Pivotal Trials Address Pressing Questions With CAR T-Cell Therapy in B-Cell Lymphoma

Nilanjan Ghosh MD, PhD

Now that chimeric antigen receptor (CAR) T-cell therapies have established a foothold in B-cell lymphoma, ongoing trials are dedicated to understanding whether this modality can be utilized earlier in the treatment paradigm and whether it can be beneficial in patients who are ineligible for transplant, according to Nilanjan Ghosh, MD, PhD.

Three phase 3 randomized clinical trials—TRANSFORM (NCT03575351), BELINDA (NCT03570892), and ZUMA-7 (NCT03391466)—are evaluating the efficacy of different CAR T-cell products following 1 line of prior treatment vs standard-of-care transplant. The primary end point of all these trials is event-free survival, and the results are eagerly anticipated, according to Ghosh.

The open-label PILOT study (NCT03483103) is the first to examine the safety and efficacy of lisocabtagene maraleucel (liso-cel; Breyanzi) as a second-line treatment in patients with aggressive, relapsed/refractory large B-cell lymphoma not eligible for transplant. Results presented during the 2020 European Hematology Association (EHA) Congress showed that the CAR T-cell therapy elicited a high objective response rate of 89% and all participants achieved an early objective response by day 30. The Kaplan-Meierestimated probability of continued response at 3 months was 63% (95% CI, 37%-81%); at 6 months, this rate was estimated to be 53% (95% CI, 25%-75%).

“This is not a phase 3 randomized study, but the results are very encouraging. [However], we do not have long-term data, so we will just have to wait and see how that pans out,” Ghosh said. “[Liso-cel] appears to be a very viable option. With most treatments in oncology, if something is very effective in [later lines], when you move it up, it will continue to be effective. The next step may be [to see whether] you could integrate it into frontline therapy, at least for high-risk patients. That is the future.”

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on CAR T-cell therapy, Ghosh, who is director of the lymphoma program and a physician with Levine Cancer Institute, Atrium Health, highlighted progress made with CAR T-cell therapies in B-cell lymphoma and some ongoing trials generating interest in the field.

OncLive^®: What are some of the key advances made with CAR T-cell therapies in B-cell lymphoma?

Ghosh: Many new products have emerged in the B-cell lymphoma [paradigm]. The recent advances have been [primarily] in the cellular therapy space; specifically, CAR T-cell therapy. Axicabtagene ciloleucel [axi-cel; Yescarta] has already been approved for diffuse large B-cell lymphoma [DLBCL] in the relapsed/refractory setting after 2 prior lines of therapy. Similarly, tisagenlecleucel [tisa-cel; Kymriah] and liso-cel were also approved for use in relapsed/refractory DLBCL and other aggressive [subtypes], such as primary mediastinal and high-grade B-cell lymphoma.

Very recently, axi-cel was also approved for patients with follicular lymphoma after 2 prior lines of therapy, based on results from the ZUMA-5 study [NCT03105336]; that is really the first approval for a CAR T-cell therapy in [this disease]. The results of the study are fantastic— more than 90% of patients responded [to treatment]. The follow-up [for the trial] is not that long, but the responses are quite durable.

In mantle cell lymphoma [MCL], we have an approval for the CAR T-cell therapy brexucabtagene autoleucel [Tecartus]. Liso-cel has good activity in that space, as well. In all CD19-expressing B-cell lymphomas, we are starting to see an expansion of CD19-targeted CAR T-cell products. The responses appear to be high in patients who have relapsed or refractory disease.

In aggressive B-cell lymphomas, we also have the advantage [of having longer follow-up], and we are seeing many durable responses. We are starting to see that in MCL, and time will tell how durable [this product] is in follicular lymphoma. Overall, there is going to be a significant uptick in the utilization of CAR T-cell therapies in B-cell lymphoma.

What trials are examining the use of this modality after 1 prior line of treatment in DLBCL?

[One important question is], is it appropriate to use CAR T-cell therapy at that point, or [should we] do salvage therapy followed by transplant? That is being tested in 3 large, phase 3 studies with 3 types of CAR T-cell products: TRANSFORM, BELINDA, and ZUMA-7. In these trials, the control arm is autologous transplant, and the experimental arm is CAR T-cell therapy. The results [of these trials] have not read out yet, so we will have to wait and see.

The PILOT trial is examining whether CAR T-cell therapy can be offered to patients who are not candidates for transplant. Could you speak to this research and the findings reported thus far?

In the PILOT study, liso-cel was tested after 1 line of therapy. [This trial enrolled] patients who are primary refractory to frontline therapy or who have relapsed after frontline therapy. For that study, [investigators] looked at patients who were not great candidates for transplant. [Patients] only needed to meet 1 of the criteria [outlined]. Patients could be 70 [years] or older or [have] a performance status of 2; they could have impaired pulmonary function, where their diffusion lung capacity for carbon monoxide could be 60% or lower, or their cardiac function could be impaired to some extent. Their renal function could be impaired, but they needed to still have creatinine clearance above 30 mL/min.

If they had any of these criteria, they could have enrolled on the study and [received] liso-cel as their second-line therapy. This study has completed accrual, but the [most recently] presented results were revealed at the 2020 EHA Congress. [Results indicated] a very nice response rate [with the CAR T-cell therapy]; we saw an 89% overall response rate, with a 56% complete response [CR] rate. Also, some partial responses converted into CRs. Mostly, the CRs appear to be durable. The [rates of] cytokine release syndrome [CRS] and neurotoxicity are very low, as has been the story with liso-cel. [The product] has clearly demonstrated very good activity in the second-line setting.

What questions need to be addressed with long-term data from this trial?

The main thing [that we want to see from] the long-term data is the durability of the response [achieved with these products]. Fortunately, we know from many of the CAR T-cell therapy studies that patients who [achieve a CR] and maintain that CR maybe for the first 3 or 6 months seem to continue to be in long-term remission for years. We do not have 5- or 10-year data, but it does appear that the curves plateau after the first 6 months or, at the most, 1 year. In some cases, [this can happen] maybe even at 3 months. Fortunately, if the read out is quick, and you get a sense of how many patients are in a CR at 6 months, that may give you an idea about the durability of the response. Of course, 3 years or 5 years is when you actually prove your hypothesis; however, if you go by what has been seen, we can get a good idea [of whether these] patients are going to do well in the long run.

In terms of toxicity, most [effects occur] early. For example, CRS and neurotoxicity occur early [on in treatment], and they do not seem to linger over a long period of time. What may linger is hypogammaglobulinemia; that may persist for a long time. Cytopenias sometimes persist for longer than what people may expect. Outside of those [effects], there is a need to follow patients who receive CAR T-cell therapy over a long period of time because they are receiving genetically modified T cells. [We need to watch for] any long-term effects, like secondary malignancies and others.

Reference

1. Lisocabtagene maraleucel (JCAR017) as second-line therapy (TRANSCEND-PILOT-017006). ClinicalTrials.gov. Updated February 8, 2021. Accessed April 7, 2021. https://clinicaltrials.gov/ct2/show/NCT03483103