How Will New Immunotherapies Fit Into the Treatment Landscape of Follicular Lymphoma?

The last two decades have witnessed numerous advances in the treatment of follicular lymphoma (FL), including anti-CD20 antibodies, the immunomodulator lenalidomide (Revlimid®; Bristol Myers Squibb), and targeted therapies, such as EZH2 inhibitors, which have resulted in longer periods of progression-free survival, more options in the relapsed/refractory setting, and, in some cases, better overall survival for patients with FL.^1,2 Despite these improvements, FL remains a generally incurable disease, toxicities with available treatments can be limiting, and most patient deaths remain lymphoma-related.³ 

A new generation of therapies leverage patients’ own T cells to destroy B-cell lymphoma, and they have shown promising efficacy in FL. Chimeric antigen receptor (CAR) T-cell therapy, using genetically engineered autologous T-cells to target CD19 on lymphoma cells, is now approved in the third line for relapsed and refractory (R/R) FL.^4,5 Bispecific antibodies, which simultaneously engage CD20 on lymphoma cells and CD3 on T cells to stimulate cytotoxic T-cell responses, have generated high response rates in trials and are expected to be incorporated into FL treatment in the near future.⁶

How we use these agents in concert with other efficacious approaches to optimize patient outcomes will be a unique opportunity and challenge.

CAR T Cells Have Expanded Treatment Options

Axicabtagene ciloleucel (axi-cel, Yescarta®; Kite Pharmaceuticals) was the first FDA-approved CAR T-cell agent for FL in 2021, based on results of the phase 2 ZUMA-5 trial (NCT03105336).⁴ In patients with R/R FL and at least 2 prior lines of therapy, overall response rate (ORR) was 94%, with 79% achieving complete response (CR); 65% of patients remained progression-free at 18 months. Following axi-cel, tisagenlecleucel (tisa-cel, Kymriah®; Novartis) was approved in March 2022 for R/R FL based on the ELARA trial (NCT03568461), with an ORR of 86%, a CR rate of 69%, and 12-month progression-free survival (PFS) of 67%.⁵

Both trials evaluated CAR T cells in heavily pretreated patients with FL, with a median of 3 prior lines of therapy for axi-cel and 4 for tisa-cel, and most patients had disease that was refractory to the last line of therapy. Although cross-trial comparisons have significant limitations, 1 apparent difference was in rates of toxicity. Cytokine release syndrome (CRS) events were less common in tisa-cel (48%; grade 3/4, 0%) compared with axi-cel recipients (82%; grade 3/4, 7%). Similarly, neurologic events were rarer and less severe with tisa-cel (37%; grade 3/4, 3%) than in axi-cel recipients (56%; grade 3/4, 15%).

Both agents offer unprecedented rates and durability of responses in heavily R/R FL, though challenges remain regarding toxicities, the logistics of treatment (including both cost and the time required for CAR T manufacturing), and the potential need for bridging therapy, along with limited access to treatment.

Bispecific Antibodies on the Horizon

Bispecific antibodies facilitate T-cell engagement with lymphoma cells to promote cytotoxic killing. Recent studies evaluating bispecific antibodies that bind CD20 on lymphoma cells and CD3 on T cells have shown significant promise across non–Hodgkin lymphomas, with exciting results in FL. In a phase 2 study (NCT02500407) of the bispecific mosunetuzumab in R/R FL with at least 2 prior lines of therapy, ORR was 80% and the CR rate was 60%, with median PFS of 18 months.⁶ Similar to CAR T, CRS and neurotoxicity were observed, but to a lesser extent; 43% had grade 1/2 CRS (grade 3 in 1%), and 5% had a neurotoxicity event, with 0% suffering grade 3/4 neurotoxicity. Based on these results, mosunetuzumab was recently approved by the European Commission and granted priority review by the FDA, with a decision on approval expected before the end of 2022.

With New Choices in Third-Line Therapy, How Should We Choose and Sequence Therapy?

At this point, systemic therapy options in the first and second lines of treatment for FL remain unaffected, with chemoimmunotherapy combining anti-CD20 therapies with bendamustine (Bendeka®; Teva Pharmaceuticals), CHOP (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone), or CVP (cyclophosphamide, vincristine sulfate, and prednisone), along with lenalidomide-rituximab (Rituxan®; Genentech, Biogen) and rituximab monotherapy, remaining. Our choices in the third-line setting have markedly expanded with these T-cell–directed therapies along with targeted agents.

It’s unlikely that one option will prove superior, and each approach provides specific advantages and disadvantages. For patients able to tolerate more intensive therapy, CAR T offers the most robust data for high response rates and durable responses. The toxicity profiles of axi-cel and tisa-cel may be distinct, and tisa-cel may be favored in patients where CRS or ICANs (immune effector cell–associated neurotoxicity syndrome) may be less well tolerated.

Bispecific antibodies such as mosunetuzumab offer advantages in that they are available off the shelf, have shown high efficacy, and seem to have lower toxicity profile than CAR T-cell therapy, though with less long-term follow-up; they also require repeated administration, as opposed to the “one-shot” approach of CAR T cells. In patients desiring a minimally toxic regimen and particularly in those with EZH2 mutations, tazemetostat (Tazverik®; Epizyme) has demonstrated efficacy with minimal toxicity.⁷ Most PI3K inhibitors have been withdrawn from the market due to concerns over safety and toxicity, and as such, these alternative therapeutic options are welcome.⁸ Non–cross-resistant chemoimmunotherapy, potentially with autologous transplant consolidation, remains an option for select patients as well.

What About Other Indolent Lymphomas, Such As Marginal Zone Leukemia (MZL)?

Clinical trials evaluating CAR T-cell and bispecific therapies have included few patients with marginal zone lymphoma. Most data come from the ZUMA-5 clinical trial, in which 25 patients with MZL were recruited, and 24 received treatment.⁴ Responses were seen in 85% of patients, with 55% achieving CR, and a median PFS of 12.7 months. Overall, data suggested that CAR T-cell therapy has high activity in MZL and is compendium-listed by the NCCN (National Comprehensive Cancer Network) in the third line or later for MZL. It is not clear at this point whether the inherent biology of MZL, or other factors such as older age with MZL patients, contributed to the lower response rates and higher rates of toxicity as compared with FL.

The other T-cell based therapies have little data in MZL. The ELARA trial (NCT03568461) evaluating tisagenlecleucel did not include patients with MZL. The TRANSCEND FL study (NCT04245839), evaluating lisocabtagene maraleucel (Breyanzi®; Bristol Myers Squibb), included patients with FL and MZL, but data from this trial have not been released. Odronextamab, another CD20-directed bispecific antibody, was evaluated in 6 patients with MZL, with 4 having a response and 2 achieving CR.⁹ For mosunetuzumab, only 2 patients with MZL were evaluated, with both having stable disease as best response.¹⁰

What Do We Know, and Not Know, About These Therapies?

Significant questions remain about CAR T cells and bispecifics in indolent lymphoma. With less than 2 years of follow-up reported, we know little about the durability of responses, an important consideration in FL. We also don’t know if these approaches will offer a functional “cure” for FL. Only time will answer these questions.

The sequencing of these therapies is also being explored. There is a biological rationale for the use of T-cell–directed therapies prior to cytotoxic and lymphodepleting agents, when patients may have better T-cell health and function.¹¹ Trials of mosunetuzumab and epcoritamab in untreated patients, and those with R/R FL after 1 line of treatment, including a phase 3 trial of mosunetuzumab plus lenalidomide vs rituximab-lenalidomide, are underway, and will give us more information on the activity of these agents with less prior treatment.

Likewise, particularly with bispecific antibodies, combination approaches may offer greater efficacy than single-agent therapy. Lenalidomide is a rational agent in combination with bispecifics, as it has been shown to reverse FL-induced T-cell immune synapse dysfunction and restore T-cell antitumor activity.12 Early results of a phase 1/2 study of epcoritamab combined with lenalidomide in 30 patients with R/R FL showed a response rate of 100% and a CR rate of 93% in 27 evaluable patients.¹³ Ongoing studies are evaluating combinations with lenalidomide, polatuzumab vedotin (Polivy®; Genentech), and investigational immune checkpoint blockade agents.

Increasing the accessibility of these therapies will also be a major challenge. Most CAR T-cell and bispecific therapy administration is currently performed at tertiary care centers. Particularly with bispecific agents available off the shelf, it is likely that these treatments could be more broadly accessible. Building familiarity with the use of these drugs, and management of the associated toxicities, is essential.

Likewise, expanding access to clinical trials and standard-of-care options to minorities and socioeconomically underrepresented groups is desperately needed; the benefits of these promising therapies will not be realized without appropriate access for everyone.¹⁴ Programs to expand both access to clinical trials and access to novel therapies across racial, socioeconomic, gender, and geographic boundaries are needed.

Conclusions

T-cell directed therapies already have a foothold in indolent lymphoma therapy, and we anticipate further developments in the near future. The CAR T-cell therapies axi-cel and tisa-cel are already available in the third-line setting for R/R FL, and the bispecific therapy mosunetuzumab is expected to be approved in the third-line setting soon. Choosing a third-line treatment option in FL among CAR T, bispecifics, targeted therapies, and chemoimmunotherapy will require a personalized approach, balancing individual patient priorities, depth and durability of responses, toxicity, and accessibility. Unfortunately, there are limited data to guide the use of these therapies in MZL, though axicabtagene ciloleucel has demonstrated efficacy and can be considered.

Future directions for these treatments include potential use earlier in treatment or as combination therapy (particularly with bispecific treatments), identifying patients who will benefit most from treatment, and minimizing the costs of therapy while maximizing accessibility.

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