CAR-T for advanced lymphoma: Options do not equal choice
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The FDA in February approved lisocabtagene maraleucel — a chimeric antigen receptor T cell therapy — for treatment of relapsed or refractory diffuse large B-cell lymphoma.
It became the third CAR T-cell therapy approved for the indication, and clinical trial results suggested this therapy may have less severe treatment-related adverse effects than the other two agents. Experts in the field applauded its commercial availability, heralding it as another important choice for patients with advanced disease.
However, choosing which CAR-T to use for patients with DLBCL is not as simple as deciding which cholesterol drug to prescribe, according to Joshua Brody, MD, director of the lymphoma immunotherapy program at Icahn School of Medicine at Mount Sinai. In fact, there may be little choice at all, he told Healio.
In this installment of In Practice, Brody explores when to refer patients with relapsed or refractory DLBCL for these therapies, how treatments differ from each other, and whether patients have a choice about which agent they will receive.
Healio: When should an oncologist consider CAR-T for patients with DLBCL?
Brody: That is a great question with an evolving answer. We have three FDA-approved products for third-line therapy. This includes patients with decent EGOG performance status, after having failed at least two prior standard therapies.
However, a couple phase 3 clinical trials are nearing completion that have a very good chance of changing the FDA labels from third-line to second-line therapy. For example, the ZUMA-7 trial is evaluating axicabtagene ciloleucel (Yescarta; Kite Pharma/Gilead Sciences) as second-line therapy for relapsed or refractory large B-cell lymphoma. Additionally, the TRANSFORM study is evaluating lisocabtagene maraleucel (Breyanzi, Bristol Myers Squibb) as second-line therapy for the same indication. I’m fairly confident that those trials will be positive and demonstrate the superior efficacy of CAR-T as second-line therapy. Even though the trials were limited to patients receiving second-line therapy for a certain type of B-cell lymphoma, I believe both products will be approved by the FDA as second-line therapy in B-cell lymphoma soon.
Healio: How do you choose which CAR-T cell therapy is best for a patient with DLBCL?
Brody: Preexisting relationships between the treating center and the CAR-T manufacturer are often the determining factor. It is frequently the case that an institution uses just one of the CAR T-cell platforms. The reasons for this limitation are multifactorial, and they include existing commercial contracts and the complexity of setting up a single CAR T system.
There is never going to be a head-to-head trial of CAR-Ts, so it will be hard to say with absolute confidence that one is better than the other. Therefore, clinicians with experience providing or referring for CAR T-cell therapy should not throw away all their contacts with a company every time a new CAR-T is approved, or some new data are published regarding the safety or effectiveness of a particular therapy. Most centers will have just one CAR T-cell therapy option available — perhaps occasionally two, but rarely ever all three.
So where is the decision is getting made? It is frequently not being made. Typically, the decision has already been made and depends on which center the patient or their local oncologist chooses.
Healio: What are the differences among the three CAR-Ts that are commercially available for DLBCL?
Brody: These products are more similar than they are different. Each contains small esoteric differences that scientists often care more about than physicians. The immunological difference between the three is that they differ in what’s called the second signal — the second ‘gas pedal’ that turns on the CAR T cells. They all have the same first gas pedal — also known as a costimulatory domain — which is called the CD3. However, axicabtagene ciloleucel has what is called a CD28 second signal, whereas tisagenlecleucel (Kymriah, Novartis) and lisocabtagene maraleucel have what is called a 4-1BB second signal. It is possible that the CD28 second signal makes the CAR T cells more rapidly expand or proliferate inside the patient, whereas products with the 4-1BB second signal result in CAR T cells that more gradually expand and proliferate. From an immunological perspective, the possible clinical sequela is cytokine release syndrome (CRS), which may be less severe according to clinical trial data with liso-cel compared with what we initially saw with axi-cel. But this is an apples-to-oranges comparison, and the clinical trials for each therapy were very different. Therefore, it is possible that a lower CRS rate seen with liso-cel could lead to some patients being treated with the therapy in an outpatient setting rather than remaining in the hospital for a period after CAR T-cell infusion.
Healio: Does this mean that different CAR constructs influence safety?
Brody: It is not clear at this point whether the lower CRS rate seen with liso-cel is related to the different costimulatory domains used in each product or whether it is attributable to some other very subtle manufacturing difference. Neurotoxicity rates appear to be similar among all three CAR T-cell therapies approved for DLBCL.
Healio: Do you present patients with a choice in CAR-T for DLBCL if more than one is available at your institution, either commercially or via clinical trials?
Brody: That would be a very hard thing to put on a patient, and it also would require having to explain the immunological differences to them. Patients eligible for CAR T cells are mostly concerned about the fact that their cancer has returned and care little about the function of a specific CAR T-cell product. At Mount Sinai, we have different types of CAR-T available for different situations. We have something available for mantle cell lymphoma, for third-line B-cell lymphoma, for multiple myeloma and so on. We offer CAR T cells for all these different indications either commercially or via clinical trials. However, like most centers that offer cellular therapy, we do not have multiple platforms available for the same indication.
Healio: Is there research being conducted on the comparative effectiveness of commercially approved CAR T cells?
Brody: There will never be any head-to-head clinical trials of CAR T-cell therapy. These are expensive therapies, and it would make more sense to dedicate money to developing newer, more effective CAR T-cell therapies rather than conducting comparative-effectiveness trials to prove some marginal advantage of one therapy over another.
Most of the new data come from prospective, nonrandomized real-world evaluations. After the CAR-T manufacturers complete their trials, typically some academic clinicians will examine results from the first 100 to 200 patients who receive the therapy nationally. Most of the prospective real-world data look very similar to the clinical trial data; therefore, the efficacy and safety of commercially approved CAR T-cell therapies in the real-world setting appears to be similar to what was seen in clinical trials.
Healio: Do you consult any professional guidelines in your decision-making process?
Brody: I am part of the expert panel that helped develop the Society for Immunotherapy of Cancer (SITC) guidelines on the use of immunotherapy to treat lymphoma. They can help clinicians determine which patients are eligible for CAR T-cell therapy, especially those who are receiving second- or third-line therapy or those with high-risk disease. The guidelines will not recommend which therapy to prescribe. The panel does not think there is a clinically significant difference among the available choices.
Healio: Is there anything else clinicians should know about choosing the most appropriate CAR T-cell therapy for their patients?
Brody: Treating patients with bulky lymphoma portends a much higher risk of toxicity, so it is preferred that patients with lower disease burden be referred and at the earliest possible line of therapy permitted. Regardless of which CAR-T platform is being used, one of the biggest predictors for severe treatment-related toxicity is the amount of tumor bulk; therefore, the optimal patient has a low amount of cancer onboard. The use of CAR T cells by at least the third line of therapy is preferable compared with later lines when patients become highly resistant to any therapy that we provide. Successful debulking strategies before CAR T cells can lead to safer and more effective results.
References:
Breyanzi (prescribing information). Bothell, WA: Bristol Myers Squibb; 2021.
Kymriah (prescribing information). East Hanover, NJ: Novartis Pharmaceuticals Corp.; 2020.
Yescarta (prescribing information). Santa Monica, CA: Kite Pharma, Inc.; 2021.
For more information:
Joshua Brody, MD, can be reached at Icahn School of Medicine at Mount Sinai, 1470 Madison Ave., New York, NY 10029; email: joshua.brody@mssm.edu.
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