Axi-cel in LBCL: fulfill two needs with one deed

In this issue of Blood, Elsawy et al¹ present the patient-reported outcomes after axicabtagene ciloleucel (axi-cel) administered as second-line therapy in large B-cell lymphoma compared with salvage chemotherapy followed by autologous stem cell transplantation (ASCT). Treatment with axi-cel resulted in clinically meaningful and statistically significant improvements in quality of life and an earlier return to baseline functioning compared with salvage chemotherapy followed by ASCT.

High-dose chemotherapy followed by ASCT has been the standard of care (SOC) for second-line therapy in large B-cell lymphoma for nearly 3 decades.² However, this approach has several limitations. First, ASCT is only indicated in patients with chemosensitive disease, and the majority of patients with primary refractory disease are not able to proceed to ASCT because their disease is often refractory to salvage chemotherapy. Second, patients with primary refractory or early relapsed disease often have poor outcomes after ASCT.³ Finally, many patients are not considered candidates for ASCT because of age or comorbidities. Advances in immunotherapy, particularly chimeric antigen receptor (CAR) T-cell therapy, have ushered in a new era in the treatment of B-cell lymphomas. Long-term remissions seen in patients who failed ≥2 prior lines of therapy led to randomized clinical trials in the second-line setting for patients with primary refractory disease and early relapse; these trials compared the efficacy and safety of CAR T-cell therapy over the SOC option of salvage chemotherapy followed by ASCT for responders.⁴ 

The ZUMA-7 study (Efficacy of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma) evaluated axi-cel vs SOC as second-line therapy in patients with large B-cell lymphoma and reported significantly longer event-free survival with axi-cel compared with SOC.⁵ These results led to approval by the US Food and Drug Administration (FDA) of axi-cel for patients with large B-cell lymphoma who are refractory to first-line chemoimmunotherapy or those who relapse within 12 months of first-line chemoimmunotherapy.⁶ Although the superior efficacy of axi-cel over salvage chemotherapy followed by ASCT was clearly shown in the ZUMA-7 study, axi-cel was associated with a relatively high incidence of cytokine release syndrome (92%), neurologic events (60%), and prolonged cytopenia (29%), raising questions about its tolerability and the overall patient experience.

Patient-reported outcomes (PROs) are commonly incorporated in oncology clinical trials as a tool for assessing a product’s safety and tolerability. To address tolerability after axi-cel, Elsawy et al measured PROs at prespecified time points after randomization (see figure). Quality of life can be affected by disease status and by the toxicity of the treatment offered. To avoid the impact of disease status, the authors stopped assessing PROs after patients had a predefined event (disease progression, death from any cause, best response as stable disease up to day 150 after randomization, or start of a new anticancer therapy). The assessment of PROs in patients who had responded to either regimen led to imbalances between the axi-cel group and the SOC group. This was due to a higher dropout rate in the SOC group because of increased events (ie, death, progression, inadequate response or starting a new therapy). However, restricting PROs to responders was essential to ensure that the quality of life results could be attributed to the toxicity of the respective treatments rather than being confounded by disease status. The results imply that axi-cel is better tolerated, and patients can return to their baseline quality of life earlier with axi-cel, compared with salvage therapy followed by ASCT.

The advancement of immunotherapy for second-line therapy in large B-cell lymphoma is not limited to axi-cel. The interim results of the TRANSFORM (A Global Randomized Multicenter Phase 3 Trial of JCAR017 Compared to Standard of Care in Adult Subjects With High-risk, Second-line, Transplant-eligible Relapsed or Refractory Aggressive B-cell Non-Hodgkin Lymphomas) study showed superior efficacy of lisocabtagene maraleucel (liso-cel) compared with salvage chemotherapy followed by ASCT as second-line therapy in patients with large B-cell lymphoma.⁷ Moreover, the PILOT study reported excellent efficacy and no new safety signals for liso-cel as second-line therapy for patients with large B-cell lymphoma who are not intended for ASCT due to age and/or comorbidities.⁸ These results led to the FDA approval of liso-cel for patients with large B-cell lymphoma who have disease refractory to first-line chemoimmunotherapy or who relapse within 12 months of first-line chemoimmunotherapy, as well as those with disease refractory to first-line chemoimmunotherapy or who relapse after first-line chemoimmunotherapy and are not eligible for SCT due to comorbidities or age.⁹ Both these studies incorporated PROs. Preliminary results from the TRANSFORM study reported favorable improvement in most PROs with liso-cel compared with salvage chemotherapy followed by ASCT.¹⁰ The PRO results from the PILOT study are much anticipated due to the elderly and comorbid population enrolled.

Although efficacy end points are standardized between the different studies, the type and timeline for PRO assessments vary between studies. Both ZUMA-7 and TRANSFORM used European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30, but there were differences in other PRO assessments and the time points at which the assessments were performed. Standardization of PRO assessments may help with a better interpretation of quality of life measures, especially as more products become available in this space.

The combination of improved efficacy and better tolerability helps us establish a new SOC option in second-line therapy for large B-cell lymphoma. How do we translate the improved efficacy and tolerability in clinical trials to benefiting patients with relapsed or refractory large B-cell lymphoma in the real world? In ZUMA-7, leukapheresis slots were available quickly; median time from leukapheresis to product release was 13 days; and 94.4% of patients who were randomized to the axi-cel group were able to receive the product. Moreover, minorities such as Black individuals were underrepresented in ZUMA-7 (6% of the population who received axi-cel). Unfortunately, in the real-world setting, there are multiple barriers such as distance to a certified CAR T-cell center, delays in financial clearance, availability of slots for leukapheresis, time taken for product availability, and the ability to keep the disease controlled while awaiting the CAR T-cell product. We are unable to estimate the proportion of patients who are unable to receive FDA-approved CAR T-cell therapy due to logistical or socioeconomic barriers but expect that number to be high. Navigating this process in a timely and efficient manner will be crucial to improving outcomes and the overall patient experience for relapsed and refractory large B-cell lymphoma in the real-world setting.

Conflict-of-interest disclosure: N.G. has received consulting fees from Seagen, TG Therapeutics, AstraZeneca, Pharmacyclics, Janssen, Bristol Myers Squibb, Gilead Sciences, Beigene, Incyte, Karyopharm, Roche/Genentech, Novartis, Loxo Oncology, Genmab, Adaptive Biotech, and ADC Therapeutics; previously served on speakers bureau for Gilead, AstraZeneca, Bristol Myers Squibb, Pharmacyclics, Janssen, and Epizyme; and has received research funding from TG Therapeutics, Genentech/Roche, Bristol Myers Squibb, Gilead, MorphoSys, and AbbVie.