ZUMA-1 | Should age limit the use of axicabtagene ciloleucel?

Older patients with B-cell lymphoma who relapse following treatment with standard therapies tend to have poor outcomes. These patients are typically not considered eligible for more intensive approaches due to the associated toxicities of these regimens and the presence of comorbidities. Thus, older patients with relapsed/refractory (R/R) disease represent an area of unmet need, with enrollment in clinical trials of new therapies being crucial to the identification of more effective treatments.

The pivotal ZUMA-1 trial (NCT02348216) investigated the anti-CD19 autologous chimeric antigen receptor (CAR) T-cell product axicabtagene ciloleucel (axi-cel; KTE-C19). The results of ZUMA-1 led to the approval of axi-cel by the United States Food & Drug Administration (FDA) and the European Medicines Agency (EMA) for adult patients with R/R large B-cell lymphoma, after two or more lines of systemic therapy.

Results from the two-year follow-up of ZUMA-1 were recently published and are summarized by Sattva S. Neelapu in the video below.

Investigators subsequently conducted a post-hoc analysis of the two-year results of ZUMA-1, by age (< 65 vs ≥ 65 years), which has recently been published in Blood and is summarized below.

Study design

• ZUMA-1 is a phase I/II single arm study in patients with R/R diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL) and transformed follicular lymphoma (tFL)
• R/R disease was defined as no response to last chemotherapy or relapse ≤ 12 months following autologous stem cell transplant (auto-SCT)
• Patients had an Eastern Cooperative Oncology Group (ECOG) score of 0–1 and had previously received treatment with an anti-CD20 monoclonal antibody and an anthracycline-containing regimen

Dosing schedule

• Conditioning lasted for three days and included:
  • Cyclophosphamide: 500mg/m²/day
  • Fludarabine: 30mg/m²/day
• Axi-cel infusion: 2x10⁶ CAR T-cells/kg

Patient characteristics and treatment

• Median follow-up: 27.1 months
• Baseline characteristics were mainly comparable between patients aged < 65 and ≥ 65 years as shown in Table 1, with the exceptions being:
  • More patients in the ≥ 65 years group had an International Prognostic Index (IPI) score of 3–4 largely due to age > 60 being a component of the IPI scoring criteria
  • More patients < 65 years old had received prior auto-SCT mainly due to older patients being excluding from auto-SCT eligibility

 Table 1. Patient characteristics by age¹

DLBCL, diffuse large B-cell lymphoma; IPI, international prognostic index; PMBCL, primary mediastinal B-cell lymphoma; auto-SCT, autologous stem cell transplant; tFL, transformed follicular lymphoma
	< 65 years N= 81	≥ 65 years N= 27
Median age, years (range)	55 (23–64)	69 (65–76)
Male, %	63	81
Disease stage III/IV, %	84	81
IPI score 3–4, %	36	70
≥ 3 prior therapies, %	72	67
Disease subtype DLBCL PMBCL tFL	79 10 11	74 0 26
Prior auto-SCT, %	30	19
Refractory to second- or later-line therapy, %	73	78

 

Efficacy

• The efficacy evaluable population included patients treated in the phase II portion only
• Table 2 shows the investigator-assessed efficacy data by patient age

Table 2. Investigator-assessed efficacy endpoints by age group¹

CR, complete response; DoR, duration of response; NE, not evaluable; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response
	< 65 years N= 77	≥ 65 years N= 24
ORR, %	81	92
Best response CR, % PR, %	53 27	75 17
Ongoing response at data cut-off	38	42
Median DoR, months (95% CI)	8.1 (2.1–NE)	12.0 (2.4–NE)
Median PFS, months (95% CI)	5.6 (3.1–18.4)	13.2 (3.1–NE)
24-month OS, %	49	54

Safety

• The safety evaluable population consisted of all patients treated in the phase I and II stages of the study
• Main grade three or higher adverse events (AEs) are shown in Table 3
• Patients aged ≥ 65 years more frequently experienced grade ≥ 3 delirium and encephalopathy compared to patients aged < 65 years, though other key AEs were comparable
• Grade 5 AEs were reported by four patients (4% of each age group)

Table 3. Grade ≥3 adverse events by age group¹

CRS, cytokine release syndrome
	< 65 years N= 81	≥ 65 years N= 27
Any, %	98	100
Hematological, % Neutropenia Anemia Thrombocytopenia	81 44 38	74 48 44
CRS, %	12	7
Neurologic events, %	28	44
Infections, %	31	19

 

Conclusion

This subgroup analysis of the 2-year follow-up of ZUMA-1 demonstrates that axi-cel was able to induce high response rates and maintain a manageable safety profile irrespective of patient age. The authors therefore do not recommend that age alone should preclude a patient from receiving axi-cel and that this novel immunotherapy represents a new treatment option within an area of unmet medical need.

Future directions

Axi-cel, and similar products such as KTE-X19* are being tested in a variety of patient populations. Recently, the results from ZUMA-2 of KTE-X19 in R/R mantle cell lymphoma led to the FDA granting priority review and the European Medicines Agency validating the marketing authorization application. Results of axi-cel use in patients with secondary central nervous system (CNS) lymphoma in the real-world setting also recently showed that patients with secondary CNS disease had comparable outcomes to patients without CNS disease.

*KTE-X19 uses the axi-cel CAR construct but the manufacturing, process includes lymphocyte enrichment