Axi-Cel Demonstrates 60% EFS Improvement in Second-Line Relapsed/Refractory LBCL

Axicabtagene ciloleucel (axi-cel; Yescarta) led to a 60% improvement in event-free survival (EFS) compared with standard-of-care (SOC) chemotherapy as second-line treatment for patients with relapsed/refractory large B-cell lymphoma (LBCL), according to primary results from the phase 3 ZUMA-7 (NCT03391466) trial presented during the 2021 American Society of Hematology Annual Meeting & Exposition.

At a median follow-up of 24.9 months, findings showed that the median EFS was 8.3 months (95% CI, 4.5-15.8) for patients on axi-cel compared with 2.0 months (95% CI, 1.6-2.8) for those on SOC chemotherapy (HR, 0.398; 95% CI, 0.308-0.514; P < .0001). The 2-year EFS rates in the investigative and control arms were 40.5% (95% CI, 33.2%-47.7%) and 16.3% (95% CI, 11.1%-22.2%), respectively.

EFS was superior with axi-cel over SOC across key patient subgroups, including age (<65 years; HR, 0.490 vs ≥65 years; HR, 0.276), response to first-line therapy at randomization (primary refractory; HR, 0.426 vs relapsed within 1 year of frontline therapy; HR, 0.342), Second-line Age-Adjusted International Prognostic Index (sAAIPI) stage (0-1; HR, 0.407 vs 2-3; HR, 0.388), and prognostic marker per central laboratory (high-grade B-cell lymphoma [HGBL]–double/ triple-hit; HR, 0.285 vs double-expressor lymphoma; HR, 0.424).

“ZUMA-7 met its primary EFS end point, demonstrating statistically significant and clinically meaningful improvement in efficacy with axi-cel vs second-line SOC in relapsed/ refractory LBCL,” lead study author Frederick Locke, MD, said in a presentation on the data during the meeting.

“Axi-cel showed superiority over standard of care with [more than] 4-fold greater median EFS, 2.5-fold greater 2-year EFS, a 33% higher objective response rate [ORR], double the complete response [CR] rate, and EFS improvements across key subgroups,” added Locke, who is vice chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center in Tampa, Florida. “Results from the ZUMA-7 trial herald a paradigm shift: Axi-cel should be a new standard for patients with second-line relapsed/refractory LBCL.”

Currently, standard second-line treatment in the curative setting is salvage chemotherapy followed by consolidation high-dose therapy (HDT)–autologous stem cell transplant (ASCT). However, most patients are unable to receive HDT-ASCT, and these patients have a poor prognosis.

Axi-cel is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy that is currently FDA approved for the treatment of adult patients with relapsed/refractory LBCL after at least 2 lines of systemic therapy.

ZUMA-7 is the first randomized, international, multicenter, phase 3 trial of axi-cel compared with SOC as a second-line treatment for patients with relapsed/refractory LBCL. A total of 359 patients with relapsed/ refractory LBCL across 77 sites were randomized 1:1 to receive axi-cel plus conditioning chemotherapy (n = 180) or SOC with investigator-selected platinumbased chemoimmunotherapy (n = 179). An initial disease assessment was done at day 50; those on axi-cel continued to day 100, day 150, and long-term follow-up. Responders to SOC, either with a complete or partial response, proceeded to HDT-ASCT; nonresponders received additional treatment off protocol.

To be eligible for enrollment, patients had to be aged at least 18 years, have LBCL that was relapsed/refractory within 12 months of frontline therapy, and intend to proceed to HDT-ASCT. Stratification factors included response to frontline therapy and sAAIPI.

Steroid-only bridging therapy, without chemotherapy, was optional.

The primary end point of the trial was EFS by blinded central review; key secondary end points were progression-free survival, safety, and patient-reported outcomes. There was no protocol-specified crossover.

Patients were enrolled between January 25, 2018, and October 4, 2019. For the EFS primary analysis, the data cutoff date was March 18, 2021, at which point 250 events had occurred.

Of the 180 patients randomized to axi-cel, 94% received treatment with the CAR T-cell therapy. Of the patients enrolled to the SOC arm (n = 179), 36% of patients received HDT-ASCT.

Baseline characteristics were generally balanced between the 2 arms. Overall, the median age was 59 years (range, 21-81), and 30% of patients were 65 years or older. Most patients (79%) had stage III/IV disease, and 45% of patients had a sAAIPI of 2 to 3. Most patients (74%) were primary refractory to their frontline therapy vs 26% who relapsed within 1 year of their prior treatment. Sixteen percent of patients had HGBL (double-/triple-hit) vs 33% who had double-expressor lymphoma and 6% who had MYC rearrangement. Fifty-four percent of patients had elevated lactate dehydrogenase levels.

Additional findings showed that the ORR was 83% with axi-cel vs 50% with SOC (odds ratio, 5.31; 95% CI, 3.1-8.9; P < .0001). In the axi-cel arm, the ORR consisted of a 65% CR rate and a 18% partial response rate; these rates were 32% and 18%, respectively, in the SOC arm.

At the time of the interim analysis, the median overall survival (OS) was not reached (95% CI, 28.3 months to not evaluable [NE]) with axi-cel compared with 35.1 months (95% CI, 18.5-NE) with SOC (HR, 0.730; 95% CI, 0.530-1.007; P = .0270).

Further data showed that 56% of patients on the SOC arm received subsequent cellular immunotherapy off protocol, and Locke said that a preplanned sensitivity analysis suggests an OS benefit with axi-cel that is likely confounded by SOC treatment switching.

“The primary OS analysis will occur in the future,” Locke noted.

Regarding safety, grade 3 or higher adverse effects (AEs) occurred in 91% of patients on axi-cel compared with 83% of those on SOC, the most common of which included neutropenia (69% vs 41%, respectively), anemia (30% vs 39%), and leukopenia (29% vs 22%). Grade 3 or higher serious AEs occurred in 42% and 40% of patients on axi-cel and SOC, respectively.

Fifty-five deaths were reported on the axi-cel arm, reasons for which included progressive disease (n = 47), grade 5 AE during protocol-specified reporting period (n = 7), and definitive therapy-related mortality (n = 1). This was in comparison with 68 deaths on the SOC arm, with the same reasons occurring in 4, 2, and 2 patients, respectively.

Grade 3 or higher cytokine release syndrome occurred in 6% of patients on axi-cel; the most common any-grade symptoms were pyrexia (99%), hypotension (43%), and sinus tachycardia (31%). CRS was managed by tocilizumab (Actemra; 65%), corticosteroids (24%), and vasopressors (6%). The median time to onset was 3 days and the median duration of events was 7 days.

Grade 3 or higher neurologic events occurred in 21% of axi-cel–treated patients and 1% of SOC-treated patients; the most common AEs included tremor (26% with axi-cel vs 1% with SOC), confusional state (24% vs 2%, respectively), and aphasia (21% vs 0%). These were all managed by corticosteroids. The median time to onset was 7 days with axi-cel and 23 days with SOC; the median duration of events was 9 days and 23 days, respectively.

Locke also noted that CAR T-cell levels were associated with objective response, and tumor burden impacted CR rate in the SOC arm.

“Higher tumor burden was associated with decreased likelihood of CR in the SOC arm,” said Locke. “In contrast, higher tumor burden did not predict for a lower likelihood for CR in the axi-cel arm.”

Reference

1. Locke F, Miklos DB, Jacobson CA, et al. Primary analysis of ZUMA‑7: a phase 3 randomized trial of axicabtagene ciloleucel (axi-cel) versus standard‑of‑care therapy in patients with relapsed/refractory large B-cell lymphoma. Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 2.