Summary
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Original Article
The Value of Axi-Cel Emerges in R/R Indolent Non-Hodgkin Lymphoma
Oncology Times
By Amy Gallagher
In an interim analysis to evaluate the investigational application of axicabtagene ciloleucel (axi-cel) in adult patients with relapsed or refractory indolent non-Hodgkin lymphoma (R/R iNHL), the phase II ZUMA-5 trial was conducted by a team of researchers led by Caron A. Jacobson, MD, from the Dana-Farber Cancer Institute, who stated the axi-cel treatment demonstrated a significant and durable clinical benefit, with a high percentage of overall response rate (ORR) and complete response (CR).
As presented at the 2020 ASCO Annual Meeting, the multicenter, interventional study of patients with R/R iNHL resulted in significant improvements (Abstract 8008). The primary endpoint of the study was ORR by central review indicating an ORR of 93 percent and a CR at 80 percent, based on the 96 patients evaluable for efficacy.
More specifically, patients with follicular lymphoma (FL) (n=80) had an ORR of 95 percent, with an 81 percent CR rate, and those with marginal zone lymphoma (MZL) (n=16) had an ORR of 81 percent, with a 75 percent CR rate.
“Advanced-stage indolent B-cell non-Hodgkin lymphomas are largely incurable with conventional therapies, with many patients experiencing multiple relapses over the natural history of their disease and remission shortening with subsequent therapies,” said Jacobson during a presentation of the data.
Adults with relapsed or refractory FL (grades 1-3a) and MZL (nodal or extranodal) after ≥2 lines of therapy (including an anti-CD20 monoclonal antibody [mAb] with an alkylating agent), and an ECOG status of 0 or 1 were eligible for the study.
In this study, patients underwent leukapheresis and received a conditioning chemotherapy
regimen of fludarabine and cyclophosphamide followed by a single infusion of CAR-transduced autologous T cells intravenously (axi-cel infusion at 2 × 106 CAR T cells/kg).
Key secondary endpoints included duration of response (DOR), progression-free survival, overall survival, safety, and blood levels of cytokines and CAR T cells.
Efficacy & Safety
Notably, the DOR showed equal promise. With a median follow-up of 15.3 months, the estimated DOR in all patients was 20.8 months, and 68 percent of patients with FL had an ongoing response as of the data end date.
“Although it is challenging to estimate the median DOR with few patients in follow-up through the 20-month mark, for the 50 percent of patients with a follow up of 15.3 months, the DOR is very meaningful,” said Jacobson.
Specifically, axi-cel demonstrated a manageable safety profile in patients with R/R iNHL.
“The infusion therapy has shown to be both efficacious and safe. Efficacy is equally important to safety in these indolent diseases with long natural histories, she added. “The safety profile results showed manageable and reversible toxicities in patients with R/R iNHL.”
All of the 140 study participants were evaluable for safety, with 119 patients (85%) experiencing grade ≥ 3 adverse events (AEs). The most commonly observed treatment-emergent AEs indicated all patients measured for safety, 83% experienced both neutropenia (34%) and anemia (22%). Additionally, 11 percent of patients experienced grade ≥ 3 cytokine release syndrome (CRS) and neurologic events were cited in 19 percent.
“The AEs were largely confined to the first 2-4 weeks after the CAR T-cell infusion therapy, followed by recovery,” she said. “As a single infusion therapy as opposed to the indefinite dosing of a drug, axi-cel is unlike other drugs that require indefinite dosing and with toxicity that can affect the patient in a more chronic fashion.”
Median onset of CRS was 4 days after infusion; this coupled with the low incidence of high-grade CRS has implications for potential outpatient dosing, Jacobson noted.
“Given the long natural history of these diseases, safety is of paramount importance,” she said. “The safety profile appeared to be at least similar to that of axi-cel in aggressive lymphomas.”
The median time to peak of anti-CD19 CAR T-cell levels after axi-cel infusion was 8 days. Furthermore, anti-CD19 CAR T cells were detectable at 18 months in most patients with evaluable samples (13/15 [87%]). Notably, in patients with FL, peak CAR T-cell expansion was associated with both grade ≥3 CRS (P = 0.0088) and neurologic events (P = 0.0076). In addition, peak serum analyses across multiple immune programs were associated with grade ≥ 3 CRS, grade ≥ 3 neurologic events, or both in patients with FL. Patients had a median of three prior lines of therapy with 66 percent progressed < 2y after initial anti-CD20 mAb-containing therapy (POD24), and 73 percent were refractory to the last prior treatment.
These interim results suggest that axi-cel may be emerging as a promising approach for treating this patient population. “Axi-cel yields high rates of response in indolent B-cell non-Hodgkin lymphoma,” said Jacobson. “Although longer follow-up is needed, these responses appear to be durable amongst FL patients.
“FL is marked as a slow growing lymphoma,” she added. “Patients usually live with the disease for 20-30 years with therapies that are very effective, but not curative. The remission time shortens with each subsequent line of therapy. After the third line, expected remissions are usually around 10-12 months. It’s very encouraging that, in the third line and beyond, 80 percent of patients with a complete response maintain that response at 15.3 months. It’s also very rewarding to know this study has had such an impact on patients. The celebration of another ‘clean scan’ with a patient never gets old.”
Implications & Next Steps
“We are eager to know if the CAR T cells change the natural history of indolent diseases such as FL and potentially cure a subset of patients,” said Jacobson. “Furthermore, the prospect of outpatient dosing is very intriguing.”
While awaiting the results from the ZUMA-7 trial to study axi-cel versus second-line chemotherapy in aggressive B-cell non-Hodgkin lymphoma, Jacobson noted the outcome will determine if CAR T-cell therapy can be moved up earlier in lines of therapy.
In 2017, based on the positive results from the phase II ZUMA-1 trial, the FDA approved CAR T-cell therapy axi-cel, making it the first approved CAR T-cell therapy for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, and high-grade B-cell lymphoma and DLBCL arising from FL.
Amy Gallagher is a contributing writer.