Behind the FDA Approval: Liso-Cel for R/R Large B-Cell Lymphoma

Manali Kamdar, MD

For adult patients with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma (LBCL), and follicular lymphoma grade 3B, lisocabtagene maraleucel (liso-cel; Breyanzi) is now an FDA approved treatment option.¹

The FDA granted approval to the therapy in June 2022 based on findings from the phase 3 TRANSFORM trial (NCT03575351) and the phase 2 PILOT trial (NCT03483103). In both studies, liso-cel demonstrated improved efficacy with tolerable safety in both transplant-eligible and transplant-ineligible patients relapsed/refractory LBCL.^2,3These combined results proved that liso-cel could fill unmet medical needs in the field.

“The key takeaways are the fact that for patients who are transplant-eligible relapsed/refractory diffuse large B-cell lymphoma that has recurred within a year after receiving primary treatment or have not responded to primary treatment at all, their survival is extremely dismal. Typically, the standard of care is certainly something that can help patients, but only a quarter of transplant-eligible patients derive long-term durable benefit. So, this huge unmet need,” said Manali Kamdar, MD, in an interview with Targeted Oncology™.

“So, I think liso-cel, based on these 2 studies filled in this unmet need not just in the transplant-eligible but also in the transplant-ineligible space for patients with aggressive large B-cell lymphoma that have relapsed or refractory disease after failure of 1 line of treatment,” added Kamdar, the clinical director of Lymphoma Services at the University of Colorado Medicine.

Under the FDA indication, liso-cel is approved to treat patients with refractory disease with first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy. The indication also includes patients with refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant due to comorbidities or age. According to Kamdar, it is the broadest FDA approval of a CAR T-cell therapy for patients with relapsed/refractory aggressive LBCL.

During the interview, Kamdar, discussed the recent FDA approval of liso-cel for the treatment of patients with relapsed or refractory large B-cell lymphoma, and how community oncologists should approach patient referrals and post-CAR T-cell therapy care.

TARGETED ONCOLOGY: Can you discuss the mechanism of action of liso-cel? How is liso-cel different from other CAR T-cell therapies?

Kamdar: Liso-cel is an autologous CD19-directed, defined composition 41BB CAR T-cell product. It differs in a way that it's administered at equal target doses of CD8- and CD4-positive CAR T cells. It also differs from the other products with respect to its co-stimulatory domain, which is called 41BB, which enhances its efficacy and improves the persistence of these cells.

This CAR T-cell product was granted FDA approval based on 2 clinical trials. What are your key takeaways from the research?

We are very delighted at this point, based on the FDA approval for liso-cel, and at this point, I do have to say it probably has the broadest approval within the CAR T-cell therapy space for patients with relapsed or refractory aggressive large B-cell lymphoma. And it comes secondary to the TRANSFORM study, which is a phase 3 pivotal, randomized study. The study compared patients who have high-risk relapsed diffuse large B -cell lymphoma and are transplant eligible. The patients were randomized to either getting is salvage chemo, which has been the standard of care for nearly three decades, followed by a transplant versus liso-cel.

The second study where the approval came from is for transplant-ineligible patients based on the PILOT study. This was a phase 2 study that was done in patients that were transplant-ineligible and have relapsed diffuse large B-cell lymphoma after 1 line of treatment.

For me the key takeaways are the fact that for patients who are transplant-eligible relapsed/refractory diffuse large B-cell lymphoma that has recurred within a year after receiving primary treatment, or have not responded to primary treatment at all, their survival is extremely dismal. Typically, the standard of care is certainly something that can help patients, but only a quarter of transplant-eligible patients derive long-term durable benefit. So, this huge unmet need.

The TRANSFORM study demonstrated that liso-cel as compared to the standard of care was statistically significant and clinically meaningful with respect to its benefit, and it met its primary end point, which is the event-free survival. It nearly quadrupled on the liso-cel ell arm with an event-free survival of 10 months versus a dismal of only 2 months on the standard of care arm. It also did meet some of its key secondary end points for example, complete response rate and progression-free survival.

Very interestingly, the overall survival data although immature, appears to favor liso-cel. So, the follow-up of this study in the primary analysis is awaited. And then, in the PILOT study, what was tested was the other unmet need, which is patients who are transplant ineligible. They also have relapsed/refractory diffuse large B-cell lymphoma after failure of 1 line of treatment. There is no standard of care for those patients, and usually, the survival is extremely dismal. In the PILOT study, they demonstrated that the overall response rate was high at 80% with a complete response rate of nearly 54%. And in patients who especially achieved the complete remission, their median duration of response was very high. So, I think liso-cel, based on these 2 studies filled in this unmet need not just in the transplant eligible but also in the transplant-ineligible space for patients with aggressive large B-cell lymphoma that have relapsed or refractory disease after failure of 1 line of treatment.

What can you tell us about the safety profile of this agent?

I have to say as one of the investigators on the study, the safety of liso-cel, of course, has been established in the third-line setting, but in the second-line setting, in the TRANSFORM as well as in the PILOT study.

I do have to say it was safe, and the toxicity was very manageable. With regards to unique toxicities that are notable in patients who receive CAR T-cell therapy, for example, cytokine release or CRS, or neurological events, they were generally low grade, and they were mostly resolved very quickly with standard protocols. Any-grade CRS was reported in less than half of the patients with grade 3 CRS reported in only 1.3% of patients. Similarly, any-grade neurological events were reported in 27% of patients. However, grade 3 was only seen in 7% of patients.

It is extremely important to note that there were absolutely no events of grade 4 or grade 5 CRS or neurological events that were reported on these clinical trials. The study results underscore the efficacy as well as the safety of this product. With liso-cel, we are able to deliver this product in the outpatient setting, and not really having to admit patients is a huge win for patients, not only overall but also from the quality-of-life standpoint. And in terms of the patient-reported outcomes in the TRANSFORM study, it was shown that patients who received liso-cel had a better quality of life as compared to patients who receive standard of care.

What tips can you provide to oncologists who may be referring their first patient for treatment with liso-cel? How should they approach this decision?

Given the favorable decision that the FDA granted liso-cel at this time for patients who have transplant-eligible relapsed/refractory diffuse large B-cell or patients who are transplant-ineligible with the relapsed or refractory diffuse large B-cell lymphoma.

It's important to bring us as academic investigators sooner into the consult. For example, if patients have failed 1 line of treatment within the first 12 months of treatment, and they are transplant eligible, or for patients who are just not simply responding to our drug, whether they are transplant eligible or not. I think bringing the patient to an academic center in order to be able to get them to liso-cel key. This primarily stems from the fact that any CAR T-cell product at this point will need manufacturing and the manufacturing takes at least 2 and a half weeks.

So, in order to make sure that we also make sure that the cadence of the lymphoma is managed while the CAR T cell therapies being manufactured is very important, and optimal therapy will then be delivered to the patient if we get into the referral program sooner than later. So, I think getting in touch with an academic oncologist who does CAR T-cell therapy is going to be important for referring oncologists who have patients who have relapsed/refractory diffuse large B-cell lymphoma after failure of 1 line of treatment.

What advice do you have on post-CAR T cancer care?

I think CAR T-cell therapy at this point in time, we now have an experience of about 5 years. So, we do know of some of the short-term, mid-term, and long-term effects that can happen with CAR T-cell therapy. But as we treat these patients in our centers, and then refer them back to the referring oncologist, it's important to be mindful that patients who go through CAR T-cell therapy could be at a higher-risk of infection.

For the first 6 to 12 months of treatment, they have what we call B-cell aplasia. As a result, we need to check the IgG, because they could be at risk of hypogammaglobulinemia. With liso-cel, the incidence was less, but that can certainly happen. We preemptively give them intravenous immunoglobulin if they fall under a certain number in order to mitigate infections that can happen. And besides that, sometimes patients can have protracted cytopenias. So, that also will need to be managed in terms of making sure that the counts are checked every so often. Usually, I think within the first 3 months, all of these side effects are completely resolved, but then there is a handful of patients who can experience cytopenias and hypogammaglobulinemia. And they need to be watched with the mindful and close eye.

How do you think this second CAR T-cell approval will impact the treatment paradigm?

I think we are living in a time where we have a lot of drug approvals for patients with relapsed/refractory large B-cell lymphoma. Probably the biggest impact that has been made with CAR T-cell therapy is the liso-cel was initially approved in the third-line setting and now it's approved in the second-line setting, which only goes to show the power of CAR T-cell therapy. With a safe and efficacious product like liso-cel, I think bringing it to the second-line setting will hopefully reduce patient morbidity and improve patient outcomes. We also have the hope that we don't have to use a lot of other therapies downstream. So, I think it will certainly impact the large B-cell lymphoma treatment landscape. But it will impact it favorably.

_REFERENCES:

_{1. U.S. FDA approves Bristol Myers Squibb’s CAR t cell therapy Breyanzi® for relapsed or refractory large b-cell lymphoma after one prior therapy. News release. June 24, 2022. Accessed June 30, 2022. https://bit.ly/3HPA7O3}

_{2. Kamdar M, Solomon SR, Arnason J, et al. GS2-02 lisocabtagene maraleucel versus standard of care (salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation) as second-line therapy in relapsed/refractory LBCL: TRANSFORM results. Paper presented by Jeremy Abramson at: 48th European Society for Blood and Marrow Transplantation Annual Meeting; March 19-23, 2022; virtual. Accessed March 21, 2022. https://bit.ly/36vjLv7}

_{3. Sehgal A, Hoda D, Riedell P, et al. Lisocabtagene maraleucel (liso-cel) as second-line (2L) therapy for R/R large B-cell lymphoma (LBCL) in patients (pt) not intended for HSCT: Primary analysis from the phase 2 PILOT study. J Clin Oncol. 2022;40(suppl 16):7062. doi: 10.1200/JCO.2022.40.16_suppl.7062}