Standards of Care and Novel Therapies Converge to Propel Advances in Follicular Lymphoma

Christopher R. Flowers, MD, MS

Although the follicular lymphoma (FL) treatment armamentarium has expanded to include classes of drugs such as bispecific antibodies and CAR T-cell therapies, future directions in this arena are predicated on the identification of optimal treatment sequencing and the incorporation of individual patient preferences.

In an OncLive® Scientific Interchange and Workshop, Christopher R. Flowers, MD, MS, of the Department of Lymphoma – Myeloma in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, moderated a discussion about current and emerging therapeutic advances in FL.¹

Unmet Needs in FL

Flowers began the discussion by explaining that although patients with FL often respond to therapies, their disease will eventually recur. “Thinking about what the right therapy is to give to the right patient at the right time and how to sequence those therapies among patients has been much more challenging because of [FL’s] indolent behavior and because patients respond to many different kinds of therapies,” Flowers emphasized.

Additionally, Flowers explained that patients with FL often exhibit treatment resistance, even after prolonged periods of survival. Therefore, these patients need effective therapies beyond those they previously received. “[Rituximab (Rituxan)] still works a little bit, but probably not very much in that patient population,” Flowers said.

Paolo Strati, MD, of MD Anderson, added that although the bispecific antibody mosunetuzumab-axgb (Lunsumio) and the CAR T-cell therapies axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) have changed the FL treatment paradigm, the optimal sequencing of these agents for patients with relapsed/refractory disease remains unknown. “These are older patients,” he added. “[They have] health conditions where it may be hard to utilize either bispecific or cellular therapies. Trying to understand how to sequence those is still an unmet need in FL.”

In the phase 3 AUGMENT trial (NCT01938001), patients with indolent non-Hodgkin lymphoma (NHL) were randomly assigned to receive rituximab plus either lenalidomide (Revlimid) or placebo.² The median progression-free survival (PFS) was 39.4 months (95% CI, 22.9–not reached) with rituximab plus lenalidomide vs 14.1 months (95% CI, 11.4-16.7) with rituximab plus placebo. Additionally, the complete response (CR) rate was 34% (95% CI, 27%-41%) in the investigational arm vs 18% (95% CI, 13%-25%) in the placebo arm. Strati emphasized that increasing the efficacy of immunotherapy may translate to an overall survival benefit for the relapsed/refractory indolent NHL population.

Furthermore, Hun Ju Lee, MD, of MD Anderson, expressed the need for biomarkers that can guide treatment decisions or watch-and-wait strategies.¹ Sameh Gaballa, MD, of Moffitt Cancer Center in Tampa, Florida, concurred, noting the importance of being able to predict how patients may respond to each agent in the array of available therapies. He explained that predictive biomarkers could also inform treatment sequencing and ensure patients receive the most effective and tolerable therapies.

Current Treatment Arena: Frontline Approaches in FL

The faculty then spotlighted treatment considerations in the frontline setting for patients with FL, noting the various available therapeutic options, including bendamustine plus rituximab, lenalidomide plus rituximab, and obinutuzumab (Gazyva)-based regimens. Flowers alluded to the phase 3 RELEVANCE trial (NCT01476787), which evaluated lenalidomide plus rituximab vs rituximab plus chemotherapy in patients with previously untreated, advanced FL.³ At a median follow-up of 72 months, the 6-year PFS rate was 60% in the lenalidomide arm and 59% in the chemotherapy arm (HR, 1.03; 95% CI, 0.84-1.27). Although this trial did not meet its primary end point, Flowers said, “[the data] demonstrate equivalence at least in terms of the kinds of expected outcomes that we see with a chemotherapy-free regimen of rituximab and lenalidomide compared with rituximab [plus] chemotherapy–based approaches.”¹

Nathan Fowler, MD, of MD Anderson, delved into the patient and disease factors that inform his rationale for choosing single-agent rituximab or lenalidomide plus rituximab, stating that he prefers to use ruxolitinib monotherapy in patients whose disease has grown for years and has reached a critical mass. Conversely, in patients with bulky disease or high tumor burden per Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria, he explained that he tends to choose rituximab plus lenalidomide.

Dai Chihara, MD, PhD, of MD Anderson, spoke about his strategy of enrolling eligible patients to first-line clinical trials, when available, as these trials offer treatments such as novel immunotherapy combinations. However, he also noted the importance of prioritizing patient preferences and tailoring treatments to their individual needs. “If they’re not interested [in clinical trials] or if they’re out of state participating in the clinic trial, I [will] discuss different options,” he said. “I try to follow what patients want. If they’re [a] teacher [who] needs to deal with kids all the time, I try to avoid chemotherapy if possible because they get viral infections all the time.”

Nirav N. Shah, MD, of the Medical College of Wisconsin in Milwaukee, lent insight to the patient characteristics that inform his decisions regarding the use of frontline maintenance therapy. He said patients who achieve a partial response (PR) with first-line therapy may benefit from this approach. “I worry that those patients are more likely to relapse sooner or younger,” he stated. “I think the first duration of response is most important.”

Strati mentioned that before the publication of the phase 3 FOLL12 trial (NCT02063685), in which patients with treatment-naive FL were randomly assigned to rituximab maintenance or a response-adapted postinduction approach,4 he recommended rituximab maintenance only in patients who achieved a PR after frontline chemoimmunotherapy. However, the FOLL12 data showed that at a median follow-up of 53 months (range, 1-92), the 3-year PFS rate was 86% in the rituximab maintenance arm vs 72% in the response-adapted postinduction arm. “Independent from COVID-19, I tend to use maintenance very rarely and mostly in patients where I want to prolong PFS because I wouldn’t know what to do if they relapse, like patients who have other cancers who are getting chemotherapy for other reasons or patients who are too overall compromised for me to be able to safely select the next line of treatment,” Strati summarized.¹

Additionally, Shah emphasized that patient age factors into his maintenance therapy recommendations. “If [a patient is] older, I worry [about] prolonged maintenance,” he noted, “If anything, COVID-19 taught me that not living with B cells is not as wonderful as we all think, and so I say, if [a patient is 75 years of age and has] a CR, let’s observe because we have a lot of therapies available.”

Current Second-Line Treatments and Investigational Combinations

Flowers spotlighted data from the phase 3 SYMPHONY-1 trial (NCT04224493) with the EZH2 inhibitor tazemetostat (Tazverik). In the phase 1b portion of this trial, the overall response rate (ORR) was 97% in the EZH2-mutant arm and 100% in the EZH2 wild-type arm.⁵

“It seems to me that [tazemetostat is] certainly a reasonable option for these patients,” Vicki A. Morrison, MD, of the University of Minnesota in Minneapolis, stated.¹ “It seems it’s easy to administer…and well tolerated.”

Matthew Lunning, DO, FACP, of University of Nebraska Medical Center in Omaha, expanded on the safety profile of the agent. “Although it has a clean adverse effect [AE] profile, with a lot of our oral drugs over time we figure out the annoying AEs that are grade [1/2] that are patient limiting…. One of them that’s common…is dysgeusia. [It’s] something that we don’t often talk about, but the patients talk about all the time.”

Regarding treatment sequencing for patients with relapsed/refractory FL, Lee mentioned that “it’s very controversial [whether] you start [with lenalidomide plus rituximab or rituximab plus chemotherapy]. [Or] you could do the opposite. If you got [rituximab plus chemotherapy up-front], you get [lenalidomide plus rituximab].” Ultimately, he said he considers patient preference and aims to deliver personalized approaches whenever possible.

Turning to newer data, Flowers highlighted findings from the phase 2 ROSEWOOD trial (NCT03332017), which compared the BTK inhibitor zanubrutinib (Brukinsa) with obinutuzumab in patients with relapsed/refractory FL.6 ROSEWOOD met its primary end point, with zanubrutinib eliciting an ORR of 69% vs 46% with obinutuzumab (P = .001). The CR rates were 39% vs 19% with zanubrutinib and obinutuzumab, respectively, and the 18-month duration of response (DOR) rates were 69% and 42%, respectively. Additionally, the median PFS was 28.0 months with zanubrutinib vs 10.4 months with obinutuzumab (HR, 0.50; 95% CI, 0.33-0.75; P < .001).

“I’m just amazed at over 20, 30 years how much some of the frontline and second-line therapies have not changed in this disease,” Morrison commented.1 “We need more drugs to use in the second- or third-line settings before we might go to bispecific antibodies or CAR T-cell therapy. [Zanubrutinib] is among other [drugs] that might be options in that setting.”

“Overall, my personal opinion is that BTK inhibitors are better tolerated than lenalidomide in terms of AEs [and] toxicities [such as] neutropenia,” Gaballa noted. “My feeling about FL is it’s a long game, and the goal is to keep [patients] alive. [The ROSEWOOD regimen] is an exciting regimen.”

Shah expressed the need for longer follow-up for the ROSEWOOD trial. “The big question is going to be: With longer follow-up, how is this going to stand? What’s the DOR going to be? Is everybody going to start relapsing 2, 3, or 4 years out? That’s going to be the main question.”

References

1. Current and emerging therapeutic advances in follicular lymphoma. Presented at: OncLive® Scientific Interchange and Workshop. September 8, 2023. Live.
2. Leonard JP, Trneny M, Izutsu K, et al. AUGMENT: a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol. 2019;37(14):1188-1199. doi:10.1200.JCO.19.00010
3. Morschhauser F, Nastoupil L, Feugier P, et al. Six-year results from RELEVANCE: lenalidomide plus rituximab (R2) versus rituximab maintenance in untreated advanced follicular lymphoma. J Clin Oncol. 2022;40(28):3239-3245. doi:10.1200/JCO.22.00843
4. Luminari S, Manni M, Galimberti S, et al. Response-adapted postinduction strategy in patients with advanced-stage follicular lymphoma: the FOLL12 study. J Clin Oncol. 2022;40(7):729-739. doi:10.1200/JCO.21.01234
5. Batlevi CL, Salles G, Park SI, et al. Tazemetostat in combination with lenalidomide and rituximab in patients with relapsed/refractory follicular lymphoma: phase 1b results of Symphony-1. Blood. 2022;140(suppl_1):2296-2298. doi:10.1182/blood-2022-166991
6. Zinzani PL, Mayer J, Flowers CR, et al. ROSEWOOD: a phase II randomized study of zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy in patients with relapsed or refractory follicular lymphoma. J Clin Oncol. Published online July 28, 2023.