CAR T Not a Clear Winner

NEW YORK — In a three-way debate on whether to prioritize chimeric antigen receptor (CAR) T-cell therapy, bispecific antibodies (BsAbs), or one of the novel oral targeted therapies for relapsed/refractory follicular lymphoma (R/R FL), no expert conceded.

Acknowledging that hers was the weakest position, even the specialist who defended novel targeted therapies mounted a staunch defense of real-world patients being treated outside of tertiary centers.

“I was told by many of my colleagues that I got the short end of the stick in this debate, but I am actually here to convince everybody that targeted therapies continue to play an important role, despite the fact that they are the least sexy of these treatment options,” said Joanna Rhodes, MD, director of the Lymphoma Program at Rutgers Cancer Institute, Hoboken, New Jersey.

Targeted Therapies Still Relevant to Advanced FL

Although even the newest or coming targeted therapies, such as the EZH2 inhibitor tazemetostat or next-generation Bruton tyrosine kinase inhibitors, are not likely to achieve the deep responses and long-term progression-free survival possible with BsAbs or CAR T-cell therapy, the sustained disease control they offer for many patients with R/R FL is not trivial, according to Rhodes.

“The majority of these [advanced follicular lymphoma] patients are being managed in the community,” Rhodes argued at the 2024 Lymphoma, Leukemia, & Myeloma Congress. Access to tertiary centers where the most advanced therapies are available in some cases might not even be feasible. 

Moreover, there are barriers to CAR T cells and BsAbs even at centers where these are available, Rhodes said. On a long list of barriers, lack of caregiver support is an example of one common disqualification at her own institution. 

The experience with CAR T cells in R/R FL has been relatively short, so Rhodes used data on CAR T cells for B-cell lymphoma to make her point. It is not just that the proportion of eligible patients is limited. 

“The majority of B-cell lymphoma patients who are eligible for CAR T cells are not getting them,” she said. “It will be the same for FL.”

In other words, Rhodes indicated that it is premature to count out targeted oral agents or lenalidomide despite the excitement surrounding BsAbs and CAR T cells. The targeted agents and immunomodulatory drugs remain appropriate choices for patients unable or unwilling to travel to tertiary centers for treatment, for frail patients, and for well-informed patients who understand their options and still consider better tolerated therapies to be more consistent with their perception of an adequate risk-benefit ratio. 

BsAbs Vie With CAR T Cells in Advanced FL

Hers might be a valid summary, but it did not derail arguments about whether CAR T-cell therapy should be prioritized over BsAbs or the other way around for patients who are candidates for both. 

There are two BsAbs currently approved for R/R FL: glofitamab and mosunetuzumab. More are coming, according to Nina Wagner-Johnston, MD, director of hematologic malignancies at Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland. She provided several reasons why BsAbs might be considered before CAR T-cell therapies in at least some individuals. 

“The biggest advantage is that these therapies…are off the shelf,” she said. This avoids the delay of T-cell manufacturing, the potential need for bridging therapies, and the need for conditioning regimens. With more experience, BsAbs offer the potential for treatment even in a community-practice setting, particularly for maintenance dosing.

“I do think this is a safe treatment in patients who are elderly or unfit,” Wagner-Johnston said, suggesting she tends to lean toward prioritizing BsAbs over CAR T cells when the ability to tolerate an aggressive strategy is a concern. She specified that these drugs are associated with a low relative incidence of grade 3 or higher cytokine release syndrome or immune effector cell–associated neurotoxicity syndrome, and faster B-cell aplasia recovery. 

The third participant in the debate, who described the efficacy and safety of the three currently approved CAR T-cell therapies for R/R FL, did not agree with this characterization. Daniel Landsburg, MD, associate professor of clinical medicine at the University of Pennsylvania, Philadelphia, acknowledged that BsAb agents have an important role to play in the advanced FL setting, but he thinks that CAR T-cell therapies should be prioritized in at least some patients. 

In particular, he would not rule out CAR T-cell therapy in patients with comorbidities or other characteristics that raise questions about fitness for aggressive treatment. 

“In fact, you might want to treat a frail patient just one time with CAR T-cell therapy rather than dose after dose with a bispecific drug,” he said. 

No Data to Compare BsAbs and CAR T-Cells Directly

Both agreed that there have been no trials directly comparing a BsAb therapy vs CAR T cells, so there is no definitive answer, and Landsburg was reluctant to take a hard line on reserving BsAbs until after CAR T-cell therapy has been tried.

“Because BsAbs and CAR Ts are approved in the third-line setting, you might consider debulking a patient getting ready for a CAR T with a bispecific,” Landsburg said. However, he acknowledged that the next step becomes complex if patients achieved a complete response after just a few BsAb doses.

“Do you stop what is already working?” Landsburg asked rhetorically, suggesting that the best way forward is not always clear.

For R/R FL, currently there are three approved products: axicabtagene ciloleucel (Yescarta), tisagenlecleucel (Kymriah), and lisocabtagene maraleucel (Breyanzi). The entry criteria and design of the three pivotal trials differed, so their specific indications vary. Looking across the trials, Landsburg suggested that there might be differences in activity as defined by objective response rates or risk for cytokine release syndrome, but these remain theoretical without head-to-head comparisons.

“My suspicion is we are going to see very similar — quote, unquote — long-term survival curves for patients treated with any of these therapies,” he said, noting that progression-free survival at 3 years has been in the vicinity of 50% for the trials that have had long enough follow-up to judge.

Rather than trying to pick the best agent, he suggested that it makes more sense now to concentrate on strategies to improve response irrespective of CAR T-cell product; these include paying attention to total metabolic tumor volume at the time of infusion, optimizing bridging therapies, and thinking about T-cell fitness, which might be impaired in some patients by recent exposure to bendamustine.

Overall, with multiple ongoing studies with both CAR T-cell therapies and BsAbs in R/R FL — as well with targeted small-molecule agents and immunomodulatory drugs — all of the debate participants acknowledged that choices in R/R FL will evolve. 

“I actually think that combinations will be the future,” Wagner-Johnston said. Singling out tazemetostat and a BsAb and one approach that seems promising, she also predicted that some of the therapies in advanced disease are likely to be moved forward to earlier stages of FL therapy.

Rhodes reported ties with AbbVie, AstraZeneca, ADC Therapeutics, BeiGene, Bristol Myers Squibb, Epizyme, Genentech, Genmab, Janssen, Loxo Oncology, MorphoSys, Pharmacyclics, and Pfizer. Wagner-Johnston disclosed relationships with Cuno Science, Dava Oncology, Epizyme, Grünenthal, Karyopharm, and Seagen. Landsburg reported ties with ADC Therapeutics, Calithera, Curis, Epizyme, Karyopharm, MorphoSys, and Novartis.

Ted Bosworth is a medical journalist based in New York City.