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)
Authors: Shah Bijal D. , Faghmous Imi , Whitmore James , Masouleh Behzad Kharabi , Xu Hairong 
Published: November 2021

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.