Cell therapy, a relatively new and expensive treatment for certain blood cancers, might soon dislodge a decades-old standard of care for people with a common type of lymphoma that's returned after initial drugs fail.
Results from two late-stage studies, presented over the weekend at the American Society of Hematology's annual conference, showed so-called CAR-T cell therapy decisively outperformed chemotherapy and a stem cell transplant, currently the go-to option for patients whose lymphoma has become resistant or relapsed.
The findings could propel earlier use of CAR-T cell therapies, three of which are approved in the U.S. for later-line treatment of diffuse large B-cell lymphoma, when patients are very sick and have run out of other options.
The Food and Drug Administration is already reviewing an application from Gilead, maker of the CAR-T therapy Yescarta, for an expanded clearance based on the study data presented at ASH Sunday. Bristol Myers Squibb, which sells the competing treatment Breyanzi, could follow using results from its trial, unveiled at the conference Saturday.
"This is a major step forward in the field," said Stephan Grupp, the director of the cancer immunotherapy program at the Children's Hospital of Philadelphia who helped study the third CAR-T therapy available in the U.S., Novartis' Kymriah.
Kymriah didn't prove superior to chemotherapy and a transplant in a similar trial set to be presented at ASH on Tuesday, though differences between study arms and delays in treating patients with the CAR-T therapy could have influenced the results.
The initial approvals of Yescarta, Breyanzi and Kymriah were based on studies without a control group. The trials presented at ASH represent a much stiffer test for CAR-T and could provide evidence for doctors to turn to the treatments sooner.
"These are not easy studies to do," said Grupp. "I think it's fantastic that we actually see randomized data."
Diffuse large B-cell lymphoma, or DLBCL, is the most common form of non-Hodgkin lymphoma. Approximately 18,000 people are diagnosed each year in the U.S., about a third of whom have their cancer relapse or become resistant after initial treatment, typically an antibody drug called Rituxan and chemotherapy.
Once that treatment fails, patients often receive what's known as salvage chemotherapy and, if feasible, a stem cell transplant, which can be curative.
A good number of patients, however, don't respond well enough to chemotherapy to get a transplant, leaving a need for another type of therapy. The study results from Gilead and Bristol Myers suggest CAR-T could fill that void.
Gilead's trial, which began soon after Yescarta's first approval in 2017, included nearly 360 people with refractory or relapsed DLBCL. After following participants for a median of more than two years, researchers reported Sunday that treatment with Yescarta significantly extended what's known as event-free survival — the time until cancer progression, subsequent treatment or death from any cause.
Participants given Gilead's drug went a median of 8.3 months without an "event," compared to 2 months for those assigned to standard of care — a risk reduction of about 60%. Additionally, more study volunteers responded and went into remission after receiving Yescarta than did those in the control group.
Follow-up is still ongoing to determine exactly how long Yescarta recipients survived following treatment, although it's at least longer than 28 months, based on statistical estimates. Results were also published in The New England Journal of Medicine.
The story was similar in Bristol Myers' study, which began more recently and enrolled 184 participants with a similar stage of lymphoma. Patients were event-free for a median of 10 months with Breyanzi, a 65% risk reduction compared to chemotherapy and a transplant. Rates of response and remission were about the same as what was observed in Gilead's study of Yescarta.
CAR-T therapy in second-line treatment of lymphoma,
versus standard treatment*
|Yescarta (Zuma-7)||Breyanzi (Transform)||Kymriah (Belinda)|
|Event free-survival||8.3 months (vs. 2 months)||10.1 months (vs. 2.3 months)||3 months (vs. 3 months)|
|Overall response rate||83% (vs. 50%)||86% (vs. 48%)||46% (vs. 43%)|
|Complete response rate||65% (vs. 32%)||66% (vs. 39%)||28% (vs. 28%)|
|Overall survival||Not reached (vs. 35 months)||Not reached||"Immature at data cutoff"|
*Standard second-line treatment is chemotherapy followed by a stem cell transplant SOURCE: Companies, ASH abstracts and presentations
Only about a third to nearly half of volunteers assigned to standard treatment in the two studies actually received a stem cell transplant, highlighting the difficulties in getting patients to that point.
The two studies show CAR-T therapy may "negate the need for high-dose chemo and autologous stem cell transplant in some patients," said Tanya Siddiqi, an oncologist and associate professor in the lymphoma division at the City of Hope, in an email.
Yet CAR-T also comes with notable side effects, most significantly a potentially overwhelming immune response known as cytokine release syndrome as well as neurotoxicity.
On that score, Breyanzi appeared to cause fewer severe reactions. Only one participant experienced cytokine release syndrome classified as Grade 3, and just 4% experienced a similar level of neurological side effects. Treatment with Yescarta, by comparison, led to Grade 3 cytokine release syndrome in 6% of patients and Grade 3 neurotoxicity in 21%.
Both CAR-T therapies carry warnings from the FDA for those side effects in their approved later-line treatment setting.
Multiple factors affect CAR-T safety and, while Yescarta and Breyanzi home in on the same cancer cell target, they are constructed differently. Bristol Myers, whose drug got to market later than Gilead's, claims Breyanzi's safety profile can help it compete.
The results are "not only favorable in terms of efficacy, but also encouraging in terms of safety," said Anne Kerber, Bristol Myers' head of cell therapy development. "We really believe it is going to be practice changing."
Even if the results presented at ASH lead to future FDA approvals, CAR-T therapy remains an expensive and complicated treatment. Yescarta costs $373,000; Breyanzi about 10% more at $410,300 — extremely high prices meant to reflect the possibility they could deliver long-lasting benefits.
Insurance coverage has improved over time, helped by national policies put in place by Medicare and Medicaid in 2019, but broader use could rekindle the debate over whether CAR-T is cost-effective.
CAR-T therapies are also custom-made for each patient, built on immune cells extracted from the body and engineered in a laboratory to seek out tumors. The manufacturing process, measured from when cells are extracted to when they are reinfused, takes a little more than two weeks for Yescarta and just over three weeks for Breyanzi.
Since launching Breyanzi earlier this year, Bristol Myers has said that it has met its turnaround target of 24 days approximately 90% of the time.
The studies of second-line CAR-T treatment "leave other important unanswered questions for the many patients who can't wait for CAR-T cell manufacturing without second-line chemotherapy and remain chemosensitive," said Alex Herrera, an oncologist at City of Hope, in a Sunday discussion of Gilead's results at ASH.
Doctors will also be eager to see how many patients who respond to CAR-T remain in remission over time, and how much longer they live than those who receive transplants.
Note: This story has been updated with additional comment.