Redefining survival in 3L+ large B-cell lymphoma with axicabtagene ciloleucel

Singapore’s Health Sciences Authority recently approved axicabtagene ciloleucel (Yescarta) for the treatment of relapsed or refractory large B-cell lymphoma (LBCL) in adults after ≥2 lines of systemic therapy. Shedding light on this innovative therapy, Dr Matthew Frank, Assistant Professor of Medicine specializing in Blood and Marrow Transplantation and Cellular Therapy at Stanford University, Stanford, California, US, discussed landmark trial data, some real-world evidence, and their implications for patient selection and adverse event management during the Yescarta Commercial Launch in Singapore in May.

Axicabtagene ciloleucel: Efficacy and safety
Axicabtagene ciloleucel (axi-cel) is a CD19-directed autologous chimeric antigen receptor (CAR) T-cell therapy that has shown efficacy in relapsed or refractory diffuse LBCL patients who have had suboptimal responses to conventional treatments. While axi-cel’s immune activation brings about its effectiveness, it comes with the risk of adverse events, including cytokine release syndrome (CRS) and neurotoxicity.

Axi-cel is US FDA-approved based on the primary analysis of the pivotal ZUMA-1 study. After 5 years of follow-up, the objective response rate among 101 axi-cel-treated patients was 83 percent; 58 percent had a complete response (CR). The median overall survival (OS) was 25.8 months. The estimated 5-year OS rate was 42.6 percent, while disease-specific survival (excluding deaths unrelated to disease progression) estimated at 5 years was 51 percent. [N Engl J Med 2017;377:2531-2544; Blood 2023;141:2307-2315]

Moreover, the safety profile of axi-cel during the 5-year follow-up of ZUMA-1 remained consistent with previous reports. Five-year follow-up of ZUMA-1 supports the curative potential of axi-cel in refractory large B-cell lymphoma. No new safety signals were reported in patients treated with axi-cel. [Blood 2023;141:2307-2315]

Real-world evidence: Implications for patient selection
The use of axi-cel in a standard-of-care setting demonstrated efficacy and safety outcomes that are comparable to that observed in ZUMA-1, even among patients with comorbidities that would have rendered them ineligible for the trial (Table 1). [Clin Oncol 2020;38:3119-3128; J Clin Oncol 2020;38:3095-3106; ASH 2019, abstract 764]

“This suggests that patients ineligible to ZUMA-1 still had durable response with axi-cel. Thus, patient selection for axi-cel should be based on consideration of comorbidities and risk-to-benefit ratio rather than strict adherence to ZUMA-1 eligibility criteria,” Frank emphasized.

“Analysis of real-world data showed that ECOG performance status of 2 or higher and elevated LDH were associated with inferior PFS and OS. Conversely, older patients (>60 years old) achieved favourable efficacy outcomes despite higher rates of CRS and neurotoxicity [J Clin Oncol 2020;38:3119-3128],” he added. “My oldest patient is actually 85 years old.”

“Bridging therapy is not associated with improved outcomes, and the optimal bridging strategy remains unknown. [Blood Adv 2020;4:2871-2883] If bridging is required, treatment should be personalized. When feasible, CAR T-cell therapy should be initiated promptly to minimize the need for bridging,” he advised.

Updates in adverse event management
“Adverse event management has also improved,” Frank continued. “Early or prophylactic use of corticosteroids and/or tocilizumab, as shown in ZUMA-1 cohorts 4 and 6, may reduce the incidence of grade ≥3 CRS and ICANS and can reduce steroid use overall.” (Figure 1) [N Engl J Med 2017;377:2531-2544; Br J Haematol 2021;194:690-700; Br J Haematol 2021;195:388-398]

There were no grade 4 or 5 CRS or NEs observed in cohort 4, and the cumulative steroid dose and total number of doses in cohort 4 were lower than in cohorts 1+2. Similarly, in cohort 6, prophylactic corticosteroids and earlier corticosteroid and/or tocilizumab intervention resulted in zero grade 3 or higher CRS, a low rate of grade 3 or higher NEs, and high response rates in this study population. [N Engl J Med 2017;377:2531-2544; Br J Haematol 2021;194:690-700; Br J Haematol 2021;195:388-398]

“As a final point, data suggest that infections are the largest cause of nonrelapse mortality. [J Clin Oncol 2020;38:3119-3128] CAR T-cell immunotherapies pose unique challenges for acute and long-term infection prevention. Serious toxicities caused by CAR T-cell therapy, including CRS and ICANS, along with underlying malignancy, prior cytotoxic treatments, and lymphodepletion chemotherapy, increase the risk of infections. Depletion of normal CD19-expressing B cells by CAR T cells can result in prolonged immune deficits. [Blood 2020;136:925-935] Thus, the use of prophylactic antimicrobials is essential,” Frank concluded.