ELIANA Study Design

Study characteristics of the global, phase 2 pivotal trial^1,2

ELIANA was an open-label, multicenter, single-arm, global Phase II trial of tisagenlecleucel in 79 patients with B-cell ALL who were primary refractory, chemorefractory, relapsed after, or were not eligible for allogeneic SCT (NCT02228096).

ELIANA Baseline Characteristics

Inclusion/Exclusion Criteria²

• Inclusion:
        — r/r B-cell ALL, aged 3-21 years^a
         — Bone marrow with ≥ 5% lymphoblasts

• Exclusion:
        — Isolated extra-medullary disease relapse
        — Prior CD19-directed or gene therapy

End Points¹

• Primary: Overall remission rate (CR/CRi) within 3 months after infusion¹
         — 4-week maintenance of remission
        — IRC assessment

• Secondary: CR or CRi with MRD-negative bone marrow, DOR, OS, EFS, cellular kinectics, safety¹

^aAge of 3 years at the time of screening to age 21 years at time of initial diagnosis.¹

ALL, acute lymphoblastic leukemia; ASH, American Society of Hematology; CR, complete remission; CRi, complete remission with incomplete blood count recovery; DOR, duration of remission; EFS, event-free survival; IRC, Independent Review Committee; MRD, minimal residual disease; NEJM, New England Journal of Medicine; OS, overall survival; SCT, stem cell transplant; USPI, United States Prescribing Information.

Read the New England Journal of Medicine (NEJM) article. ↗

ORR and MRD-Negative Remission

WITH KYMRIAH, THE MAJORITY OF PATIENTS ATTAINED AND SUSTAINED MRD-NEGATIVE REMISSION¹

About 8/10 patients achieved minimal residual disease negative (MRD-negative) remission at 3 months after treatment with KYMRIAH^® (tisagenlecleucel).¹ MRD-negative status is a strong marker for positive prognosis.⁴

ORR, overall response rate.

^bORR 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.<sup>2

c</sup>MRD-negative was defined as MRD by flow cytometry <0.01%.<sup>2

d</sup>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.<sup>2

e</sup>Day 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.⁵

REMISSION WAS ACHIEVABLE WITH KYMRIAH REGARDLESS OF CLINICAL CHARACTERISTICS^5,6

KYMRIAH demonstrated consistent response rates across all subgroups evaluated, including high-risk patient subgroups

NR, not reported.

^fFive 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

^gThe 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.⁵

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

RFS and OS

KYMRIAH DELIVERS DURABLE RESPONSES IN PATIENTS WITH R/R ALL (≤25 YEARS)¹

Median relapse-free survival (RFS) was not reached at 24 months¹

ⁱRFS 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.³

USPI: 4.8 MONTHS⁶

As reported in the USPI at 4.8 months after response, 75% of responders were estimated to still be in remission at 6 months, and 64% of responders were estimated to still be in remission at 9 and 12 months.⁶

KYMRIAH Persistence Based on Pharmacokinetics²

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

TWO-THIRDS OF PATIENTS TREATED WITH KYMRIAH WERE ALIVE AT 2 YEARS¹

Median OS was not reached at 24 months¹

• OS was a secondary efficacy end point of the global phase 2 pivotal trial¹

• 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

NE, not evaluable.

STEM CELL TRANSPLANT AFTER KYMRIAH DOES NOT APPEAR TO IMPROVE OVERALL SURVIVAL^3,7

At a median follow-up of 13.1 months postinfusion, 87% of responders did not proceed to stem cell transplant (SCT).

No difference in OS was observed between the full patient population (including the 13% of patients who underwent SCT while in remission after KYMRIAH infusion) and those who did not receive SCT.

• OS was a secondary efficacy end point of the global phase 2 pivotal trial¹

• 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

Patient-reported QOL

PATIENTS REPORTED INCREASES IN QUALITY-OF-LIFE MEASURES AFTER KYMRIAH INFUSION⁸

KYMRIAH led to a decrease in severity of problems at Months 3 and 6 compared with baseline as assessed via the EQ-5D questionnaire.⁸

• 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 that did not include patients with pediatric ALL. The patient population decreased over time. The study’s statistical significance was not evaluated and, therefore, should be interpreted cautiously.

IMPROVEMENTS IN QUALITY-OF-LIFE⁹

• MOBILITY

• SELF-CARE

• ANXIETY/DEPRESSION

• USUAL ACTIVITIES (ie, going back to school)

• PAIN/DISCOMFORT

QUALITY-OF-LIFE IMPROVEMENTS WERE OBSERVED AS EARLY AS 3 MONTHS AND SUSTAINED THROUGH 12 MONTHS AFTER KYMRIAH INFUSION^9,j

PedsQL^TMk

(Pediatric QOL Inventory; baseline n=43)

The minimal change considered clinically
important in the PedsQL questionnaire is 4.4
(for self reports; 4.5 for proxy reports)^5,10

EQ-5D VAL^l

(EuroQol Visual Analogue Scale; baseline n=40)

The minimal change considered clinically
important in the EQ VAS questionnaire is 7 to 10¹¹

QOL, quality of life.

^j107 patients were screened for the ELIANA trial between April 8, 2015, and April 25, 2017; 92 were enrolled, 75 received KYMRIAH, and 58 were aged 8 to 23 years and included in the analysis displayed here. Tumor response was evaluated on Day 28, every month, to Month 6, then every 3 months until Month 12. Patients are being followed for efficacy and safety for 5 years unless withdrawn from study by patient or investigator choice or lost to follow-up. The data shown are from the mixed model analysis.<sup>8

k</sup>The 23-item PedsQL addresses the physical, emotional, social, and school functioning of healthy children and children with chronic disease (scale, 0‐100).<sup>8,10

l</sup>The EQ-5D includes questions on the 5 dimensions of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression and a VAS that records self-rated overall health state (range, 0-100).^8,11

Supporting Trial: CHP 959

CHP 959 study characteristics^12,13

• CHP 959 was an open-label, single-site, phase 1/2, supportive, proof-of-concept study of KYMRIAH in pediatric and young adult patients with r/r B-cell precursor ALL (N=62) initiated by University of Pennsylvania in 2012. These data were not included in the KYMRIAH Prescribing Information¹²

• Enrolled patients aged 1-24 years (median, 11 years)¹²

• Primary end point: Safety, feasibility, and duration of CAR-T cells in vivo^12,m

• Secondary end point: Anti-tumor activity, including¹³:

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

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

CNS, central nervous system.

^mDetermined via reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of whole blood.¹²

Safety results from CHP 959¹⁴

The majority (89.3%) of patients with non–CNS3 ALL in CHP 959 experienced at least 1 serious adverse event any time after CTL019 infusion. The most common (incidence ≥20%, all grades) serious adverse events regardless of study drug relationship were CRS (82.1%), febrile neutropenia (71.4%), hypotension (39.3%), encephalopathy (26.8%), and pyrexia (23.2%). The most common (incidence >30%, all grades) adverse events regardless of study drug relationship in the non–CNS3 ALL group were decreased white blood cell count (WBC; 94.6%), decreased hemoglobin (92.9%), decreased neutrophil count (91.1%), CRS (89.3%), decreased platelet count (87.5%), lymphopenia (82.1%), febrile neutropenia (78.6%), vomiting (78.6%), aspartate aminotransferase (AST) increased (75.0%), headache (75.0%), nausea (75.0%), alanine aminotransferase (ALT) increased (71.4%), decreased appetite (69.6%), hypogammaglobulinemia (66.1%), diarrhea (57.1%), cough (55.4%), hypotension (51.8%), pain (48.2%), tachycardia (46.4%), fatigue (44.6%), chills (39.3%), increased blood creatinine (35.7%), pyrexia (35.7%), activated partial thromboplastin time prolonged (33.9%), hyperphosphatemia (33.9%), and abdominal pain (32.1%). The most frequently reported (in at least 30% of patients) grade 3/4 adverse events by preferred term (PT), regardless of study drug relationship, were febrile neutropenia (78.6%), decreased neutrophil count (69.6%), lymphopenia (67.9%), decreased WBC count (62.5%), decreased platelet count (48.2%), CRS (46.4%), decreased appetite (35.7%), hypotension (32.1%), decreased hemoglobin (30.4%) and increased ALT (30.4%).

Primary End Point: Safety in Non-CNS3 ALL Patients (n=56)

Secondary End Point

REMISSION RATES BY BASELINE DISEASE BURDEN (N=60)¹⁴

 CR, complete response.

ⁿMRD-negative was defined as MRD by flow cytometry <0.01%.¹⁵

Patients Responded to Treatment With CTL019, Across Disease Characteristics¹⁵

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

CNS INVOLVEMENT (N=60)¹⁴

^oCNS2 status defined as blast cells detected in a sample with <5 leukocytes per cubic millimeter and <10 erythrocytes per cubic millimeter.¹⁶

^pCNS3 status defined as blast cells detected in a sample with ≥5 leukocytes per cubic millimeter and <10 erythrocytes per cubic millimeter.¹⁶

Remission Rates by CNS Status¹⁵

• Experience with KYMRIAH in patients with active CNS leukemia is limited, and these data should be interpreted with caution

Persistence Based on Pharmacokinetics¹⁵

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

For information about the safety profile, continue to the next page