FDA Approves Second-Line Axi-Cel for Adults With LBCL

The FDA has granted approval to axicabtagene ciloleucel (Axi-cel;Yescarta) for the treatment of adult patients with large B-cell lymphoma (LBCL) that is refractory to first-line chemoimmunotherapy or relapses within 12 months of first-line chemoimmunotherapy, according to an announcement from the FDA.

Findings from the phase 3 ZUMA-7 clinical trial supported the approval. In adult patients with primary refractory LBCL or relapse within 12 months following completion of first-line therapy, axi-cel led to a 60% improvement in event-free survival (EFS) compared with standard of care (SOC) chemotherapy.

The EFS benefit in the axi-cel arm was significant with a hazard ratio of 0.40 (95% CI: 0.31, 0.51; stratified P <0.0001). The estimated 18-month EFS rate was 41.5% (95% CI, 34.2, 48.6) with axi-cel vs 17.0% (95% CI, 11.8, 23.0) with SOC. The estimated median EFS was 8.3 months (95% CI, 4.5, 15.8) with axi-cel vs 2.0 months (95% CI, 1.6, 2.8) with SOC.

The SOC second-line treatment in the curative setting for LBCL is salvage chemotherapy followed by consolidation high-dose therapy (HDT)–autologous stem cell transplant (ASCT). But due to poor prognosis, many patients are ineligible for SOC.

ZUMA-7 is a randomized, open-label, multicenter study of 359 patients with LBCL who had not yet received treatment for relapsed or refractory lymphoma and were potential candidates for autologous hematopoietic stem cell transplantation. Patients were randomized 1:1 to receive axi-cel plus conditioning chemotherapy (n = 180) or SOC with investigator-selected platinum-based chemoimmunotherapy (n = 179). In addition to the primary end point of EFS, the key secondary end points of the study were progression-free survival, safety, and patient-reported outcomes.

Eligible patients for treatment in the study were those with LBCL that was relapsed/refractory within 12 months of frontline therapy and had intentions to proceed to HDT-ASCT. Stratification factors included response to frontline therapy and sAAIPI. Patients were required to be aged 18 years or older.

At baseline, the treatment arms were well balanced. The median patient age was 59 years (range, 21-81), and 30% of patients were 65 years and 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 high-grade BL (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.

With a data cutoff date of March 18, 2021, for the primary analysis, 94% of the 180 patients randomized received CAR T-cell therapy, and 36% of those randomized to the SOC arm underwent HDT-ASCT.

The objective response rate 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% complete response rate and an 18% partial response rate; these rates were 32% and 18%, respectively, with SOC.

At the time of the interim analysis, the median overall survival (OS) was not reached (95% CI, 28.3–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).

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

There were 55 deaths in the axi-cel arm due to progressive disease (n = 47), grade 5 AE during protocol-specified reporting period (n = 7), and definitive therapy-related mortality (n = 1). In comparison, the SOC arm had 68 deaths.

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

Finally, grade 3 or higher neurologic events occurred in 21% of axi-cel arm compared with 1% of SOC-treated patients, of which the most common were tremor, confusional state, and aphasia. All events appeared to be managed by corticosteroids. The median time to onset was 7 days in the axi-cel arm was 9 days compared with 23 days in the SOC arm.

_REFERENCES:

_{1. FDA approves axicabtagene ciloleucel for second-line treatment of large B-cell lymphoma. News release. FDa website. April 1, 2022. Accessed April 1, 2022. https://bit.ly/3u07jNx}

_{2. 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.}