An earlier version of this article included numbers from study abstracts and has now been updated with results presented at the ASH annual meeting.
NEW YORK – Two studies presented during the American Society of Hematology's annual meeting suggest that patients with slow-growing non-Hodgkin lymphoma subtypes may benefit from currently available CD19 CAR T-cell therapies.
Autologous CAR T-cell therapies axicabtagene ciloleucel (Gilead's Yescarta) and tisagenlecleucel (Novartis' Kymriah) are approved in multiple countries to treat patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. However, research presented at this meeting also showed that drugmakers are eager to move CD19 CAR T cells into earlier treatment settings for large B-cell lymphoma patients.
At the ASH annual meeting, Caron Jacobson of the Dana Farber Cancer Institute presented results from the Phase II ZUMA-5 trial, which evaluated axicabtagene ciloleucel (axi-cel for short), a product made by Gilead subsidiary Kite Pharma, in 146 patients with relapsed or refractory indolent NHL, including 124 patients with follicular lymphoma and 22 patients with marginal zone lymphoma. Follicular lymphoma comprises 22 percent of NHL cases and marginal zone lymphoma accounts for 8 percent of NHL cases. The trial's primary endpoint was objective response rate, and researchers also looked at secondary endpoints, including complete response rate, duration of response, progression-free survival, overall survival, levels of CAR T cells in the blood, cytokines in serum, and the incidence of adverse events.
For all of the 146 patients, the ZUMA-5 study investigators were able to successfully manufacture the axi-cel CAR T-cell product, and Jacobson noted that, at 12 months of follow up, 93 percent of patients remained alive.
At a median follow-up time of 17.5 months, the objective response rate among 104 evaluable patients in the study was 92 percent. Complete responses were observed in 76 percent of patients. Broken down by lymphoma subtype, the researchers observed a 94 percent objective response rate and an 80 percent complete response rate among patients with follicular lymphoma, and in patients with marginal zone lymphoma, these rates were 85 and 60 percent, respectively.
Median duration of response, progression-free survival, and overall survival data were not available at the time of the analysis. Still, the researchers estimated that at one-year follow up, 72 percent had experienced tumor shrinkage, 74 percent were alive without disease progression, and 93 percent were still alive, respectively.
Researchers noted the treatment had a manageable safety profile, with lower rates of more severe neurological events in patients with follicular lymphoma than in patients with marginal zone lymphoma.
"Given the long natural history of these diseases, safety is of paramount importance," Jacobson emphasized in her presentation of the data, noting that fewer severe neurologic adverse events and incidences of cytokine release syndrome occurred in patients with follicular lymphoma than in patients with marginal zone lymphoma.
ZUMA-5's investigators also tracked patients' CAR T-cell levels over time, and found that these concentrations peaked at nine days following infusion.
"The pattern of CAR T-cell expansion of resolution was consistent with that which has been seen with [axi-cel] across disease indications," said Jacobson. After 12 months' follow-up, she noted, CAR T cells were detectable in 78 percent of patients with evaluable samples.
In terms of CAR T-cell levels, patients with follicular lymphoma who experienced continued response to treatment at 12 months' follow-up tended to have higher levels of CAR T cells in their samples than did patients who did not experience continued response. Patients who experienced higher-grade adverse events, including cytokine release syndrome and neurological events, also tended to have higher levels of CAR T cells detected in their blood.
Interestingly, Jacobson noted in her presentation that there were nine patients in ZUMA-5 who responded to the CAR T-cell treatment but who, upon analysis with immunohistochemistry, were found to have CD19-negative disease.
"We know [immunohistochemistry] is not a perfect test to measure CD19 positivity," Jacobson offered as a possible explanation during her presentation. These patients may have had low levels of CD19 expression that did not show up with testing, or, she suggested, the CAR T-cell treatment may have set other immunologic cells into effect, leading to anti-tumor activity. "I don't believe we really know [the answer], but I have a feeling it's a combination of both," she said.
Turning to Novartis' CAR T-cell therapy tisagenlecleucel (or tis-cel for short), Nathan Fowler of the MD Anderson Cancer Center presented interim results of the Phase II ELARA trial. The study, which is still ongoing, is designed to evaluate the autologous treatment specifically in patients with relapsed or refractory follicular lymphoma. The results presented at the meeting were based on six months of follow up on 52 heavily pretreated follicular lymphoma patients. On average, Fowler pointed out, these patients had undergone four prior lines of treatment before receiving the autologous CAR T cells.
Among the 52 patients evaluated, the complete remission rate — ELARA's primary endpoint — was 65 percent. The best overall response rate was 83 percent, and although median duration of response and median progression-free survival data were not yet available, the investigators reported a 73 percent six-month progression-free survival rate was 73.2 percent. The final results of the study among the full cohort of patients, Fowler said, would likely be presented in a future meeting.
Exploring the frontline setting
Beyond these two studies showing that CAR T-cell therapy could someday benefit a wider population of patients, additional research presented at the ASH annual meeting suggested that this form of treatment could someday be administered earlier in the course of patients' treatment.
Specifically, Sattva Neelapu of MD Anderson presented interim results from the ongoing Phase II ZUMA-12 study, in which patients with high-risk large B-cell lymphoma were treated with axi-cel in the first-line setting. The interim data were derived from a cohort of 27 patients who had received the CAR T-cell therapy and had been tracked for a median of 9.3 months.
Of response-evaluable patients, the objective response rate was 85 percent, and the complete response rate was 74 percent. Researchers reported that the safety profile among the treated patients was manageable, and the peak levels of CAR T cells observed were greater than they had been in refractory patients treated in cohort 1 of the previously reported ZUMA-1 trial.
In a discussion of the ZUMA-12 data, Neelapu reminded that while the interim response rates were encouraging and the safety profile was manageable, the field must await the final data readout to truly understand the front-line potential of axi-cel in high-risk large B-cell lymphoma.
"We definitely first need to wait for the final analysis of this trial, as well as longer follow-up, to ensure that the durability is maintained," Neelapu said. "Currently, this interim analysis indicates that this product has really high efficacy … in the frontline setting, which is quite encouraging compared to historical data in this high-risk population where the [complete remission] rate has generally been less than 50 percent."
Even if the final analysis ends up confirming what has been seen in this interim analysis, he expects that a randomized, Phase III trial will be necessary to move axi-cel into the first line. That randomized clinical trial, Neelapu suggested, might compare axi-cel head-to-head with frontline chemoimmunotherapy.