The Comparison of Kte-X19 to Current Standards of Care: A Pre-Specified Synthetic Control Study Utilizing Individual Patient Level Data from Historic Clinical Trials (SCHOLAR-3)

Abstract

Background: The ZUMA-3 trial of KTE-X19 in relapsed/refractory (r/r) adult B-cell precursor acute lymphoblastic leukaemia (B-ALL) utilizes a single arm design. To contextualize these results, a synthetic control (SC) study derived from individual patient-level data (IPD) sampled from historical clinical trials (CTs) was constructed. Aims: To compare the overall survival (OS) and objective complete response rate at week 24 (OCR24) results of the ZUMA-3 pivitol study using a matched (SC) derived from IPD from CTs. Methods: This study had two distinct phases: firstly, CTs from which patients were sampled were identified using the medidata enterprise data store (MEDS). The second phase of this study constructed SCs to the ZUMA-3 population, one SC for patients naïve to blinatumomab (blin) or inotuzuamab (ino) therapy (SCA-1) and one in blin or ino pre-treated patients (SCA-2). All analysis were pre-specified and conducted by an external third party to Kite Pharma. For the trial identification phase, the MEDS database was searched to identify CTs that had inclusion and exlusion criteria congruent with ZUMA-3 and treatment assignments representative of current standards of care inclusive of blin, ino or chemotherapy regimens. Once appropriate CTs had been identified the endpoints were re-engineerd to match the same defintions as the ZUMA-3 trial. For the SC construction phase, propensity score (PS) matching was used. The PS was derived as a function of the number of previous lines of therapy, prior allo-SCT, age, sex, ECOG, Philadelphia chromosome status, percentage bone marrow blasts and extramedullary disease. For outcomes analysis, time-to-event endpoints of interest were analyzed using the Kaplan-Meier method and compared using a Cox proportional hazard regression model. OCR rate was described through crude incidence rates and corresponding 95% CI. ln addition, an odds ratio together with associated 95% CI and 2-sided p-value were estimated from a logistic regression model. Results A total of 20 SCA-1 patients were matched to 20 patients from ZUMA-3 and a total 20 SCA-2 patients were matched to 29 patients from ZUMA-3. Analysis of the SCA-1 cohort shows an OCR24 of 85% (95% CI 62.1%, 96.8%) in the Zuma-3 patients and 35.0% (95% CI 15.4, 59.2) among propensity matched controls. This corresponds to an OR of 10.5 (95% CI 2.3, 48.7; p-value 0.0031). No OCR24 data was available for SCA-2. A post hoc analysis was conducted in order to further contextualize the OCR24 rate. ZUMA-3 patients irrespective if they had been pre-treated with blin or ino were matched to patients from HCTs who were previously naïve to blin or ino therapy (SCA-3). The OCR24 rate in the ZUMA-3 arm was 69.8% (95% CI 55.7%, 81.7%) while for SCA-3 patients was 35.8% (95% CI 23.1%, 50.2%) meaning that ZUMA-3 patients had 4.1 times higher odds of achieving OCR in comparison to SCA-3 patients (95% CI 1.8, 9.3) p-value 0.0009. The comparison of overall survival (OS) between all matched ZUMA-3 and all SCA patients demonstrated a significantly higher median OS of 18.20 months (95% CI 12.22, NE months) for patients in ZUMA-3 versus 5.49 months (95% CI 3.32, 9.23 months) in SCA-3. A cox regression model showed that ZUMA-3 patients had a 64% lower risk of death with a hazard ratio 0.36 (95% CI 0.20, 0.66) p-value 0.0005. Conclusion: This comparative study demonstrated a clinically relevant improvement of OCR24 and OS following KTE-X19 vs available therapies and provides strong evidence for its use in adult patients with R/R B-ALL Disclosures Shah: Jazz Pharmaceuticals: Research Funding; Servier Genetics: Other; BeiGene: Consultancy, Honoraria; Incyte: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; Pfizer: Consultancy, Other: Expenses; Amgen: Consultancy; Novartis: Consultancy, Other: Expenses; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Precision Biosciences: Consultancy; Adaptive Biotechnologies: Consultancy. Faghmous: Kite A Gilead Company: Current Employment, Current equity holder in publicly-traded company. Whitmore: Kite, A Gilead Company: Current Employment, Current equity holder in publicly-traded company. Masouleh: GSK: Current equity holder in publicly-traded company; Kite, A Gilead Company: Current Employment, Current equity holder in publicly-traded company; Immatics: Current equity holder in publicly-traded company; Roche: Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company. Xu: Gilead Sciences: Other: stock or other ownership ; Kite, A Gilead Company: Current Employment.

Two-year follow-up of KTE-X19 in patients with relapsed or refractory adult B-cell acute lymphoblastic leukemia in ZUMA-3 and its contextualization with SCHOLAR-3, an external historical control study

“…Detailed methodology of the retrospective cohort study SCHOLAR-3 was previously reported (Additional file 1 : Supplemental Methods) [ 8 ]. Briefly, propensity scoring was used to match adult patients with R/R B‑ALL treated in historical clinical trials (synthetic control arm [SCA]) with ZUMA-3-treated patients based on key baseline characteristics and prior therapies.…”

“…To better assess the unmet need for patients with R/R B-ALL and to estimate the benefit of KTE-X19 compared with standard-of-care regimens in this setting, we recently performed the retrospective, external historical control study SCHOLAR-3 [ 8 ]. Outcome comparisons were made based on matched individual patient-level data from historical clinical trials with ZUMA-3 patients [ 8 ].…”

“…To better assess the unmet need for patients with R/R B-ALL and to estimate the benefit of KTE-X19 compared with standard-of-care regimens in this setting, we recently performed the retrospective, external historical control study SCHOLAR-3 [ 8 ]. Outcome comparisons were made based on matched individual patient-level data from historical clinical trials with ZUMA-3 patients [ 8 ]. SCHOLAR-3 results demonstrated high unmet need among patients with R/R B-ALL with standard-of-care therapies providing a median OS of 5.5 months ( n = 40) in historical clinical trials, whereas in matched patients receiving KTE-X19 therapy in ZUMA-3, the median OS was 18.2 months ( n = 49) [ 8 ].…”

“…Outcome comparisons were made based on matched individual patient-level data from historical clinical trials with ZUMA-3 patients [ 8 ]. SCHOLAR-3 results demonstrated high unmet need among patients with R/R B-ALL with standard-of-care therapies providing a median OS of 5.5 months ( n = 40) in historical clinical trials, whereas in matched patients receiving KTE-X19 therapy in ZUMA-3, the median OS was 18.2 months ( n = 49) [ 8 ].…”

Cost-Effectiveness of KTE-X19 for Adults with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia in the United States

“…Arm A scenario analysis was performed to compare outcomes of patients treated with KTE-X19 to IPD sampled from historical clinical trials of patients who had not previously failed blinatumomab. A post hoc analysis of the SCHOLAR-3 study was done using a synthetic control matching patients from ZUMA-3 (irrespective of pre-treatment with BLIN or INO) to BLIN-or INO-naı ¨ve patients from historical clinical trials (synthetic control arm 3 [SCA-3]) [27]. As patients in SCA-3 could have received either BLIN (92.5%) or standard of care chemotherapy (7.5%), the study population was further restricted to only reflect patients who received BLIN in the SCA-3 arm.…”