FDA Approves Axicabtagene Ciloleucel for Second-Line LBCL

FDA

The FDA has approved axicabtagene ciloleucel (axi-cel; Yescarta) for the treatment of adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or relapses within 12 months of first-line chemoimmunotherapy.¹

The regulatory decision is based on findings from the phase 3 ZUMA-7 trial (NCT03391466), which showed that at a median follow-up of 24.9 months, the estimated median EFS with the CAR T-cell therapy was 8.3 months (95% CI, 4.5-15.8) vs 2.0 months (95% CI, 1.6-2.8) with standard-of-care (SOC) treatment (HR, 0.4-; 95% CI, 0.31-0.51; P < .0001). The estimated 18-month EFS rates in the investigative and control arms were 41.5% (95% CI, 34.2%-48.6%) and 17.0% (95% CI, 11.8%-23.0%), respectively.

Axi-cel was also found to improve objective response rate (ORR) over SOC, at 83% (95% CI, 77%-88%) vs 50% (95% CI, 43%-58%), respectively (odds ratio, 5.31; 95% CI, 3.1-8.9; P < .0001). In the axi-cel arm, the ORR was comprised of a 65% CR rate and a 18% PR rate; these rates were 32% and 18%, respectively, in the SOC arm.

The first randomized, international, multicenter phase 3 ZUMA-7 trial compared the safety and efficacy of second-line axi-cel with that of the current SOC as second-line treatment in patients with relapsed or refractory LBCL.

To be eligible for inclusion, patients needed to be at least 18 years of age, have LBCL that was relapsed or refractory within 1 year of frontline treatment, and intention to proceed to consolidation high-dose therapy–autologous stem cell transplant (HDT-ASCT).

A total of 359 patients were enrolled to the trial and were randomized 1:1 to receive either a single infusion of axi-cel (n = 180) or SOC in the form of investigator-chosen platinum-based chemoimmunotherapy (n = 179) as second-line treatment. The age of the study participants ranged from 22 years to 81 years; 30% were aged 65 years or older.

An initial disease assessment was performed at day 50; those on the CAR T-cell therapy continued to day 100, day 150, and long-term follow-up. Those who responded to treatment with SOC, either with a complete response (CR) or partial response (PR), went on to HDT-ASCT. Nonresponders received additional treatment off trial protocol. Steroid-only bridging therapy, without chemotherapy, was optional.

Key stratification factors included response to frontline therapy and Second-line Age-Adjusted International Prognostic Index (sAAIPI) stage.

The primary end point of the trial was EFS per blinded central review, and key secondary end points comprised ORR, overall survival (OS), progression-free survival, patient-reported outcomes (PRO), and safety.

Between January 25, 2018, and October 4, 2019, participants were enrolled. For the EFS primary analysis, the data cutoff date was March 18, 2021, at which point 250 events had been reported. Of the 180 patients who were randomized to the investigative arm, 94% received treatment with the CAR T-cell therapy.² Of the patients enrolled to the SOC arm, 35% received on-protocol HSCT, and lack of response to chemotherapy was the most common reason for not receiving autologous HSCT.¹

Baseline characteristics were balanced between the 2 treatment arms. Overall, the median age was 59 years (range, 21-81), and 30% of patients were aged 65 years or older. Seventy-nine percent of patients had stage III/IV disease, and 45% had a sAAIPI of 2 to 3. Seventy-four percent of patients 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 data presented during the 2021 ASH Annual Meeting showed that the benefit in EFS achieved with axi-cel over SOC was observed across key patient subsets including age (<65 years; HR, 0.490 vs ≥65 years; HR, 0.276), response to frontline treatment at randomization (primary refractory; HR, 0.426 vs relapsed within 1 year of therapy; HR, 0.342), sAAIPI stage (0 to 1; HR, 0.407 vs 2 to 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).

At the time of the interim analysis, the median OS was not yet 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).

Regarding safety, grade 3 or higher adverse effects (AEs) were experienced by 91% of patients on the CAR T-cell therapy vs 83% of those on SOC. The most common toxicities that were grade 3 or higher included neutropenia (69% vs 41%, respectively), anemia (30% vs 39%), and leukopenia (29% vs 22%). Grade 3 or higher serious toxicities were observed in 42% and 40% of patients on axi-cel and SOC, respectively.

A total of 55 deaths were reported on the CAR T-cell therapy 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). Sixty-eight deaths were reported on the SOC arm, with the same reasons occurring in 4, 2, and 2 patients, respectively.

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

Grade 3 or higher neurologic events were experienced by 21% of those who received the CAR T-cell therapy vs 1% of those given SOC; the most common AEs comprised tremor (26% with axi-cel vs 1% with SOC), confusional state (24% vs 2%, respectively), and aphasia (21% vs 0%). These events 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.

Axi-cel was also found to have a clinically meaningful improvement in quality of life vs SOC in the second-line setting for patients with relapsed or refractory LBCL, according to findings from the trial shared during the 48th Annual Meeting of the EBMT.³ Specifically, the QOL benefit with the CAR T-cell therapy was observed at day 100 as measured by multiple validated PRO instruments.

Previously, in October 2017, the FDA approved axi-cel for use in adult patients with relapsed/refractory LBCL after 2 or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from FL.⁴ The decision was based on complete remission rates reported in the phase 2 ZUMA-1 trial (NCT02348216).

References

1. FDA approves axicabtagene ciloleucel for second-line treatment of large B-cell lymphoma. News release. FDA; April 1, 2022. Accessed Aprl 1, 2022. https://bit.ly/3iSQ8XT
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. Blood. 2021;138(suppl 1):2. doi:10.1182/blood-2021-148039
3. Elsawy M, Chavez JC, Avivi I, et al. Patient‑reported outcomes in ZUMA‑7, a phase 3, randomized, open‑label study evaluating the efficacy of axicabtagene ciloleucel (axi‑cel) versus standard‑of‑care therapy in relapsed /refractory large B‑cell lymphoma. Presented at: 2022 EBMT Annual Meeting; March 19-23, 2022; virtual. Abstract P104.
4. FDA approves axicabtagene ciloleucel for large B-cell lymphoma. News release. FDA; October 18, 2017. Accessed March 29, 2022. https://bit.ly/3F8EzFE