Lisocabtagene Maraleucel (Breyanzi) FDA Approval: 10 Stats

Lisocabtagene Maraleucel has been approved by the FDA for the second-line treatment of large B cell lymphoma LBCL

Lisocabtagene Maraleucel Key Statistics:

• 65% risk reduction of event-free survival in the Lisocabtagene Maraleucel arm.

• 10.1 months (95% confidence interval: 6.1, not evaluable) estimated median event-free survival compared to 2.3 months (95% confidence interval: 2.2, 4.3). 

• 59% risk reduction in progression-free survival in the Lisocabtagene Maraleucel arm compared to standard of care.

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• Lisocabtagene Maraleucel is not approved to treat people with primary central nervous system lymphoma.

• Hazard ratio (HR) of 0.34 (95% CI:0.22, 0.52; p-value0.0001), event-free survival was substantially longer in the Lisocabtagene Maraleucel arm.

• 45% (95% CI: 29, 59) and 24% (95% CI: 14, 35) in the usual treatment predicted 1-year event-free survival in the Lisocabtagene Maraleucel arm.

• The suggested dose of lisocabtagene maraleucel for second-line therapy is 90 to 110 106 CAR-positive T cells with a 1:1 CD4:CD8 ratio.

• Cytokine release syndrome occurred in 45% of patients (Grade 3 or higher, 1.3%) in investigations with Lisocabtagene Maraleucel as second-line therapy for large B-cell lymphoma, while neurologic toxicities occurred in 27% (Grade 3, 7%).

• 184 patients were randomly assigned to either a single infusion of Lisocabtagene Maraleucel after fludarabine and cyclophosphamide lymphodepleting chemotherapy or second-line standard therapy, which included three cycles of chemoimmunotherapy followed by high-dose therapy and autologous HSCT in patients who achieved CR or partial response (PR).

• 33% to 38% of serious adverse events occurred in patients.

So, as the community here is very well aware, patients with large B-cell lymphoma whose diseases are primary refractory LBCL, meaning they have never responded to frontline chemotherapy (systemic therapy) or relapsed within 12 months of initial chemo and immunotherapy, have exceptionally poor outcomes. Salvage immunochemotherapy followed by high-dose chemotherapy and hematopoietic stem cell transplantation has been the standard of care.

Second-line treatment for transplant-eligible, high-risk, large B-cell lymphoma for nearly three decades. Unfortunately, though, only about a quarter of these transplant-eligible patients with relapse-refractory disease achieve durable long-term remission. So, clearly, this is an unmet need. And this is where the pivotal Phase III TRANSFORM study was uniquely designed.

What is Lisocabtagene Maraleucel used for?

Whereas in Lisocabtagene Maraleucel, a CAR T construct was designed to challenge the current standard of care and thus address this unmet need. So, the TRANSFORM study enrolled patients whose disease was primary refractory LBCL or relapsed 12 months or less after frontline chemotherapy and compared Lisocabtagene Maraleucel with the standard of care, which consisted of 3 cycles of salvage immunochemotherapy followed by high-dose chemo and hematopoietic stem cell transplantation.

The Primary Endpoint for Patients with large B Cell Lymphoma LBCL

The primary endpoint of this study was event-free survival, and the key secondary endpoints will be complete response rate progression, free survival, and overall survival. Nearly 75% of patients in both arms did not have a response to first-line treatment or had primary refractory disease. The study met its primary endpoint with the superiority of Lisocabtagene Maraleucel over the standard of care.

Lisocabtagene Maraleucel Clinical Trial Data

Lisocabtagene Maraleucel demonstrated a 65% risk reduction of event-free survival events with the median EF. Or event-free survival of 10.1 months, compared with only 2.3 months in the standard of care arm, a higher percentage of patients achieved a complete response with Lisocabtagene Maraleucel compared with standard of care Lisocabtagene Maraleucel, thus led to a 59% risk reduction of progression-free survival compared to standard of care.

Lisocabtagene Maraleucel Overall Survival Data

Overall survival data at this point is certainly immature for this analysis, but it’s extremely interesting to see that the curves are showing a trend favoring mature data, which continues to be awaited and will be presented very shortly at the next few meetings. Lisocabtagene Maraleucel also showed an extremely manageable safety profile with very low rates of severe cytokine release syndrome and neurological events.

No new safety signals were observed with Lisocabtagene Maraleucel in the second line setting. And with regards to the low incidence of grade 3 CAR T-cell therapy toxicities that we talked about, which are CRS and neurologic toxicities events, it is extremely important to also remember that there were absolutely no grade 4 or grade 5 events that were reported.

Overall, these adverse events were manageable with treatments as per standard practice. So overall, this study, which compared with the standard of care, Lisocabtagene Maraleucel demonstrated a highly statistically significant and clinically meaningful improvement in terms of the primary, as well as key secondary endpoints. It reduced the risk of EFS by 65% achieved the 29, 27% higher complete response rate.

And it reduced the risk of progression-free survival events by 59%. No new safety signals will be observed with Lisocabtagene Maraleucel in the second line setting grade 3 CRS and neurological events, which generally low with no grade 4 or 5 events that were reported. Thus Lisocabtagene Maraleucel showed superiority over auto transplant as a new standard of care in the second-line treatment for patients with relapse refractory Large B-Cell Lymphoma.

What are the most common questions that my colleagues asked me about this study? I think it’s important to remember that these patients are extremely high risk. Especially as the overall outcomes for these patients remain exceptionally poor. Thus, it’s really important to get them to a CAR T center.

The minute the patients get identified with primary refractory disease or a disease that relapses within 12 months of treatment. Important to also remember that within the study, besides just Diffuse Large B-Cell Lymphoma NOS, high-grade B-Cell lymphoma with double. Gene rearrangements, T-cell Rich B-Cell Lymphoma, primary media style, B-Cell Lymphoma, Follicular Lymphoma grade 3B as well as Transformed Lymphomas from indolent lymphoma histologies were also included.

Patients with CNS involvement were also included. In terms of some of the other questions that my colleagues pose, where was this infusion given? So, yes, there were sometimes patients admitted to the hospital, but there was also a cohort of patients within this study where Lisocabtagene Maraleucel could be administered in an outpatient setting.

With regards to toxicities, a lot of colleagues ask me, how was the construct tolerated in this transplant-eligible population? The cohort construct with lysis with the Lisocabtagene Maraleucel was exceptionally well tolerated. There were no grade 4 or grade 5 cytokine release syndrome or neurological events that were reported.

I do believe that this data will affect clinicians as of today. And it’s really important to highlight that Breyanzi or Lisocabtagene Maraleucel is now approved for patients with high risk relapsed Large B-Cell Lymphoma were transplant eligible in the second-line setting, as well as based on the pilot study that looked at second-line options for relapsed, diffused, Large B-Cell Lymphoma patients.

This study Lisocabtagene Maraleucel is now approved for transplant-ineligible patients in the second line setting.

So thus, as you can see, it has definitely challenged the age-old standard of autotransplant. So, it will absolutely affect clinicians in terms of their daily practice because when they do see patients with primary refractory A Large B-Cell Lymphoma or Large B-Cell Lymphoma that have relapsed within 12 months of frontline, chemo, immunotherapy, or patients who are transplant ineligible, who have relapsed after frontline chemo, immunotherapy.

At this point in time, CAR T-cell therapy with Lisocabtagene Maraleucel is now FDA approved. It’s thus really important for them to refer these patients to the CAR T center sites so as to expeditiously walk these patients and be able to get them CAR T-cell therapy.

In terms of the next step for this research, obviously, it is heartening to see that after a very long time. We now have something better as compared to autotransplant. Something that is definitely more efficacious in terms of toxicity, but absolutely manageable. So, in terms of the next steps for research, I would say that it is.

It is probably going to be helpful to see how CAR T-cell therapy compares to auto transplant in patients who have a relapse of diffused Large B-Cell Lymphoma. That’s more than AR. Would CAR T-cell therapy beat auto transplant in that setting? Given how efficacious CAR T-cell therapy is and just how oncology research evolves as it keeps being brought into the earlier settings, it would be interesting to see what CAR T-cell therapy would do for patients in the frontline setting.

So, I think these are some of the next steps that we all, as clinical investigators, are really curious to see and excited to see what this field of CAR T-cell therapy unravels for our patients with Large B-Cell Lymphoma, as well as many other subtypes of Lymphoma, like relapsed or refractory LBCL.

So, with regards to this data, what else do medical oncologists and hematologists need to know about this data? I think there are a few things that I do need to highlight based on the transform study, which is a positive study. It is important to remember that patients with high-risk relapse, Large B-Cell Lymphoma, meaning patients who have relapsed after.

Frontline chemotherapy within 12 months, or having just not responded to frontline chemoimmunotherapy, Lisocabtagene Maraleucel was statistically significant, clinically meaningful, and superior compared to an autotransplant. Thus, at this point, it remains the standard of care. It is the new standard of care for patients in the second-line setting who are transplanted.

It is also important to remember that based on the pilot data, which showed some excellent, which showed excellent efficacy and manageable safety for patients who are transplant ineligible with relapse or refractory Large B-Cell Lymphoma, as their outcomes are exceptionally poor. What they did demonstrate in the pilot study.

Was with Lisocabtagene Maraleucel, this cohort of patients had an excellent response rate as well as durability with regards to remission and a very manageable toxicity profile. So, it’s really important to highlight that it’s pertinent that medical oncologists and hematologists in the community identify these patients and refer them to the CAR T-cell therapy site soon.

Lisocabtagene Maraleucel Eligibility For TRANSCEND-PILOT-017006 Trial

It is important to highlight that this is an extremely efficacious and manageable (with regards to toxicity) construct. Even if there is a question about eligibility, it never hurts to send them over to CAR T-cell therapy sites to assess if they could be potential candidates to get Lisocabtagene Maraleucel, given how efficacious and tolerable it is.

It could be given in the outpatient setting. Thus, it definitely plays a huge role with regards to the quality of life for our patients, as it’s obviously much, much better preferred to stay in the outpatient setting versus being admitted to the inpatient setting for days. It is important to highlight that with regards to subtypes of lymphoma, diffuse, Large B-Cell Lymphoma, High-Grade B-Cell Lymphoma, and T-cell Rich B-Cell Lymphoma.

Primary Media Cell B-Cell Lymphoma, Follicular Lymphoma grade 3B, and Large B-Cell Lymphoma with CNS involvement. There were also subtypes that were included in the transform study. And I think at this point in time, stay tuned for more updates with regards to the primary analysis of this study. As crossover was permitted, and despite that, the overall survival data at this point, albeit immature, looks like it is favoring license.

So, I would say these would be the key themes to highlight in terms of what I believe medical oncologists and hematologists should know about this data.

From Juno Therapeutics, Inc., a Bristol-Myers Squibb Company:

Manali Kamdar, MD, MBBS, is an Associate Professor at the University of Colorado Denver. In this video, she speaks about FDA approves lisocabtagene maraleucel for second-line treatment of large B-cell lymphoma.

Is Lisocabtagene Maraleucel FDA approved?

On June 24, 2022, the Food and Drug Administration approved lisocabtagene maraleucel (Breyanzi, Juno Therapeutics, Inc., a Bristol-Myers Squibb Company) for adult patients with large B-cell lymphoma (LBCL) who have refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy. It is not approved to treat people with primary central nervous system lymphoma. This FDA approval of Lisocabtagene Maraleucel for relapsed or refractory LBCL, is a big step forward.

TRANSFORM Study

TRANSFORM (NCT03575351), a randomized, open-label, multicenter trial in adult patients with primary resistant LBCL or relapse within 12 months of attaining a complete response (CR) to first-line therapy, was used to assess efficacy. Patients had not yet been treated for relapsed or refractory lymphoma and were candidates for autologous HSCT. A total of 184 patients were randomly assigned to either a single infusion of lisocabtagene maraleucel after fludarabine and cyclophosphamide lymphodepleting chemotherapy or second-line standard therapy, which included three cycles of chemoimmunotherapy followed by high-dose therapy and autologous HSCT in patients who achieved CR or partial response (PR).

How it’s Reviewed

An independent review group chose the primary efficacy metric to be event-free survival (EFS) (IRC). With a hazard ratio (HR) of 0.34 (95 percent CI:0.22, 0.52; p-value0.0001), EFS was substantially longer in the lisocabtagene maraleucel arm. The predicted 1-year EFS in the lisocabtagene maraleucel arm was 45 percent (95 percent CI: 29, 59) and 24 percent (95 percent CI: 14, 35) in the usual treatment arm. The estimated median EFS was 10.1 months (95 percent confidence interval: 6.1, not evaluable) and 2.3 months (95 percent confidence interval: 2.2, 4.3), respectively. Patients assigned to standard therapy obtained autologous HSCT as intended in 47 percent of cases, with lack of response to chemotherapy being the most common reason for not obtaining HSCT. The IRC-assessed progression-free survival in the lisocabtagene maraleucel arm was likewise significantly longer, with an HR of 0.41 (95% CI: 0.25, 0.66; p-value 0.0001).

PILOT Study

PILOT (NCT03483103), a single-arm, open-label, multicenter trial in transplant-ineligible patients with relapsed or refractory LBCL after one line of chemoimmunotherapy, was also investigated for efficacy. Patients who were ineligible for high-dose therapy and HSCT due to organ function or age were enrolled in the research, but had appropriate organ function for CAR-T cell therapy. Efficacy was measured by an IRC based on CR rate and duration of response (DOR). 61 (82 percent) of 74 patients who underwent leukapheresis (median age, 73 years) received lisocabtagene maraleucel, with 54 percent (95 percent CI: 41, 67) achieving CR. The median DOR in individuals who obtained CR was not reached (95 percent CI: 11.2 months, not reached) and 2.1 months (95 percent CI: 1.4, 2.3) in patients with a best response of PR. The CR rate was 46% among all leukapheresed patients (95% CI: 34, 58).

What is Breyanzi (Lisocabtagene Maraleucel) approved for?

Because of the potential for catastrophic or life-threatening cytokine release syndrome (CRS) and neurologic toxicities, the FDA authorized lisocabtagene maraleucel with a Risk Evaluation and Mitigation Strategy. CRS occurred in 45 percent of patients (Grade 3 or higher, 1.3 percent) in investigations with lisocabtagene maraleucel as second-line therapy for LBCL, while neurologic toxicities occurred in 27 percent (Grade 3, 7 percent ). Serious adverse events occurred in 33% to 38% of the individuals.

The suggested dose of lisocabtagene maraleucel for second-line therapy is 90 to 110 106 CAR-positive T cells with a 1:1 CD4:CD8 ratio.

What is hematopoietic stem cell transplantation used for?

Hematopoietic cell transplantation (also known as bone marrow or stem cell transplantation) is a method of cancer treatment (and a few other conditions as well). Understanding stem cell transplantation will be aided by a study of normal bone marrow activity.

Hematopoietic stem cell function: bone marrow is the soft, spongy interior of several of the body’s bigger bones. The marrow is responsible for the production of all blood cells, including red blood cells, white blood cells (of various types), and platelets. In the bone marrow, all immune system cells are produced. All of these cells arise from a type of bone marrow cell known as a “hematopoietic stem cell.”

The body may control the development of hematopoietic stem cells into the blood components required at any given time. The bone marrow produces millions of different cells per hour, making this a tremendously busy process. The majority of stem cells remain in the bone marrow until they mature into distinct blood cells, which are then released into the bloodstream to serve specialized roles such as carrying oxygen, protecting against infection, and aiding in blood clotting. However, small amounts of stem cells can be discovered in circulating blood, allowing them to be collected under particular conditions. Many techniques can be used to enhance the number of hematopoietic stem cells in the blood prior to collection.

Hematopoietic cell transplantation: Chemotherapy and radiation, two of the most powerful cancer treatments, are toxic to the bone marrow. In general, the larger the dose, the more harmful the effects on the bone marrow.

You will be given very high doses of chemotherapy or radiation therapy during hematopoietic cell transplantation, which is meant to target cancer cells that may be resistant to more typical doses of chemotherapy. Regrettably, this also destroys normal cells in the bone marrow, including stem cells. You must have a good supply of stem cells reintroduced or transplanted after the procedure. The transplanted cells then restart the bone marrow’s blood cell manufacturing process. In rare cases, lower doses of radiation or chemotherapy that do not fully destroy the bone marrow may be employed.

The cells to be transplanted can be obtained from the bone marrow (referred to as a bone marrow harvest), the bloodstream (referred to as a peripheral blood stem cell collection, which requires you to take medication to increase the number of hematopoietic stem cells in your blood), or, in rare cases, blood obtained from the umbilical cord after the birth of a normal newborn (which is stored in umbilical cord blood banks).

Hematopoietic Cell Transplantation Types

Hematopoietic cell transplantation is classified into two types: autologous and allogeneic.

Autologous transplantation: In autologous transplantation, your own hematopoietic stem cells are extracted prior to the administration of high-dose chemotherapy or radiation, and they are then frozen for future use. Following the completion of your chemotherapy or radiation, the collected cells are frozen and returned to you.

Allogeneic transplantation: entails receiving hematopoietic stem cells from a donor, ideally a brother or sister with a similar genetic makeup. If you do not have a genetically comparable sibling, an unrelated person may be substituted. In some cases, a parent or kid who is only half-matched can be used; this is referred to as a haploidentical transplant. Umbilical cord blood may also be used in umbilical cord blood transplants in some cases.

Myeloablative transplant: A myeloablative transplant involves the use of extremely high doses of chemotherapy or radiation prior to transplanting autologous or allogeneic hematopoietic stem cells.

Non-myeloablative transplant: A non-myeloablative transplant, also known as a reduced intensity transplant, permits you to receive less rigorous chemotherapy before receiving allogeneic hematopoietic stem cell transplantation. This technique may be suggested for a number of reasons, including your age, disease kind, other medical conditions, or previous therapies.

What is the best sort of hematopoietic stem cell transplantation? — Your doctor will decide whether allogeneic or autologous transplantation is ideal for you based on a variety of variables, including the underlying condition, your age, overall health, and the availability of a compatible donor. Because different types of transplantation have varying dangers, this is a complex decision that frequently incorporates your perspectives. Because you are given cells from your own body, autologous transplantation is associated with fewer major adverse effects. However, in the treatment of certain types of cancer, an autologous transplant may be less beneficial than an allogeneic transplant.

References

1. UpToDate – Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics). UpToDate Article, May 6, 2022

2. FDA – FDA approves lisocabtagene maraleucel for second-line treatment of large B-cell lymphoma – FDA Resources for Information | Approved Drugs, May 27, 2022

For more in-depth information on Manali Kamdar, MD, study on lisocabtagene maraleucel for large B-cell lymphoma, click here.