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Responses to CAR T-cell therapy deepen over time for lymphoma
CHICAGO — Complete response rates to axicabtagene ciloleucel among patients with refractory large B-cell lymphoma increased through long-term follow-up of the ZUMA-1 trial, according to study data presented at the ASCO Annual Meeting.
Some patients with initial partial responses developed complete responses as late as 1 year following treatment, suggesting response to therapy deepens over time.
“Over half of the patients who progress will have progressed before 3 months after treatment,” Frederick Lundry Locke, MD, program co-leader of immunology at Moffitt Cancer Center, told HemOnc Today. “We did an analysis of the ZUMA-1 trial to figure out what to do with patients at 3 months. If we have a patient in remission at 3 months — whether it be a partial or a complete response — can we wait it out? Or, do we need to deliver chemotherapy or transplantation? We found that over 80% of patients, whether they are in partial or complete response at 3 months, remained in remission 1 year after the therapy, which is pretty remarkable.”
Earlier results from ZUMA-1 showed axicabtagene ciloleucel (Yescarta; Kite Pharma, Gilead) — an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy — induced significant clinical benefit with a manageable safety profile for patients with refractory large B-cell lymphoma. As HemOnc Today previously reported, these data led to the therapy’s FDA approval as the second-ever approved CAR T-cell product.
Locke and colleagues conducted extended follow-up of the ZUMA-1 trial after a median of 15.4 months.
The analysis included 108 patients with refractory B-cell lymphoma who received low-dose conditioning followed by 2 x 106 CAR T cells/kg.
The best objective response rate remained consistent at 82% from the primary analysis — which occurred after a median of 8.7 months — and at long-term follow-up. Fifty-eight percent of patients achieved complete response.
Forty-two percent of patients had ongoing responses, including 40% with complete response.
Median OS was not reached, and 60% of patients achieved 12-month OS.
“These clinical results compare very favorably to robust historical controls, which suggest that this same set of patients would at best expect a 25% chance of having a response to another therapy besides CAR T cells,” Locke said during his presentation.
Twelve percent of patients experienced grade 3 or worse cytokine release syndrome, and 31% of patients experienced grade 3 or worse neurologic events.
Overall median duration of response was 11.1 months (95% CI, 3.9-not reached).
Locke and colleagues then evaluated the time to response for patients with an objective response and a complete response, and they assessed partial and complete response at month 3 as a prognostic factor for PFS.
“One-third of patients in complete response initially attained a partial response, and that response deepened over time,” Locke said. “Over half of patients who progressed did so by the 3-month time point, leading to the need to define treatment practices at this time. We believe month 3 is clinically relevant to understand patient outcomes.”
Overall, time to response among the 84 responders was “quite rapid,” Locke said, occurring at a median of 1 month.
Forty-one percent of patients with a partial response converted to a complete response, and this conversion occurred as late as 12 months after a single infusion of CAR T-cell therapy.
Landmark PFS analyses showed that most of the 60 patients who achieved stable disease or better at 3 months had prolonged disease control, with a corresponding 12-month PFS rate of 73%.
Twelve-month PFS rates reached 79% among 42 patients with complete response at 3 months and 78% among nine patients with partial response at 3 months.
“If I have a patient I am going to treat with CAR T cells, I will tell them that the 3-month time point is really important,” Locke told HemOnc Today. “We will wait to see how they are doing at 3 months and, if they are in remission, that is good news, because it means they have a very high likelihood of sustaining that response for at least 1 year without an additional therapy, just a single infusion of CAR T cells.
“We do not need to give additional chemotherapy or stem cell transplant.” Locke added. “This answers a big question about whether we should be consolidating with transplant. I would not want to give additional therapy to this patient. It would be better to ride it out and see how things go.” – by Alexandra Todak
Reference:
Locke FL, et al. Abstract 3003. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.
Disclosures: Kite Pharma supported this trial. Locke reports honoraria from Kite Pharma; a consultant/advisory role with Cellular Biomedicine Group; research funding from FORMA Therapeutics and Kite Pharma; and a patent for the survivin vaccine. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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This is a game-changing therapy in a patient population that had few options, with only a small percentage able to undergo transplant if they respond to salvage therapy. The response rate is very high, at greater than 80%. The response rate at 3 months seems like it is predictive of long-term outcomes, and one-third of patients in partial response converted to complete response over time, sometimes more than a year later. The complete response rate increased from 48% to 54% with longer follow-up, which is not a significant difference, but it is a substantial finding because it is not decreasing.
Some of these patients are potentially cured. Typically, a patient in partial response with large B-cell lymphoma in the third or fourth salvage therapy progresses and dies very quickly. Having the ability to induce a partial response that remains stable is very important. Here, there have been some patients who remain in partial response and are not progressing at a year, which suggests that how we assess response through imaging may not be effective. Having in this population — at almost year and a half — more than 50% of patients doing well is unusual.
In some responders who were tested, researchers observed residual CAR T cells, but we’re not 100% sure if persistence is required. One-third of the long-term responders at 15 months had no residual detectable CAR T cells, whereas others did. We are still researching the importance of this.
The TRANSCEND and JULIET studies of CAR T-cell therapy allowed patients to bridge to therapy, whereas ZUMA did not. These patients would not be cured with additional chemotherapy, because they were a chemotherapy-refractory population. But, it might prepare them better to have a less toxic reaction to CAR T cells, because the more inflammation and the more tumor cells and burden at the time of CAR T, the more toxicity.
We will have to do more work to compare tisagenlecleucel (Kymriah, Novartis) — also approved for this population — with axicabtagene ciloleucel. There seems to be a little less cytokine release syndrome and toxicity with tisagenlecleucel, which might present a window of opportunity for patients to receive therapy more easily, thus affecting reimbursement. This is a new form of cell therapy that will need to be performed in centers with a lot of experience with cell therapy and transplant, because it is toxic.
Ideally, mitigating toxicity will become easier as we can intervene earlier. Initially, the impression was that we shouldn’t slow down toxicity, because that would decrease response. However, a brief course of steroids and tocilizumab (Actemra, Genentech) doesn’t affect the T cells and response. The data are early, but it appears higher T-cell count is a really important criterion for activity. These patients are beat up — they have had multiple lines of therapy and active lymphoma — so if we are able to debulk them before, or if we could give CAR T cells earlier in the course of treatment, it would address cost and toxicity. Their lymphocytes would work better.
The ongoing research is fascinating and will change how we care for our patients.
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