Treatment of relapsed or refractory (R/R) follicular lymphoma (FL) with axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor (CAR) T-cell therapy, offered substantial clinical benefit relative to existing therapeutic options, according to a comparative effectiveness analysis published in Blood.
“It is [difficult] to establish a ‘standard of care’ for a disease like [FL] where from the first line of treatment there is a great difference in how these patients are treated, how they respond, and how long the response lasts. This results in increased heterogeneity of treatment with each line of therapy,” said study author John Gribben, MD, DSc, of Barts Cancer Institute in London. “Whereas no study can replace randomized clinical trials, it is extremely difficult to design a study with a comparator arm that will be appropriate for many patients in later lines of therapy. If we want to use instead real-world data, then we must use methods that allow best matching of the patients with those in the clinical trial.”
To do that, Dr. Gribben and colleagues developed SCHOLAR-5, an international, retrospective, observational cohort study from real-world clinical sites. SCHOLAR-5 was designed to “recapitulate” the population of ZUMA-5, which was the basis for the regulatory approval of axi-cel; it applied key ZUMA-5 trial eligibility criteria.
The cohort included 143 patients with R/R disease from institutions in five countries and from one historical clinical trial of patients who had initiated three or more lines of therapy after July 2014. Patient characteristics were balanced using propensity scoring on pre-specific prognostic factors using standardized mortality ratio (SMR) weighting. According to Dr. Gribben, the propensity-score method allowed for better matching of patients in SCHOLAR-5 with those treated in ZUMA-5.
The 143 patients were reduced to an effective sample of 85 patients after SMR weighting and compared with 86 patients in ZUMA-5.
“What was clear from the SCHOLAR-5 cohort was the heterogeneous ways that patients with FL are treated in later lines of therapy and how there is no established standard of care,” Dr. Gribben said. “This makes it difficult to have a comparator arm for studies in later lines of therapy such as in the ZUMA-5 study of CAR T cells.”
Median overall survival (OS) was 59.8 months in SCHOLAR-5 and was not reached in ZUMA-5 (hazard ratio [HR] = 0.42, 95% CI 0.21-0.83), a 58% reduction in the risk of death. Among patients with three or more prior lines of therapy, the OS improvement was even more pronounced (HR=0.31, 95% CI 0.15-0.66), the researchers noted.
Median progression-free survival (PFS) was 12.7 months in SCHOLAR-5 and was not reached in ZUMA-5 (HR=0.30, 95% CI 0.18-0.49). Overall response rate (ORR) was 49.9% in SCHOLAR-5 with a complete response (CR) rate of 29.9%. Comparatively, in ZUMA-5 the ORR was 94.2% with a CR rate of 79.1%.
Median time to next treatment (TTNT) was not reached for ZUMA-5 compared with 23.4 months in SCHOLAR-5. The researchers noted that “assessment of TTNT could be considered more comparable between cohorts since date of initiation of next line is captured in routine clinical care, whereas scans are not routine, so follow-up in the SCHOLAR-5 study, and therefore time to progression, are differently assessed in ZUMA-5 and SCHOLAR-5.”
The researchers discussed limitations of this study, including its retrospective nature and the potential for missing or incomplete data from clinical practice databases. Additionally, certain patient characteristics that could be used to adjust for imbalances were excluded from analyses because of missing data, including Follicular Lymphoma International Prognostic Index and bone marrow involvement.
“With an unprecedented improvement in OS compared to available therapies for R/R FL, SCHOLAR-5 highlights the durable treatment effect of axi-cel,” the researchers concluded. “Moreover, axi-cel demonstrated superiority in additional clinically meaningful endpoints of PFS, TTNT, ORR, and CR. In this context, the striking improvement in OS with axi-cel compared to available therapies highlights the suboptimal outcomes with existing therapies and the benefit of therapeutic advances in this population.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Ghione P, Palomba ML, Patel A, et al. Comparative effectiveness of ZUMA-5 (axi-cel) vs. SCHOLAR-5 external control in relapsed/refractory follicular lymphoma [published online ahead of print, 2022 June 9]. Blood. doi: 10.1182/blood.2021014375.
