CAR-T destined for earlier lines of therapy in blood cancers, experts say
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Despite data on the approach still being accumulated, a panel of experts at Chemotherapy Foundation Symposium predicted that chimeric antigen receptor T cells will become front-line therapy for multiple hematologic malignancies.
"CAR-Ts are blowing the historic response rates out of the water,"Ajai Chari, MD, professor of medicine and director of clinical research in the multiple myeloma program at Icahn School of Medicine at Mount Sinai, told the audience.
“The real question is how long will we need to wait for current indications to change and will this mean a move toward earlier therapy in the future?” he added.
Two commercially approved CAR T-cell therapies have been approved for multiple myeloma. Both require previous lines of therapy, including disease progression after receiving three specific classes of drugs. The initial success of CAR-T in these heavily pretreated patients had led to the opening of several ongoing trials examining its use as earlier therapy, according to Shambavi Richard, MD, assistant professor of medicine, hematology and medical oncology at Icahn School of Medicine at Mount Sinai.
“Clearly, we need to study CAR-T in earlier lines of therapy,” she said, noting that CAR T cells — in certain ways — are more well-tolerated than hematopoietic stem cell transplants. However, she said CAR-T presents unique toxicities that clinicians must negotiate.
"The conventional wisdom is that if something works well in advanced disease then it should work even better in earlier lines of treatment,” she told the audience. “However, CAR-T’s use of the immune system means oncologists are in ‘uncharted territory’” she added.
"We are seeing amazing results with CAR-T, and it makes us want to move it up into earlier lines of therapy,” Richard said. “But I am going to reserve my judgment to see if they flatten out our survival curves and we no longer need to keep treating these patients with endless lines of therapy.”
The end goal is not just to extend lives, Richard said. The objective is to provide a treatment that does not require constant visits to a doctor's office, thereby also improving quality of life.
“My gut feeling is that CAR-T will move to earlier lines of therapy, improve T-cell fitness and replace transplant as consolidative therapy,” she said. “As long as T cells stay fit, then I believe the immune system has more flexibility than tumor cells that learn to become resistant [to treatment].”
Two FDA approved commercial CAR-T products are also available for treatment of B-cell acute lymphoblastic leukemia. Tisagenlecleucel (Kymriah, Novartis) has shown durable remissions in younger patients aged 25 and younger and may be curative in up to 40% of patients, according to panelist Jae Park, MD, acting chief of the cellular therapy service and associate attending physician at Memorial Sloan Kettering Cancer Center.
Brexucabtagene autoleucel (Tecartus, Kite Pharma) has also been approved for B-cell ALL but is indicated for adults only.
"The indication for this treatment is broader," Park noted, adding that prescribing information does not specify a specific line of therapy for brexucabtagene autoleucel.
Park said relapse rates among adults who receive the CAR-T are “slightly higher” than those observed among younger patients receiving tisagenlecleucel.
"The question still remains whether [CAR-T] can be definitive therapy or a bridge to allogeneic transplant in adult ALL, whereas its role in pediatric ALL is clearer,” Park said, adding that more follow-up data are needed in adults with ALL to determine whether it would be beneficial as earlier therapy.
"Regardless, [CAR-T] is a highly effective therapy in patients with relapsed or refractory disease,” he told the audience.
"CAR-T for ALL will definitely work better in an earlier line setting, especially autologous CAR T cells,” he said. “The difficult part is determining whether we can provide CAR-T as earlier therapy instead of a [hematopoietic stem cell] transplant, and a randomized study will be the best way to answer this question.”
The first CAR-T approvals in non-Hodgkin lymphoma came in the third-line setting, with more recently expanded indications for lisocabtagene maraleucel (Breyanzi, Bristol Myers Squibb) and axicabtagene ciloleucel (Yescarta; Kite Pharma/Gilead Sciences) in the second-line setting for certain patients with diffuse large B-cell lymphoma.
Clinical experience has taught Lori A. Leslie, MD, and her fellow cell therapy specialists that many patients can be safely treated with CAR-T who would have likely been ineligible for the pivotal trials that lead to their approvals, including older patients over the age of 80 and those with comorbidities.
“If they have well-controlled comorbidities and they can tolerate the process, then some patients may be a candidate for CAR-T even if they are not a candidate for transplant,” Leslie, assistant professor at Hackensack Meridian School of Medicine and director of the indolent lymphoma and chronic lymphocytic leukemia research programs at John Theurer Cancer Center, told the audience.
Conversations about the timing of CAR-T with patients will differ depending on the disease type, she noted, adding that patients with aggressive, high-risk disease may benefit from CAR-T as earlier therapy while those with indolent lymphomas may not need such a personalized treatment done as quickly.
"We need to find molecular markers that can better risk stratify patients as we shift CAR-T into earlier lines of therapy,” Leslie said. “Figuring out what to do with patients after CAR-T failure — or consolidation therapy after CAR-T — are the next steps needed to improve long-term outcomes in patients with lymphoma.”
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Chari A, et al. CAR T: Now or later (lines of therapy)? Presented at: 40th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow; Nov. 9-11, 2022.
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