KYMRIAH® (tisagenlecleucel) Efficacy Data & ELIANA Clinical Trial

KYMRIAH attained and sustained remission in the majority of patients

A potentially definitive treatment

Pivotal Trial Design

ELIANA was a global phase 2 pivotal trial to evaluate the efficacy and safety of KYMRIAH^® (tisagenlecleucel) in patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (ALL).¹ The Prescribing Information reports the interim analysis, which formed the basis for FDA approval of KYMRIAH and was based on 68 infused patients, of whom 63 were evaluable for response at 3 months.² Since the approval of KYMRIAH in 2017, an updated analysis with longer-term data has been published.

The updated analysis is based on 75 infused patients, all of whom were evaluable for response at 3 months³

Enrolled patients were between 3 and 23 years of age (median age, 11 years)
8% of participants had primary refractory disease⁴
Patients received a median of 3 prior therapies, with 53% having received 1 stem cell transplant (SCT) and 8% having received 2 SCTs³
Median time from most recent relapse to KYMRIAH infusion was 3.5 months³

Primary end point: Overall remission rate (ORR)* within 3 months postinfusion.

*The trial required remission status to be maintained for at least 28 days without clinical evidence of relapse.¹

Overall Remission Rate

~8 of 10 patients achieved minimal residual disease negative (MRD–)^† remission at 3 months after treatment with KYMRIAH.^1,2 MRD– status is a strong marker for positive prognosis.⁵

ORR AT 3 MONTHS^‡

100‭% ‭MRD–‬‬‬‬

All patients in remission were MRD– ‭in both the interim analysis (n=52) and the ‭updated analysis (n=61)^{1,2‬‬‬‬‬‬‬}

Day 28 Assessment^{1,2,6‬‬‬‬‬‬}

≥95% ‭of responders achieved MRD– remission by Day 28 ‭assessment^ǁ‭ in both the interim analysis (n=52) and the ‭updated analysis (n=61)‬‬‬‬‬‬‬‬‬‬‬‬‬

^†MRD– was defined as MRD by flow cytometry <0.01%.²

^‡ORR consisted of complete remission (CR) and complete remission with incomplete blood count recovery (CRi, defined as less than 5% of blasts in the bone marrow, no evidence of extramedullary disease, and without full recovery of peripheral blood counts with or without blood transfusion). Remission status was required to be maintained for at least 28 days without clinical evidence of relapse.²

^§Five patients who were infused with KYMRIAH were excluded from the efficacy set in the interim analysis. The efficacy analysis set (n=63) is a subset of the full analysis set (N=68), which consisted of all patients treated with KYMRIAH at least 3 months prior to data cutoff.^2,6

^ǁDay 28 assessment initially defined as ±7 days; definition changed to ±4 days after 1 site was enrolled, 3 patients were enrolled, and 1 patient was treated.³

Remission Was Achievable With KYMRIAH Regardless of Patients’ Clinical Characteristics^3,6

NR, not reported.

^§Five patients who were infused with KYMRIAH were excluded from the efficacy set in the interim analysis. The efficacy analysis set (n=63) is a subset of the full analysis set (N=68), which consisted of all patients treated with KYMRIAH at least 3 months prior to data cutoff.^2,6

^¶The area of each box is proportional to the number of patients in the particular grouping. The 95% CIs are exact Clopper-Pearson CIs calculated for each subgroup.⁶

^#Includes 8 patients categorized with chemorefractory disease at study entry.⁶

DOR and OS

Durable Remission^1,2

The median duration of CR/CRi among the responders was not reached in both the updated analysis (n=61) and the interim analysis (n=52).

Updated analysis median follow-up: 7.5 months from response (maximum 19.3 months)
Interim analysis median follow-up: 4.8 months from response (range: 1.2 to 14.1+ months)

DURATION OF REMISSION** (UPDATED ANALYSIS [n=61/75])^1,3

^**DOR was defined as time since onset of CR or CRi to relapse or death due to underlying cancer, whichever is earlier, censoring for new cancer therapy including SCT.²

Interim Analysis (n=52/63)⁶

75% of responders estimated to still be in remission at 6 months
64% of responders estimated to still be in remission at 9 and 12 months

KYMRIAH Persistence Based on Pharmacokinetics²

KYMRIAH was present in the blood and bone marrow, and was measurable beyond 2 years.

OVERALL SURVIVAL (OS, UPDATED ANALYSIS [N=75])^1,3,4

76% estimated OS of infused patients at 12 months³

OS was a secondary efficacy end point of the global phase 2 pivotal trial³
OS data are not in the Prescribing Information and should be interpreted with caution in a single-arm trial. The statistical significance of OS is not known
Transplant does not appear to improve the estimated OS⁴
87% of responders did not proceed to SCT at a median follow-up of 13.1 months after KYMRIAH infusion to data cutoff¹
Median follow-up for OS: 10.5 months³

NE, not evaluable.

Patient-Reported QOL

KYMRIAH led to a decrease in severity of problems related to mobility, self-care, usual activities, pain/discomfort, and anxiety/depression at Months 3 and 6 compared with Baseline as assessed via the EQ-5D questionnaire.³

Quality of Life (QOL) Improvements Were Observed as Early as 3 Months After KYMRIAH Infusion^3,a

^aPatient-reported outcome results are mean values from patients ≥8 years of age who achieved CR or CRi during 3 months (n=48). Population at each time point is the number of patients with nonmissing score at that time point.³

The QOL study is not part of the Prescribing Information. The PedsQL, EQ VAS, and EQ-5D models were evaluated and validated in a patient population other than pediatric ALL, N values decreased over time, and the study’s statistical significance was not evaluated, and therefore should be interpreted cautiously

Pedi-CART19 (CHP 959) Supportive Trial

A supportive, proof-of-concept study of CTL019

Supporting Trial: CHP 959

CHP 959 was a single-site, phase 1/2, supportive, proof-of-concept study of CTL019 (N=62) initiated in 2012.⁹ These data were not included in the KYMRIAH Prescribing Information.

CHP 959 comprised 3 cohorts:

56 patients with non–CNS3 ALL
4 patients with CNS3 ALL
2 patients with lymphoma

All the patients infused in this trial received product manufactured by the University of Pennsylvania
Enrolled patients between 1 and 24 years of age (median, 11 years) (n=56 non–CNS3 ALL)
95% of participants had relapsed disease; 5% were refractory to initial therapy
89% of patients received ≥3 prior regimens; 64% received prior SCT
57% of patients had high baseline disease burden (≥5% blasts) (n=56 non–CNS3 ALL)

Primary end point: Safety, feasibility, and duration of CAR-T cells in vivo.^††
Secondary end point: Anti-tumor activity, including¹⁰:

Day 28 overall response rate (CR + CRi)
DOR (from the date of CR/CRi to relapse or death due to underlying cancer)

CNS, central nervous system.

^††Determined via reverse transcriptase–polymerase chain reaction (RT-PCR) analysis of whole blood.⁹

There were some differences noted between this study and the pivotal ELIANA study and results should be interpreted with caution

DURATION OF REMISSION (N=56 non–CNS3 ALL)⁹

Patients Responded to Treatment With CTL019, Across Disease Characteristics¹¹

Data presented here are based on a different analysis of CHP 959 with a population of 60 patients

REMISSION RATES BY BASELINE DISEASE BURDEN (N=60)¹¹

CR, complete response.

^‡‡<0.01% MRD by flow cytometry.¹¹

CNS INVOLVEMENT (N=60)¹¹

CNS status at infusion	Patients, n (%)
CNS1	54 (90)
CNS2^§§	4 (7)
CNS3^ǁǁ	2 (3)
CNS3^ǁǁ within 12 months of infusion	16 (27)

Remission Rates¹¹

83% of patients with CNS2 or CNS3 status at infusion (n=5/6) achieved CNS remission
73% of evaluable patients with prior CNS disease (n=11/15) achieved continuous remission as long as 2.5 years
No CNS relapses in entire cohort (N=60), with 4 bone marrow relapses in CNS cohort (n=15) at time of analysis
Experience with KYMRIAH in patients with active CNS leukemia is limited and these data should be interpreted with caution

Persistence Based on Pharmacokinetics¹¹

98% of all patients treated had detectable levels of CTL019 in cerebrospinal fluid (CSF), with lumbar puncture showing detectable CTL019 at 1 year

^§§CNS2 status defined as blast cells detected in a sample with <5 leukocytes per cubic millimeter and <10 erythrocytes per cubic millimeter.¹²

^ǁǁCNS3 status defined as blast cells detected in a sample with ≥5 leukocytes per cubic millimeter and <10 erythrocytes per cubic millimeter.¹²

See Adverse Reactions for safety information from the CHP 959 trial.

References: 1. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439-448 2. Kymriah [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018. 3. Data on file. Study CTL019B2202. Novartis Pharmaceuticals Corp; Sept 2017. 4. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia [online supplemental appendix]. N Engl J Med. 2018;378(5):439-448. 5. Borowitz MJ, Wood BL, Devidas M, et al. Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children’s Oncology Group study AALL0232. Blood. 2015;126(8):964-971. 6. Data on file. Study CTL019B. Novartis Pharmaceuticals Corp; Feb 2017. 7. Varni JW, Burwinkle TM, Seid M, Skarr D. The PedsQL™* 4.0 as a pediatric population health measure: feasibility, reliability, and validity. Ambul Pediatr. 2003;3(6):329-341. 8. Pickard AS, Neary MP, Cella D. Estimation of minimally important differences in EQ-5D utility and VAS scores in cancer. Health Qual Life Outcomes. 2007;5:70. 9. Data on file. Study CTL019B2101J. Novartis Pharmaceuticals Corp; Sept 2017. 10. Data on file. Study CTL019B2101J. Novartis Pharmaceuticals Corp; Dec 2016. 11. Maude SL, Teachey DT, Rheingold SR, et al. Sustained remissions with CD19-specific chimeric antigen receptor (CAR)-modified T cells in children with relapsed/refractory ALL. Presented at: ASCO Annual Meeting; May 2016; Chicago, IL. 12. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507-1517.