Liso-cel Approval Provides Earlier, Expanded Access to CAR T-cell Therapy in Second-line LBCL

Second-line lisocabtagene maraleucel (liso-cel; Breyanzi) provides an earlier CAR T-cell treatment option that improves survival outcomes and produces a manageable safety profile in patients with relapsed/refractory large B-cell lymphoma (LBCL), including those who are older and have comorbidities, according to Nilanjan Ghosh, MD, PhD.

On June 24, 2022, the FDA approved liso-cel in the second line for patients with relapsed/refractory LBCL, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal LBCL, follicular lymphoma grade 3B, and high-grade B-cell lymphoma. This approval was supported by data from the phase 3 TRANSFORM trial (NCT03575351) and the phase 2 TRANSCEND-PILOT-017006 study (NCT03483103).

“Liso-cel is a fantastic option, because it has a great efficacy profile and is also a safe product amongst the available CAR T-cell products, with a relatively low incidence of cytokine release syndrome [CRS] and neurological events [NEs], the majority of which are low grade,” Ghosh said.

In an interview with OncLive^®, Ghosh, director of the Lymphoma Program at the Levine Cancer Institute of Atrium Health, discussed the significance of the liso-cel approval in this patient population. He also highlighted how liso-cel will influence current treatment sequencing, which patients might derive the most benefit from this therapy, and the adverse effects (AEs) to be aware of and try to mitigate when prescribing liso-cel.

OncLive^®: What is the significance of the FDA approval of liso-cel in the second-line setting for patients with relapsed/refractory LBCL?

Ghosh: This approval is highly significant. The majority of patients with primary refractory DLBCL and early relapsed DLBCL do not derive benefit from standard-of-care [SOC] salvage chemotherapy followed by ASCT [autologous stem cell transplant], [which had been the best option until now].

The data from the TRANSFORM study showed liso-cel to be superior to high-dose salvage chemotherapy and ASCT. This approval will allow earlier access to CAR T-cell therapy for this group of patients.

How do you see the approval affecting current practice patterns, both for academic centers, and as well as for your community partners?

Most patients with LBCL receive frontline therapy in the community setting. In addition to making our community aware of this indication, we need to educate our community about the time it takes to receive CAR T-cell therapy. The process includes many steps, such as gaining financial clearance and setting a date for T-cell collection, or leukapheresis. This date must be acceptable to both the institution [providing the treatment] and the company manufacturing the CAR T cells. [We also need to factor in] the time spent manufacturing the CAR T cells, often known as the vein-to-vein time. This entire process can take 6 weeks or more.

We often focus on just the vein-to-vein time, but there are many other steps even before leukapheresis. These patients are also refractory or have early relapsed disease that must be controlled while they are waiting to receive CAR T-cell therapy. Early referral to a CAR T-cell center is crucial to get the process going while discussing with the referring physician ways and means to control the disease in the interim. Those might include strategies like bridging therapy, which was allowed on the TRANSFORM study.

In some patients, liso-cel may end up being a third-line therapy, despite its indication as a second-line therapy, because you may have to give another therapy to control the disease while the patients are waiting to receive CAR T cells. That discussion would best be done with the treating center and the referring physician, because some treatments can be toxic to lymphocytes, and you may want to avoid those kinds of treatments prior to collecting the lymphocytes. At the same time, we must make sure we control the disease so the patients can receive the treatment they may benefit from in the future.

Now that CAR T-cell therapy is becoming more prominent, more real-world datasets are showing that patients outside of the strict clinical trial criteria also benefit from this therapy. Which factors, such as comorbidities and patient fitness, would clinicians need to weigh when deciding when to administer liso-cel? 

Many factors must be taken into account before giving liso-cel. We look at the ECOG performance status [PS], as well as cardiac function and renal function.

Looking at comorbidities, fortunately, the TRANSCEND-PILOT-017006 trial included patients with comorbidities who were not considered good candidates for ASCT. To enroll in the study, the investigators needed to verify that the patients were not good candidates for transplant. [They also needed to meet at least 1 of the criteria], which included being over 70 years of age, having impaired renal function, having impaired cardiac function, or having a decrease in [diffusing capacity of the lungs for carbon monoxide], which is reflective of pulmonary function. The investigators also looked at hepatic function.

The outcomes of this study were good. The bottom line is that patients who are going to receive liso-cel need not only be candidates you would otherwise consider for ASCT. The eligibility for liso-cel is much broader than standard transplant eligibility in terms of age, comorbidities, and disease status. That is the most important thing. A patient who is older, has some comorbidities, and has relapsed or refractory LBCL can still benefit from liso-cel with high efficacy and low toxicity, which is what liso-cel offers in this patient population.

What specific data were seen in the TRANSFORM trial regarding liso-cel vs high-dose salvage chemotherapy and ASCT, and what is the significance of these findings?

TRANSFORM was a randomized study of patients with DLBCL not otherwise specified, which includes de novo DLBCL and those who have transformed from indolent non-Hodgkin lymphoma; high-grade B cell lymphoma, which includes double-hit and triple-hit lymphoma; follicular lymphoma grade 3B; primary mediastinal B-cell lymphoma; and T-cell or histiocyte-rich DLBCL. Eligible patients needed to have either developed refractory disease from frontline therapy or relapsed within 12 months after frontline therapy. The frontline therapy should have included an anthracycline and a CD20 agent, which is the SOC. In addition, these patients should have been otherwise considered to be eligible for ASCT and had an ECOG PS of 0 to 1.

Eligible patients underwent leukapheresis and then were randomized to receive liso-cel or SOC, which was salvage chemotherapy followed by ASCT for those who responded to salvage chemotherapy. Importantly, this study included crossover from the SOC arm to the liso-cel arm. This was allowed for those who failed to respond to SOC by 9 weeks post-randomization, those who progressed at any time, or those who started a new antineoplastic therapy after transplant.

The primary end point was event-free survival [EFS]. Events were defined as death from any cause, progressive disease, failure to achieve complete response [CR] or partial response by 9 weeks post randomization, or the start of an antineoplastic therapy, whichever occurred first. The median EFS with liso-cel was 10.1 months compared with 2.3 months with SOC. At 12 months, the EFS rates were 44.5% with liso-cel and 23.7% with SOC. That was a significant margin of benefit.

In terms of responses, in this recent population, we’re most interested in CR. A total of 66% of the patients who received liso-cel achieved a CR compared with 39% of those who received SOC.

Progression-free survival [PFS] was also a secondary end point. The median PFS was 14.8 months with liso-cel and 5.7 months with SOC. Efficacy-wise, liso-cel hit all the marks. Overall survival [OS] data is maturing, so we’ll need some longer follow-up, but we are starting to see trends in the right direction.

We have to remember that this study included crossover. Of the 91 patients in the SOC arm, 50 [crossed over to receive] CAR T-cell therapy with liso-cel. Those data will affect the OS data, but even so, we’re starting to see some separation of the OS curves in the TRANSFORM study.

What additional data from the TRANSCEND-PILOT-017006 trial stood out to you?

The TRANSCEND-PILOT-017006 study is a little different because it’s a single-arm study. It was not intended for patients who would be otherwise considered transplant candidates. These patients did not need to relapse within 1 year [of frontline therapy], and they could have relapsed or refractory disease. A total of 25% of patients had late relapses as well, which was not the case in TRANSFORM. Otherwise, they all had 1 prior line of therapy, [like in TRANSFORM].

This is also a second-line study but in a different population of patients. This was an elderly population. Compared with the TRANSFORM study, the median age in the TRANSCEND-PILOT-017006 study was 74 years, with the oldest patient being 84 years of age. In total, 33% of patients in this study had double-hit and triple-hit disease, which I want to highlight because this is the toughest group of patients to treat. A total of 54% of the patients had primary refractory disease, [and many patients had comorbidities].

Additionally, 44% of the patients had an HCT-CI [Hematopoietic Cell Transplantation-Specific Comorbidity Index] score of 3 or more. We don’t know the relevance [of this score] for CAR T-cell therapy, but outcomes are typically poor in patients who have an HCT-CI score of 3 or higher who undergo allogeneic transplant or ASCT.

[In this trial], the overall response rate was great, at 80%, with 54% achieving CR. Responses were seen in all prespecified subgroups, including patients with high-risk features, with no notable differences in efficacy or safety outcomes based on HCT-CI score. Investigators did separate out patients who had scores of less than 3 vs 3 or higher, and they didn’t see any differences.

The median duration of response [DOR] was [11.2 months in patients with an HCT-CI score under 3, and not reached in patients with an HCT-CI score of 3 or higher]. In patients who achieved a CR, the median DOR was 21.7 months.

The median PFS was [7.4 months in patients with an HCT-CI score under 3, and NR in patients with an HCT-CI score of 3 or higher]. The median OS was not reached.

Importantly, 32.8% of the patients were monitored as outpatients in this study, and 35% of those needed to be hospitalized for concerns of CRS and neurotoxicity after receiving liso-cel. Most of the patients who received liso-cel as outpatients did not need hospitalization within 3 days of receiving it. These results support liso-cel as a second-line treatment in patients with LBCL in whom transplant is not intended.

What AEs associated with liso-cel should clinicians and patients be aware of, and what interventional strategies can be used to manage these toxicities?

In general, the acute AEs that occur with any CAR T-cell therapy, but which are much lower with liso-cel, are CRS and NEs. These occur immediately post-CAR T-cell therapy, within days.

However, the incidence of CRS and NEs was low in both [TRANSFORM and TRANSCEND-PILOT-017006]. Most CRS events were grade 1 or grade 2. In total, 1 patient in each study had grade 3 CRS, and there were no instances of grade 4 CRS [in either study].

The incidence of neurotoxicity was also quite low. [A total of 4% of patients in the TRANSFORM study and 5% of patients in the TRANSCEND-PILOT-017006 study experienced] grade 3 neurotoxicity. Most of the neurotoxicity that was seen was grade 1 or grade 2. Importantly, the utilization of tocilizumab [Actemra] and steroids was also low [in both trials].

However, there are other AEs which we need to monitor. For example, by the time a patient is out of that CRS and neurotoxicity window and thinking of going back to their referring physician, they may still [be at risk for AEs such as] prolonged cytopenias, [which some patients exhibited in these trials]. In the [TRANSFORM] study, prolonged cytopenias were defined as [grade 3 cytopenias that persisted] at day 35 or beyond. [In the TRANSCEND-PILOT-017006 study, prolonged cytopenias were defined as grade 3 or higher cytopenias that persisted at day 29 or beyond.]

We should also monitor for hypogammaglobulinemia. This is important because if a patient has hypogammaglobulinemia or lymphopenia, and neutropenia, they are more prone to infection. Preventing infection, providing supportive care, and giving treatment medications [as early as possible] is important, and monitoring AEs is crucial.

What else would you like to mention about treatment evolution in the field of LBCL?

The field of LBCL has exploded with new treatments over the past few years, including what we saw recently in the frontline setting. CAR T-cell therapy, in general, is a huge advancement within this field.

Having said that, it’s important to be aware of and monitor the AEs. A question that comes up is: How accessible are CAR T-cell therapies going to be? We need to work as a community to make them more accessible to patients, cut down the time from when we first consider CAR T-cell therapy to when we deliver it, and make that process more efficient, so more patients can benefit from it.

We also need to be aware of the many other treatments that have come out in the space, such as bispecific antibodies that are in development and antibody-drug conjugates. Over the next few years, we need to figure out how to sequence these therapies so that we can maximize the benefits and help our patients who still have unmet needs. We do have to recognize that even though CAR T-cell therapy has excellent outcomes, there are many patients who are still refractory to CAR T-cell therapy and relapse after CAR T-cell therapy. [We need to find] the best way to sequence the other treatments that are out there to help these patients. That’s an area of active investigation.

I hope we are in a much better place in the years to come. However, we’ve made huge strides in the past several years, and it’s been great to be a part of that research.