Chemotherapy-Free Combos Lead the Way in R/R Follicular Lymphoma

Matthew Lunning, DO, FACP

The treatment paradigm of relapsed/refractory (R/R) follicular lymphoma has undergone a drastic transformation in recent years with the FDA approval of lenalidomide (Revlimid) plus rituximab (Rituxan) offering a platform for investigators to build additional combination regimens in the second-line setting.

In the third line of treatment and beyond, chimeric antigen receptor (CAR) T-cell agents such as axicabta- gene ciloleucel (axi-cel; Yescarta), tisagenlecleucel (tisa-cel; Kymriah), and lisocabtagene maraleucel (liso-cel; Breyanzi) have transformed the landscape by providing sustained disease control, offering patients multiple effective treatment options.

“What we’ve seen [with recent developments] are the number of options that patients with follicular lymphoma now have. So many of these options are not relying on chemotherapy; they’re relying on immunotherapy or other targeted mechanisms, and I believe that is going to be the way forward for follicular lymphoma,” Laurie H. Sehn, MD, MPH, said. “Many [new] options are moving forward with randomized trials
in the second-line setting, [as well as] the frontline setting. I
believe we will be replacing chemotherapy at some point and
these immunotherapy options are going to offer patients choices
in an earlier setting. It is going to be confusing for a while moving forward [and] there is not going to be 1 answer for every patient.”

OncologyLive was onsite at the 2024 American Society of Hematology
(ASH) Annual Meeting and Exposition to film a Peer Exchange that
featured commentary from experts in the field of follicular lymphoma. The
panelists provided their view on the impact of the data updates that were
shared during the meeting, weighed in on how these data will affect treatment options and therapeutic sequencing strategies, and looked ahead to the future of treatment for patients with R/R follicular lymphoma.

Lenalidomide Plus Rituximab Provides the Basis for Second-Line Therapy

For patients with high-risk, R/R follicular lymphoma, there is currently no definitive standard of care.1 The combination of lenalidomide and rituximab is an FDA-approved option; the regimen received approval for this patient population from the agency in May 2019, based on findings from the phase 3 AUGMENT (NCT01938001) and MAGNIFY (NCT01996865) studies.2 Since this approval, investigators have been evaluating the addition of other agents to lenalidomide and rituximab with the hope of achieving even greater efficacy for these patients.

One such study, the phase 3 inMIND trial (NCT04680052), was a double-blind, placebo-controlled, multicenter study that enrolled adult patients with grade I to IIIA follicular lymphoma or marginal zone lymphoma (MZL) who received at least 1 prior line of therapy, including an anti-CD20 monoclonal antibody.3

Patients were randomly assigned 1:1 to receive tafasi- tamab-cxix (Monjuvi) in combination with lenalidomide and rituximab or placebo plus lenalidomide and rituximab. The primary end point was progression-free survival (PFS); overall survival (OS) and PET-complete response (CR) rate in the fluorodeoxy- glucose (FDG)-avid population represented key secondary end points.

At a median follow-up of 14.1 months, the median investigator-assessed PFS in the investigational arm (n=273) was 22.4 months (95% CI, 19.2-not evaluable [NE]) compared with 13.9 months (95% CI, 11.5-16.4) in the placebo arm (n=275; HR, 0.43; 95% CI, 0.32-0.58; P<.0001). Among patients who were FDG-avid in the tafasitamab (n=251) and placebo (n=254) arms, the PET-CR rates were 49.4% (95% CI, 43.1%-55.8%) and 39.8% (95% CI, 33.7%- 46.1%), respectively (OR, 1.5; 95% CI, 1.04-2.13; nominal P=.0286).

“This is the first time we’ve combined a CD19[- directed] monoclonal antibody with a CD20[-directed] monoclonal antibody; [these data] improve upon the standard that we’ve been using with lenalidomide and rituximab in the second-line setting for follicular lymphoma,” Cyrus M. Khan, MD, commented. “Any improvement that prolongs the duration of response [DOR] and delays [therapy] in the third line is great. Toxicity wise, it’s [tolerable]. [Additionally], we always add rituximab to anything we do in follicular lymphoma later and we never exactly know what the response will be for [a given] patient. In the case that there is a detriment where rituximab isn’t as efficacious, at least you’re also blocking CD19 and getting the benefit there.”

In the phase 1/2 EPCORE NHL-2 trial (NCT04663347), investigators combined lenalido- mide and rituximab with the CD20- and CD3-directed bispecific antibody epcoritamab-bysp (Epkinly) in patients with R/R, grade I to IIIA, stage II to IV, CD20-positive follicular lymphoma who received
at least 1 prior treatment including an anti-CD20 antibody.1

The primary end point was objective response rate (ORR) per Lugano criteria; key secondary end points included CR rate, DOR, PFS, and OS. Epcoritamab monotherapy previously received FDA approval in June 2024 for the treatment of adult patients following at least 2 prior lines of systemic therapy.

Findings from arm 2 of EPCORE NHL-2 (n=111) demonstrated that the ORR among patients who received the combination was 96%, including a CR rate of 87%.3 The median DOR and median duration of CR were both not reached (NR; 95% CI, 26.3 months-NR); notably deep CRs were also reported regardless of high-risk features. The median PFS was NR (95% CI, 27.6 months-NR) and the median OS was NR (95% CI, NR-NR).

“[In terms of the inMIND vs EPCORE NHL-2 regimens], I am pro-choice; the more options we have for our patients, the better,” Sehn said. “We don’t have head-to-head comparison data, but we do know that not every patient may be appropriate for a bispespecific [antibody] so [you] have the choice of something [else] that can be easily given in a community center.

We know that bispecifics are making their way into the community, but it’s still a bit challenging for all physicians to administer them. The data [from EPCORE NHL-2] are very promising but we need to see randomized data to [better understand] the toxicity profile.”

“I would like to see how these 2 regimens are doing with longer follow-up. We need to remind ourselves, both trials are reporting data at ASH at a time when most patients are still on treatment, or [are] close to the end of treatment,” Paolo Strati, MD, added. “I’m more optimistic about EPCORE NHL-2 [because] the CR rates are very impressive.”

CAR T-Cell Agents Lead the Way in the Third Line and Beyond

When it is necessary for a patient to undergo a third line of treatment, or additional lines, there are several available options, including bispecific antibodies.

The space has also seen the approval of multiple CAR T-cell agents in recent years, providing additional options for patients. “Looking at claims data, we were scratching our heads a couple of years ago in [third-line] follicular lymphoma. There was ibrutinib [Imbruvica] utilization; we know that zanubrutinib [Brukinsa] plus obinutuzumab [Gazyva] has some data in the [R/R] space and is moving into randomized trials. We [also have] tazemetostat [Tazverik], our EZH2 inhibitor. We’ve grown up with this drug and learned that you can probably use it [in patients] without an EZH2 mutation and in a wild-type population,” Matthew Lunning, DO, FACP, outlined.

Mosunetuzumab-axgb (Lunsumio), a bispecific CD20-directed CD3 T-cell engager, represents an FDA-approved option for adult patients with R/R follicular lymphoma following at least 2 prior lines of systemic therapy, earning accelerated approval from the agency in this population in December 2022.5 The regulatory decision was supported by findings from the phase 1/2 GO29781 trial (NCT02500407). The study enrolled patients with grade I to IIIA R/R follicular lymphoma who received at least 2 prior therapies including an anti-CD20 antibody and an alkylator.6

Updated data from GO29781 presented during ASH 2024 showed that the investigator-assessed ORR in the overall population (n=90) was 77.8%, with a CR rate of 60.0%.6 The median DOR was 46.4 months
(95% CI, 18.7-NE) and the median duration of CR was 51.8 months (95% CI, 46.4-NE). The median PFS was 24.0 months (95% CI, 12.0-NE) and the median OS was NR (95% CI, NE-NE).

“I’ve used both [epcoritamab and mosunetuzumab] in the third line,” Tara Graff, DO, said. “Mosunetuzumab is fixed-duration, which is wonderful for our patients, but it’s also intravenous [IV]. So, if you have a patient who doesn’t want to get an IV put in, they might be better suited for subcutaneous- ous delivery like we have with epcoritamab. A patient who [doesn’t want to stop] treatment might be better suited for epcoritamab and someone who wants to get off therapy as quickly as possible [could be treated with] mosunetuzumab. Options are good, but none of us can say, ‘I’m only going to use this or I’m only going to use that.’”

Presently, there are 3 CAR T-cell therapies approved by the FDA in R/R follicular lymphoma: axi-cel, tisa-cel, and liso-cel.7-9 The approvals were supported by findings from the phase 2 ZUMA-5 (NCT03105336), ELARA (NCT03568461), and TRANSCEND FL (NCT04245839) studies, respectively. During ASH 2024, investigators presented updated findings from the 3 trials.

ZUMA-5 enrolled patients with R/R grade I to IIIA follicular lymphoma or MZL following at least 2 prior lines of therapy, including an anti-CD20 monoclonal antibody combined with an alkylating agent (Figure).10 The primary end point was ORR per Lugano criteria; key secondary end points included CR rate, DOR, PFS, OS, and safety.

At a median follow-up of 65.7 months (range, 56.7-81.4), updated findings from the 5-year analysis of the follicular lymphoma cohort of ZUMA-5 (n=127) showed that the ORR was 94% with a 79% CR rate. The median PFS was 57.3 months (95% CI, 30.9-NE) and the 60-month PFS rate was 49.8% (95% CI, 39.8%-59.0%). The median OS was NR (95% CI, NE-NE) and the 60-month OS rate was 68.9% (95% CI, 59.8%-76.3%).

“I believe we still need longer-follow up [to say that the ZUMA-5 regimen is curative]. Follicular lymphoma is a very different disease compared with diffuse large B-cell lymphoma and I’m not ready to say yet that we are curing [patients with] follicular lymphoma,” Khan noted.

ELARA enrolled adult patients with grade I to IIIA R/R follicular lymphoma who received no prior anti-CD19 therapy or allogeneic hematopoietic cell transplant.11 The primary end point was the CR rate per independent review committee. Secondary end points included DOR, PFS, OS, and safety.

At a median follow-up of 53 months (range, 46-62), the CR rate in the total efficacy population was 69.1% (95% CI, 58.8%-78.3%); notably, high-risk disease characteristics such as double-refractory disease, bulky disease, disease progression within 24 months, and high Follicular Lymphoma International Prognostic Index score, were not associated with infe-
rior overall or CR rates. The median PFS was 53.3 months (95% CI, 18.2-NE) and the 48-month PFS rate was 50.2%. The median OS was NR and the 48-month OS rate was 79.3%.

TRANSCEND FL enrolled adult patients with R/R follicular lymphoma who received a prior anti-CD20 monoclonal antibody in combination with an alkylator.12 The study included cohorts of patients in the second, third, and fourth line and beyond of treatment. The primary end point was ORR per Lugano criteria; secondary end points included CR rate, DOR, PFS, OS, and safety.

At a median follow-up of 23.1 months, the median DOR among patients in at least the third line of treatment (n = 100) was NR (95% CI, 30.85-NR) and the 24-month DOR rate was 74.6% (95% CI, 64.8%-82.1%). At a median follow-up of 24.0 months, the median PFS in these patients (n = 103) was NR (95% CI, 31.8-NR) and the 24-month PFS rate was 72.5% (95% CI, 62.7%- 80.1%). At a median follow-up of 29.5 months, the median OS in this group was NR (95% CI, NR-NR) and the 24-month OS rate was 88.2% (95% CI, 80.1%-93.1%).

“Liso-cel has an attractive toxicity profile compared with axi-cel, but, just as we said for the bispecifics, it’s not going to be one size fits all,” Sehn said. “We don’t have head-to- head comparisons. All [the CAR T-cell agents] are very effective in follicular lymphoma. What perhaps stands out are the slight differences in the toxicity profiles, and that’s where a patient-selected approach makes the most sense in terms of pushing CAR T-cell therapy forward into the second-line setting.”

The panelists concluded their discussion by highlighting findings from a matching-adjusted indirect comparison presented during ASH 2024 that aimed to compare the safety and efficacy of liso-cel vs axi-cel and tisa-cel in the third line of treatment or later.13

Following match adjustment and weighting, patients treated in TRANSCEND FL (effective sample size [ESS] = 19.9) experi- enced an ORR of 99.9% vs 94.2% (relative risk [RR], 1.06; 95% CI, 1.00-1.12) among patients who were treated in ZUMA-5 (n = 86); the respective CR rates were 99.2% vs 79.1% (RR, 1.25; 95% CI, 1.09-1.45). After match adjustment and weighting, patients treated in TRANSCEND FL (ESS = 19.0) achieved an ORR of 93.6% vs 86.2% among patients treated in ELARA (n = 94; RR, 1.09; 95% CI, 0.95-1.25); the CR rates were 91.9% vs 69.1%, respectively (RR, 1.33; 95% CI, 1.06- 1.68). Additional findings from the analysis demonstrated that the PFS and DOR of the 3 treatments were determined to be largely similar.

“[Analyses such as this] shine a light on where we should [consider] whether a trial should be done or not,” Khan said. “It gives us some information and a thought process, but I don’t believe that we need to make big decisions [based on this analysis]. Matching-adjusted indirect comparisons have gained popularity over the past few years in all kinds of situations. It goes [to the point] that we have a lot of treatments in every disease now. Head-to-head [comparisons] are very difficult, and we should take it with a grain of salt whenever we are making decisions based on these.”

References

1. Falchi L, Balari AS, Leppä S, et al. Fixed-duration epcoritamab + R2 drives deep and durable responses in patients with relapsed or refractory follicular lymphoma: 2-year follow-up from arm 2 of the Epcore NHL-2 trial. Blood. 2024;144(suppl 1):342. doi:10.1182/blood-2024-200262
2. FDA approves lenalidomide for follicular and marginal zone lymphoma. FDA. May 28, 2019. Accessed January 27, 2025. bit.ly/44XvZFt
3. Sehn LH, Luminari S, Scholz CW, et al. Tafasitamab plus lenalidomide and rituximab for relapsed or refractory follicular lymphoma: results from a phase 3 study (inMIND). Blood. 2024;144(suppl 2):LBA-1. doi:10.1182/blood-2024-212970
4. FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory follicular lymphoma. FDA. June 26, 2024. Accessed January 27, 2025. bit.ly/4gz1MlX
5. FDA grants accelerated approval to mosunetuzumab-axgb for relapsed or refractory follicular lymphoma. FDA. Updated December 23, 2022. Accessed January 27, 2025. bit. ly/4jVyelC
6. Shadman M, Bartlett NL, Matasar M, et al. Mosunetuzumab continues to demonstrate clinically meaningful outcomes in patients with relapsed and/or refractory follicular lymphoma after ≥2 prior therapies including those with a history of POD24: 4-year follow-up of a pivotal phase II study. Blood. 2024;144(suppl 1):4407. doi:10.1182/ blood-2024-197897
7. FDA grants accelerated approval to axicabtagene ciloleucel for relapsed or refractory follicular lymphoma. FDA. Updated March 8, 2021. Accessed January 27, 2025. bit.ly/4jMVBO9
8. FDA approves tisagenlecleucel for relapsed or refractory follicular lymphoma. FDA. Updated May 31, 2022. Accessed January 27, 2025. bit.ly/4jQYzRH
9. FDA grants accelerated approval to lisocabtagene maraleucel for follicular lymphoma. FDA. May 15, 2024. Accessed January 27, 2025. bit.ly/4jVaQ7B
10. Neelapu SS, Chavez JC, Sehgal AR, et al. 5-year follow-up analysis from ZUMA-5: a phase 2 trial of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory indolent non-Hodgkin lymphoma. Blood. 2024;144(suppl 1):864. doi:10.1182/blood-2024-194627
11. Thieblemont C, Dreyling M, Dickinson MJ, et al. Clinical outcomes of patients with high-risk relapsed/refractory follicular lymphoma treated with tisagenlecleucel: phase 2 ELARA
    4-year update. Blood. 2024;144(suppl 1):3034. doi:10.1182/ blood-2024-201730
12. Nastoupil L, Dahiya S, Palomba ML, et al. Lisocabtagene maraleucel (liso-cel) in patients (pts) with relapsed or refractory (R/R) follicular lymphoma (FL): Transcend FL 2-year follow-up. Blood. 2024;144(suppl 1):4387. doi:10.1182/ blood-2024-198509
13. Boardman AP, Reguera JL, Spin P, et al. Matching-adjusted indirect comparison (MAIC) of efficacy and safety outcomes for lisocabtagene maraleucel (liso-cel) versus axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) for the treatment of third-line or later (3l+) relapsed or refractory (R/R) follicular lymphoma (FL). Blood. 2024;144(suppl 1):3028. doi:10.1182/blood-2024-197948