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

Nilanjan Ghosh MD, PhD

Now that CAR T-cell therapies have exploded in the B-cell lymphoma paradigm, ongoing trials are dedicated to understanding whether this modality can be utilized after 1 prior line of treatment and whether it can be beneficial in patients who are ineligible for transplant, according to Nilanjan Ghosh MD, PhD.

Three randomized clinical trials—the phase 3 TRANSFORM study (NCT03575351), the phase 3 BELINDA study (NCT03570892), and the phase 3 ZUMA-7 study (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 2020 European Hematology Association 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-Meier–estimated probability of continued response at 3 months was 63% (95% CI, 37%-81%); at 6 month 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 Perspective in Cancer webinar on CAR T-Cell Therapies, 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 follicular lymphoma after 2 prior lines of therapy, based on results from the ZUMA-5 study; that is really the first approval for a CAR T-cell therapy in [this disease]. The results of the study are fantastic—over 90% of patients responded [to treatment]. The follow-up [for the trial] is not that long, but the responses are quite durable.

We also know that in mantle cell lymphoma [MCL], we have an approval for the CAR T-cell therapy brexucabtagene autoleucel [Tecartus; formerly KTE-X19]. 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 studies with 3 different types of CAR T-cell products: the phase 3 TRANSFORM study, the phase 3 BELINDA study, and the phase 3 ZUMA-7 study. 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 aged 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 have [received] liso-cel as their second-line therapy. This study has completed accrual, but the [most recently] presented results were revealed at the2020 European Hematology Association 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