CI, 46.2%-67.0%). The 24-month OS rate with tisa-cel was 87.7% (95% CI, 78.3%-93.2%). In the first reports from this study,⁶ CRS rates were seen in 48% of patients, with none being grade 3 or higher in severity. Neurological events were experienced by 11.3% of patients, with 3% being grade 3 or higher in severity.

Although not yet approved, the anti-CD19 CAR T-cell therapy lisocabtagene maraleucel (liso-cel; Breyanzi®, Juno/Bristol-Myers Squibb) is also on the horizon. This agent has a 4-1BB costimulatory domain. Positive data for the agent were presented at the 2023 International Conference on Malignant Lymphoma (ICML) meeting from the phase 2 open-label TRANSCEND-FL study. These results are being discussed with health authorities, according to the developers of the agent.

In the TRANSCEND-FL trial,⁷ which enrolled 101 patients with FL, the ORR was 97% with liso-cel (95% CI, 91.6%-99.4%), with a complete response rate of 94% (95% CI, 87.5%-97.8%). The median PFS had not yet been reached with a 12-month PFS rate of 80.7%. CRS occurred in 58%, with grade 3 CRS in 1% of patients. Neurologic events were seen in 15% of patients with 2% having a grade 3 event. There were no cases of grade 4 or 5 neurologic events or CRS.

“For CAR T cells, the advantage is obviously that it’s a single infusion with a discrete toxicity window, and the toxicities are manageable and reversible. The incidence is improving over time with experience, and it is decreased and more favorable in follicular lymphoma. For the 4-1BB CARs, high grade toxicity is very rare,” Jacobson said. "I think we have enough data to say [CAR T cells] offer the most durable response and treatment-free interval of any available therapy for a broad range of high-risk disease features. I do think it is unclear if it could be definitive therapy for a subset of patients, we need longer follow-up to say that."

Bispecifics

Bispecific antibodies targeted toward CD20 and CD3 have gained considerable interest for patients with iNHL, with several new agents in the pipeline. The furthest along of these agents in FL is mosunetuzumab-axgb (Lunsumio™; Genentech), which gained accelerated approval in late 2022 for the treatment of R/R FL. Findings from the GO29781 study (NCT02500407) were instrumental in this approval.

Among 90 patients with FL enrolled in the GO29781 study,⁸ the ORR was 78% and the CR rate was 60.0%. The median PFS was 17.9 months and OS was not yet available. The CRS rate with this agent was 44%, which was primarily grade 1/2 in severity. There was 1 case of grade 3 CRS and 1 case of grade 4 CRS.

“The disadvantages of the CD20 bispecifics are that in many parts of the country, they still require a referral to a specialized center for at least 1 month around the time of the first cycle and first full dose, given their risk profile,” said Jacobson. “This is as logistically challenging of getting patients to CAR T cells, and requires prolonged dosing, with frequent clinic visits for infusion and ongoing risk of immune disfunction and infection.”

A host of other CD20-targeted bispecific antibodies are on the horizon, with clinical results available from phase 1/2 studies. Of note, Jacobson mentioned glofitamab (Columvi™, Genentech), epcoritamab (Epkinly™, Genmab, AbbVie), and odronextamab (Regeneron). Both glofitamab and epcoritamab have gained FDA approvals for relapsed/refractory large cell lymphomas but are not yet approved for FL.

“The risk of significant CRS [with bispecifics] is low, and there’s almost no risk of neurologic toxicities. Most of this risk is limited to the first cycle,” said Jacobson. “This can be administered in a wider number of oncology clinics and hospitals allowing for more universal and more ready access.”

References

1. Jacobson CA. Bispecific Antibodies or CAR T-Cells for Indolent NHL? Presented at: 11th Annual Meeting of the Society Hematologic Oncology (SOHO 2023), September 7, 2023. Houston, TX.
2. Neelapu SS, Chavez J, Sehgal AR, et al. 3-year follow-up analysis of ZUMA-5: A phase 2 study of axicabtagene ciloleucel (Axi-Cel) in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Blood. 2022;140 (suppl 1):10380-10383. doi:10.1182/blood-2022-156120.
3. Jacobson C, Chavez JC, Sehgal AR, et al. Primary analysis of ZUMA-5: A phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Blood. 2020;136 (suppl 1):40-41. doi:10.1182/blood-2020-136834.
4. Jacobson C, Hemmer MT, Hu Z-H, et al. Real-world early outcomes of axicabtagene ciloleucel for relapsed or refractory follicular lymphoma. HemaSphere. 2023;7:e31464ce. doi: 10.1097/01.HS9.0000967804.31464.ce.
5. Dreyling M, Dickinson M, Lopez JM, et al. Long-term clinical outcomes and correlative efficacy analyses in patients (pts) with relapsed/refractory follicular lymphoma (R/R FL) treated with tisagenlecleucel in the ELARA trial. Blood. 2022;140 (Suppl 1):1459-1463. doi:10.1182/blood-2022-158024.
6. Thieblemont C, Dickinson M, Martinez-Lopez J, et.al. Efficacy of tisagenlecleucel in adult patients with high-risk relapsed/refractory follicular lymphoma: Subgroup analysis of the phase II ELARA study. Blood. 2021;138 (suppl 1):131. doi:10.1182/blood-2021-145025.
7. Morschhauser F, Dahiya S, Palomba ML et al. TRANSCEND FL: Phase 2 study results of lisocabtagene maraleucel (liso-cel) in patients with relapsed/refractory (R/R) follicular lymphoma (FL). Abstract presented at: ICML 2023, June 13-17, 2023.
8. Budde LE, Sehn LH, Matasar M, et al. Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study. Lancet Oncol. 2022;23(8):1055-1065. doi:10.1016/S1470-2045(22)00335-7.