FDA Approval Summary: Axicabtagene Ciloleucel for Second-Line Treatment of Large B-Cell Lymphoma

Although standard chemoimmunotherapy can cure up to 60% of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), approximately 10% to 15% have primary refractory disease and the remainder relapse despite an initial complete response (CR; ref. 1). In patients fit for intensive therapy, chemoimmunotherapy followed by high-dose therapy (HDT) and autologous hematopoietic stem cell transplantation (HSCT) has been the standard second-line approach, provided there is a sufficient chemotherapeutic response (2). Although this approach has curative potential, patients with primary refractory disease or early relapse (variably defined as relapse within 1 year of initiating chemoimmunotherapy, completing chemoimmunotherapy, or attaining CR) tend to have poorer outcomes than patients with longer initial remissions (3, 4), as early treatment failure often signals chemo-refractory disease. Second-line chemoimmunotherapy for primary refractory and early relapsing DLBCL has resulted in response rates of approximately 29% with a transplant rate of only 26% (4) and an estimated 3-year event-free survival (EFS) rate of 20% (3).

In April 2022, the FDA granted regular approval to axicabtagene ciloleucel (axi-cel) for adult patients with large B-cell lymphoma (LBCL) that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy. At the time of this approval, no therapies were FDA-approved for the potentially definitive management of relapsed or refractory (R/R) LBCL in the second-line setting. The only approved therapy in the second-line setting was tafasitamab in combination with lenalidomide (5), which is under accelerated approval for the treatment of adult patients with R/R DLBCL not otherwise specified (NOS) who are transplant-ineligible.

Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that binds to CD19-expressing cells. Following CAR T-cell engagement with target cells, the CD28 and CD3-zeta co-stimulatory domains activate downstream signaling cascades that lead to T-cell activation, proliferation, and killing of CD19-expressing cells. Axi-cel was originally FDA-approved for relapsed R/R LBCL after two or more lines of systemic therapy (regular approval, October 2017; 6) and then for R/R follicular lymphoma after two or more lines of systemic therapy (accelerated approval, March 2021; ref. 7). Herein, we summarize the FDA clinical review and basis for regular approval of axi-cel as a second-line treatment for selected patients with LBCL, with a focus on key regulatory considerations.

ZUMA-7 (NCT 03391466) is a phase III, randomized, open label, multicenter study comparing axi-cel with standard second-line therapy in adults with primary refractory LBCL (defined as no CR to first-line therapy) or biopsy-proven relapse of LBCL ≤ 12 months of initiating or completing first-line therapy (8). All patients were potential candidates for autologous HSCT and had not yet received second-line treatment. The study excluded patients with primary mediastinal B-cell lymphoma (PMBL), need for urgent therapy due to tumor mass effect, prior CD19-directed therapy, or a history of central nervous system (CNS) lymphoma or CNS disorders.

In total, 359 patients were randomized in a 1:1 ratio to receive either a single infusion of axi-cel at the approved dose (target 2×10⁶ CAR-positive viable T-cells/kg, with a maximum of 2 × 10⁸ CAR-positive viable T cells), preceded by lymphodepleting chemotherapy (cyclophosphamide 500 mg/m² and fludarabine 30 mg/m² intravenously on Day -5 to -3), or standard second-line therapy. Bridging therapy was limited to corticosteroids and administered to 60 patients in the axi-cel arm following leukapheresis. Standard therapy consisted of 2 or 3 cycles of an investigator's choice of protocol-defined, platinum-based chemoimmunotherapy followed by HDT and autologous HSCT in patients who achieved at least a partial response (PR). The trial design did not incorporate crossover. Randomization was stratified by response to first-line therapy and the second-line age adjusted International Prognostic Index (aaIPI) score.

The primary efficacy endpoint was EFS, as determined by a blinded independent review committee (IRC) using Lugano criteria (9). EFS was defined as the time from randomization to the earliest date of the following events: disease progression, commencement of new anti-lymphoma therapy (NALT), death from any cause, or a best response of stable disease by the Day 150 assessment. The study was powered to detect an EFS HR of 0.67, corresponding to a 50% improvement in median EFS from 4 months to 6 months. The key secondary endpoints were overall response rate (ORR) per IRC and overall survival (OS), to be tested hierarchically. All reported P values are two-sided.

Of the 359 patients randomized, 30% were ≥ 65 years of age, 74% had primary refractory disease, and 26% had relapse within 12 months of first-line therapy. The main diagnoses were de novo DLBCL NOS (63%), high-grade B-cell lymphoma (HGBL; 19%), and large cell transformation of follicular lymphoma (13%). The arms were generally balanced in baseline characteristics, apart from more HGBL cases in the axi-cel arm (Table 1).

Of 180 patients randomized to the axi-cel arm, 170 (94%) received the CAR-T product (of which 2 received non-conformal product), with a median time from leukapheresis to product delivery of 18 days (range: 13 to 49 days). In contrast, of 179 patients randomized to receive standard therapy, 62 (35%) ultimately received HDT and HSCT on-protocol. The major reason that precluded HSCT was lack of response to chemoimmunotherapy; of the 168 patients who received any chemoimmunotherapy, 80 (48%) had an objective response per investigator, of whom 15 progressed before HSCT and 3 did not receive HSCT for other reasons.

Efficacy results by intention-to-treat analysis are presented in Table 1; Fig. 1. ZUMA-7 demonstrated superior EFS per IRC in the axi-cel arm compared with the standard therapy arm with a HR of 0.40 [95% confidence interval (CI), 0.31–0.51; stratified P value < 0.0001; Fig. 1A]. The axi-cel arm had an estimated median EFS of 8.3 months, compared with 2.0 months in the standard therapy arm. The treatment effect was consistent across most major subgroups, such as primary refractory versus relapsed disease, second-line IPI risk category, histologic subtypes, and demographic characteristics.

The IRC-assessed ORR was significantly higher in the axi-cel arm: 83% (95% CI, 77–88) versus 50% (95% CI, 43–58) in the standard therapy arm (P value < 0.0001). This difference in ORR was driven primarily by a numerically higher CR rate in the axi-cel arm (65%, versus 32% in the standard therapy arm; Table 1).

A prespecified interim OS analysis was performed at the time of the primary EFS analysis, at a 75% information level. After a median follow-up of 2.1 years, OS was not significantly different between the two arms. However, the OS results tended to favor the axi-cel arm, with a HR of 0.71 (99.1% CI, 0.46–1.08) and P value of 0.03 (P value boundary, 0.009; Fig. 1B).

The progression-free survival (PFS) outcomes also favored the axi-cel arm (Fig. 1C), with estimated median PFS per IRC of 14.9 months compared with 5.0 months in the standard therapy arm (HR, 0.56; 95% CI, 0.41–0.76). In this analysis, recipients of NALT in the absence of progression were censored at the last disease assessment before NALT. The PFS analysis was descriptive, with no prespecified hypothesis testing.

As seen in R/R LBCL after at least 2 prior lines (10), the duration of response to axi-cel correlated with the depth of response, with primarily the CRs being durable (Fig. 2). The estimated median duration of response was 28.4 months (95% CI, 26.9–NE) in patients achieving CR, versus 1.6 months (95% CI, 1.4–1.9) in patients with a best response of PR.

The U.S. Prescribing Information (USPI) for axi-cel includes a boxed warning for cytokine release syndrome (CRS) and neurologic toxicity, which are the basis for implementing a risk evaluation and management strategy (REMS). Other warnings include serious infections, prolonged cytopenias, hypogammaglobulinemia, and secondary malignancies (11).

The safety of axi-cel arm in ZUMA-7 is briefly reviewed, with a focus on adverse reactions (AR) of special interest. A comparative toxicity analysis between the two study arms was not performed, given the fundamentally different treatment strategies with known distinct toxicity profiles. Table 2 summarizes selected ARs in recipients of the conformal CAR T-cell product in ZUMA-7 (N = 168). ARs affecting ≥ 30% of patients, excluding laboratory terms, included fever, CRS, fatigue, hypotension, encephalopathy, tachycardia, diarrhea, headache, nausea, musculoskeletal pain, and febrile neutropenia. Grade ≥ 3 ARs occurred in 91% of patients, with Grade ≥ 3 ARs of special interest including prolonged cytopenia (33%), febrile neutropenia (31%), neurologic toxicities (25%), infections (14%), and CRS (7%). Serious ARs occurred in 50% of patients, and 3 (1.8%) patients had fatal ARs (encephalopathy, progressive multifocal leukoencephalopathy, and sepsis).

In ZUMA-7, CRS occurred in 92% of patients (Grade ≥ 3, 7%) based on modified Lee and colleagues criteria (12), with a median time from axi-cel infusion to CRS onset of 3 days (range: 1 to 10). CRS resolved in all cases, after a median duration of 7 days. Management included tocilizumab, with or without steroids, in 72% of cases.

Neurologic toxicity, as defined by the FDA, was reported in 74% of patients, with a 25% incidence of Grade ≥ 3 neurologic toxicity. The most common neurologic toxicities (≥ 10%) included encephalopathy, headache, tremor, dizziness, aphasia, delirium, and peripheral neuropathy. The median time-to-onset was 5 days from infusion (range: 1 to 133), with 75% of cases presenting within 7 days. Neurologic toxicity included steroid management in 47% of cases and resolved in 85% of cases. Of the cases that resolved, the median time to resolution was 15 days (range: 1 to 546), with 75% of those cases resolving by 2.3 months.

Axi-cel is the first CAR T-cell therapy approved for the second-line management of primary refractory and early relapsed LBCL, and represents a fundamentally different treatment modality than the historical standard. In June 2022, the FDA-approved lisocabtagene maraleucel, another autologous CD19 CAR T-cell therapy for adult patients with LBCL who have refractory disease or relapse within 12 months of first-line chemoimmunotherapy (13, 14), as well as for patients with primary refractory or first relapse of LBCL who are transplant-ineligible due to comorbidities or age (14).

Herein, we outlined key clinical review issues and regulatory considerations regarding the second-line indication for axi-cel. The FDA's multidisciplinary reviews of this licensing application are available publicly (15). Table 3 outlines the FDA's benefit-risk analysis for approval of axi-cel in the second-line LBCL setting.

The safety profile of axi-cel in ZUMA-7 was consistent with the safety profile described in other registrational trials of axi-cel (10). The rate and grading of CRS were comparable in the applicant's and the FDA's assessments. However, larger differences were noted between the applicant's and the FDA's assessment of neurotoxicity. The applicant defined neurologic toxicity based on the approach described by Topp and colleagues, which includes events associated with anti-CD19 immunotherapy, primarily blinatumomab (16). The applicant considered 54% of axi-cel recipients to have CAR T-cell related neurotoxicity, with a 21% rate of Grade ≥ 3 neurologic toxicity. The FDA took a broader view of the neurologic toxicity assessment, considering all adverse events classified under the system organ class of psychiatric and nervous system disorders, with the exception of select low-grade neuropsychiatric events that were isolated and nonspecific. The broader definition includes CNS processes indicative of immune effector cell-associated neurotoxicity syndrome such as encephalopathy, aphasia, motor weakness, and seizures (17) and other ARs that may be regimen-related such as headache, tremor, myoclonus, myelitis, and peripheral neuropathy. The FDA adopted this broader approach because, as the understanding of the spectrum of CAR T-cell neurotoxicity is evolving, toxicities not previously categorized as CAR-T related neurotoxicity have been recognized as potentially attributable to this treatment platform (18, 19). The review team identified additional ARs that were considered manifestations of neurologic toxicity but were misclassified under different system organ classes. In total, the FDA identified 34 additional patients (20%) regarded as having regimen-related neurologic toxicity.

By intention-to-treat analysis, ZUMA-7 demonstrated the superiority of axi-cel compared with standard second-line therapy in a refractory or poor-risk relapsed LBCL population. Compared with the standard therapy arm, in which only 35% of randomized patients underwent HSCT per protocol, 94% of patients randomized to the axi-cel arm received the intended CAR T-cell infusion. In the standard therapy arm, chemotherapeutic resistance was the leading reason for not proceeding with HSCT. Although cross-trial comparisons are limited, efficacy outcomes in the standard therapy arm, including the subgroup of patients who received HSCT on protocol, were consistent with historical trials evaluating second-line chemoimmunotherapy and HSCT for DLBCL (3, 4, 20), suggesting that the standard therapy arm did not underperform in ZUMA-7.

In ZUMA-7, the difference in types of EFS events was driven by the use of NALT (6% in the axi-cel arm vs. 35% in the standard therapy arm). In the control arm, there was a lower ORR to chemoimmunotherapy by investigator assessment compared with IRC assessment, resulting in NALT due to concerns for inadequate chemotherapeutic response. Because of the open-label trial design, the FDA conducted a conservative sensitivity analysis that excluded selected events of NALT; the improvement in EFS was maintained in this analysis.

On PFS analysis, censoring in the axi-cel arm was primarily due to ongoing responses and tended to occur in the later part of the Kaplan–Meier curve, whereas censoring in the standard therapy arm was mostly due to NALT and occurred in the earlier part of the Kaplan–Meier curve (Fig. 1C). Although there was no prespecified statistical testing for PFS, the PFS data were consistent with the EFS and ORR data.

Although the difference in OS between the two arms was not statistically significant at the time of the interim analysis, the direction of the observed treatment effect was consistent with the EFS and PFS data. Results of the OS analysis may be confounded by the fact that 55% of patients randomized to the standard therapy arm received CD19-directed CAR T-cell therapy after experiencing an event. An updated analysis of OS is prespecified. Importantly, longer-term follow-up would be needed to inform the curative potential of axi-cel in the second-line LBCL setting.

In determining the indication statement, the FDA considered the following:

• 1. Scope of second-line indication: The applicant sought a broad indication for the treatment of patients with R/R LBCL. However, ZUMA-7 enrolled a subset of R/R LBCL with primary refractory disease or relapsed within one year of first-line chemoimmunotherapy which is a prognostically poor risk subgroup. The study does not provide data to inform the use of axi-cel in patients that relapse more than 1 year after completion of first-line therapy as these patients were excluded from the study. Therefore, the indication statement was modified to reflect the population that was evaluated in the study.

• 2. The study question: ZUMA-7 was not designed to determine chemosensitivity of the study participants prior to randomization. Therefore, the study was not designed to inform the clinical benefit of axi-cel versus standard therapy in patients with first chemosensitive relapse who are able to undergo HSCT. Furthermore, in this high-risk disease setting, a minority of patients randomized to standard therapy underwent HSCT, limiting exploratory comparisons of axi-cel versus HSCT in first chemosensitive relapse. Hence, the comparative efficacy of axi-cel and HSCT in patients with first chemosensitive relapse remains uncertain and would require a separate study with a different design. The stringent eligibility criteria of ZUMA-7, in particular the requirement for candidacy for HDT and HSCT, the exclusion of patients with CNS disorders, and the exclusion of patients requiring immediate cytoreduction, limit the generalizability of the study outcomes. While the indication statement is not qualified to list these patient factors, the eligibility criteria and a description of the patient population enrolled in ZUMA-7 are provided in the efficacy portion of the USPI to facilitate an understanding of how to use the drug safely and effectively.

• 3. Data by histologic subtype: The “LBCL” indications for axi-cel encompass a heterogeneous group of aggressive lymphomas, including lymphomas that were either underrepresented or not represented in the axi-cel registrational trials. PMBL was excluded from ZUMA-7, presumably because radiation therapy, used commonly as part of salvage therapy, may have confounded the efficacy assessment. Because management of R/R PMBL is similar to other histologies included in the study, and 8% of the efficacy population in ZUMA -1 (the basis for the original approval in LBCL) had PMBL, we extrapolated the efficacy data of axi-cel in the second-line setting to include PMBL in the indication statement.

Patients with primary CNS lymphoma were ineligible for ZUMA-7, and there are few efficacy and safety data with use of axi-cel in this disease (21). Furthermore, there are concerns with safety if neurotoxicity were to develop in patients with increased intracranial pressure and/or space-occupying mass lesions within the brain. Therefore, the FDA added a limitations of use statement for the second-line indication, that axi-cel is not indicated for the treatment of patients with primary CNS lymphoma. The same limitations of use statement is in place for the originally approved indication in multiply relapsed LBCL.

In summary, ZUMA-7 has demonstrated substantial improvement in EFS in the axi-cel arm compared with standard therapy, supported by ORR, interim OS, and PFS data. The magnitude of the clinical benefit, coupled with an acceptable safety profile, is the basis for the regular approval of axi-cel for the treatment of adult patients with LBCL that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.The approval enables a potential paradigm shift for the second-line management of selected patients with poorer-risk LBCL. However, the stringent eligibility criteria of ZUMA-7, the notable toxicity profile of axi-cel, and the scope of the study question are important considerations for the safe and effective use of axi-cel in the second-line setting.

No disclosures were reported.

The Editor handling the peer review and decision-making process for this article has no relevant employment associations to disclose.