ZUMA-12 Trial Assesses Axicabtagene Ciloleucel as First-Line Therapy for High-Risk B-Cell Lymphoma

Take-aways:

• ZUMA-12 indicated that first-line treatment with axicabtagene ciloleucel resulted in a 78% complete response rate in patients with high-risk B-cell lymphoma.
• The safety of axicabtagene ciloleucel in this high-risk patient population was manageable, with no new safety signals reported in this earlier-line setting.
• Six months post-infusion, 62% of patients (n=13/21) with evaluable samples maintained low but detectable levels of CAR gene-marked calls in the blood.

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The phase II ZUMA-12 study assessed the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel as part of first-line treatment for patients with high-risk large B-cell lymphoma (LBCL) and observed a 78% complete response rate (CRR), with 73% of patients maintaining an objective response after nearly 16 months of follow-up.

The primary analysis of the study was published in Nature Medicine by Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston, Texas, and co­­authors.

LBCL is the most common subtype of non-Hodgkin lymphoma, accounting for up to 40% of cases worldwide. Patients with high-risk LBCL “have lower response rates and lower progression-free and overall survival (OS) with standard chemoimmunotherapy,” Dr. Neelapu told Blood Cancers Today. Axicabtagene ciloleucel is approved by the U.S. Food and Drug Administration for patients with relapsed/refractory LBCL after two or more lines of systemic therapy.

The prospective, multicenter, single-arm, phase II ZUMA-12 study assessed the safety and efficacy of axicabtagene ciloleucel as part of first-line therapy after an incomplete treatment regimen of two cycles of chemoimmunotherapy in patients with high-risk LBCL (defined by the dynamic risk assessment of interim positive positron emission tomography result with either double- or triple-hit lymphomas or high-intermediate and high-risk International Prognostic Index [IPI] scores).

A total of 42 patients were enrolled between February 6, 2019, and October 22, 2020. Axicabtagene ciloleucel was manufactured for all patients and administered in 40 patients (median age, 61 years; range, 23-86 years). Median time from leukapheresis to axicabtagene ciloleucel delivery was 18 days (range, 14-32 days). Median weight-adjusted axicabtagene ciloleucel dose for patients <100 kg (n=31) was 2 × 10⁶ cells/kg. Patients weighing >100 kg received the per-protocol maximum flat dose of 2 × 10⁸ cells/kg.

More than half of patients (55%; n=22) had diffuse LBCL not otherwise specified, and 40% (n=16) had double- or triple-hit lymphoma. Best response to two cycles of previous systemic therapy included partial response (53%; n=23), progressive disease (40%; n=16), and stable disease (5%; n=2); one patient (3%) had a response that was not estimable.

Data cutoff for the primary analysis was May 17, 2021, after which all treated patients had the opportunity to be followed for six months after the first disease assessment post-infusion. In the primary analysis cohort (n=37), median follow-up was 15.9 months (range, 6.0-26.7 months); median follow-up among all treated patients was 17.4 months (range, 6.0-26.7 months).

Safety and efficacy outcomes

Among the primary analysis cohort, the CRR (primary endpoint) was 78% (95% CI, 62-90). Median time to first complete response was 30 days (range, 27-207 days). The objective response rate (secondary endpoint) was 89% (95% CI, 75-97), and median time to first objective response was 29 days (range, 27-207 days).

As of data cutoff, 25 patients (85% of complete responses and 68% in the primary efficacy analysis) had an ongoing complete response, while 27 patients (82% of complete responses and 73% in the primary efficacy analysis) had an ongoing objective response. “This is quite remarkable in two ways: 1) The durability of >70% is far higher than what would be expected with standard chemoimmunotherapy in these patients (expectation of <40% durability with standard chemoimmunotherapy), and 2) axicabtagene ciloleucel induces durable responses in about 40% of patients in the second- and third-line setting,” explained Dr. Neelapu. “However, when used as part of first-line therapy in this study, durable responses were observed in >70% of patients, suggesting that the efficacy of axicabtagene ciloleucel may be much higher when used in the first-line setting.”

All patients (n=4) with double- or triple-hit lymphoma and an IPI score ≥3 achieved a complete response, and all patients aged ≥65 years (n=13) achieved an objective response.

Duration of response, progression-free survival, and event-free survival were not reached at 15.9 months of follow-up; estimated 12-month rates for these secondary endpoints were 81%, 75%, and 73%, respectively. Estimated 12-month OS rate (secondary endpoint) was 91%. Among the primary efficacy analysis cohort, 32 patients (86%) were alive at data cutoff.

Five patients had disease progression after initial response to axicabtagene ciloleucel; one was retreated and achieved a partial response.

All 40 patients were evaluated for safety outcomes and experienced at least one any-grade adverse event, the most common of which were pyrexia (100%), headache (70%), and decreased neutrophil count (55%). Most patients (85%; n=34) experienced grade ≥3 adverse events, the most common of which were decreased neutrophil count (53%), reduced white blood cell count (43%), and anemia (30%).

Cytokine release syndrome (CRS) occurred in all patients, and most cases were grade 1 or 2 (93%). Median time to onset of CRS after infusion was four days (range, 1-10 days). About three-quarters of patients (n=29; 73%) experienced neurologic adverse events: seven events (18%) were grade 3 and two (5%) were grade 4. Median time to onset of neurologic events was nine days (range, 2-44 days).

A third of patients (33%; n=13) experienced any-grade infection. Six patients (15%) treated with axicabtagene ciloleucel died: four died from progressive disease after proceeding to subsequent therapies, one died from COVID-19, and the died other from septic shock.

Detectable CAR levels

CAR T-cell expansion was observed in peripheral blood in all patients. Median peak CAR T-cell level (secondary endpoint) was 36.27 cells/µL^-1, and median time to peak anti-CD19 CAR T-cell levels in the blood was eight days (range, 8-37 days). Six months post-infusion, 62% of patients (n=13/21) with evaluable samples maintained low but detectable levels of CAR gene-marked cells in the blood.

“Recent randomized, controlled trials of second-line CAR T-cell therapy in LBCL … suggest that treatment with CAR T-cell therapy in earlier lines is a viable option regardless of high-risk disease characteristics,” the researchers wrote.

The primary analysis of this study was not designed to assess complete response to axicabtagene ciloleucel, and durability of responses would be better assessed at longer follow-up, the researchers noted as limitations of the study.

“The results of the ZUMA-12 study indicate that treatment of high-risk patients with axicabtagene ciloleucel may improve that cure rate substantially,” Dr. Neelapu concluded. “We think the results of the study indicate that some patients may be able to avoid chemotherapy altogether in the future, but this needs to be confirmed in a randomized, phase III trial.”

Disclosures: This study was funded by Kite Pharma, Inc., manufacturer of axicabtagene ciloleucel, which participated in the design, data collection, analysis and interpretation, and writing of the report.

Reference

Neelapu SS, Dickinson M, Munoz J, et al. Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. Nat Med. 2022;28(4):735-742.