Comparative effectiveness of ZUMA-5 (axi-cel) vs SCHOLAR-5 external control in relapsed/refractory follicular lymphoma

Abstract

In the pivotal ZUMA-5 trial, axicabtagene ciloleucel (axi-cel; an autologous anti-CD19 chimeric antigen receptor T-cell therapy) demonstrated high rates of durable response in relapsed/refractory (r/r) follicular lymphoma (FL) patients. Here, outcomes from ZUMA-5 are compared with the international SCHOLAR-5 cohort, which applied key ZUMA-5 trial eligibility criteria simulating randomized controlled trial conditions. SCHOLAR-5 data were extracted from institutions in 5 countries, and from 1 historical clinical trial, for r/r FL patients who initiated a third or higher line of therapy after July 2014. Patient characteristics were balanced through propensity scoring on prespecified prognostic factors using standardized mortality ratio (SMR) weighting. Time-to-event outcomes were evaluated using weighted Kaplan-Meier analysis. Overall response rate (ORR) and complete response (CR) rate were compared using weighted odds ratios. The 143 ScHOLAR-5 patients reduced to an effective sample of 85 patients after SMR weighting vs 86 patients in ZUMA-5. Median follow-up time was 25.4 and 23.3 months for SCHOLAR-5 and ZUMA-5. Median overall survival (OS) and progression-free survival (PFS) in SCHOLAR-5 were 59.8 months and 12.7 months and not reached in ZUMA-5. Hazard ratios for OS and PFS were 0.42 (95% confidence interval [CI], 0.21-0.83) and 0.30 (95% CI, 0.18-0.49). The ORR and CR rate were 49.9% and 29.9% in SCHOLAR-5 and 94.2% and 79.1% in ZUMA-5, for odds ratios of 16.2 (95% CI, 5.6-46.9) and 8.9 (95% CI, 4.3-18.3). Compared with available therapies, axi-cel demonstrated an improvement in meaningful clinical endpoints, suggesting axi-cel addresses an important unmet need for r/r FL patients. This trial was registered at www.clinicaltrials.gov as #NCT03105336.

Graphical abstract

Figure 1.

Flow diagram of patient enrolment, selection, and analysis of SCHOLAR-5 and comparative analysis set. Full eligibility criteria are listed in supplemental Appendix, section 2. Key eligibility criteria for SCHOLAR-5 cohort were: (1) diagnosed r/r FL; (2) starting third or higher line of therapy; (3) on or after 23 July 2014. Prior line of therapy with anti-CD20 monotherapy did not count as line of therapy for eligibility. Key exclusion criteria for the SCHOLAR-5 cohort were (1) transformed FL, (2) FL histological grade 3b, and (3) prior anti-CD19 CAR T-cell therapy or other genetically modified T-cell therapy. Patients were eligible for inclusion in the ZUMA-5 sample if they met the criteria for a minimum follow-up of 18 months.

Figure 2.

PS distribution before weighting, after weighting, and after matching. Panel A shows a PS distribution before weighting and shows trend for SCHOLAR-5 to have lower propensities and ZUMA-5 to have higher ones. Patients with near-zero PS were all in SCHOLAR-5, and patients with higher propensities were almost all in ZUMA-5. Panel B shows the results after application of SMR weighting, with comparable distributions. Panel C shows that in the matched analysis, patients with scores that were only present in 1 study (eg, scores >0.80 in ZUMA-5) were removed, leading to a better PS overlap but reduced common support data set.

Figure 3.

Kaplan-Meier plots comparing ZUMA-5 to SCHOLAR-5 for PFS, OS, and Time-to-next-treatments. Kaplan-Meier curves showing (A) PFS, (B) OS, and (C) time to next treatment in ZUMA-5 (blue) compared with SCHOLAR-5 (red). Shaded area represents 95% CI. Number at risk for the SCHOLAR-5 analysis of PFS was reduced due to the exclusion of DELTA participants from this analysis as PFS was not available in this subgroup. See supplemental Figure 2 for results of all time-to-event outcomes with DELTA participants excluded prior to SMR weight.