ODAC Unanimously Recommends Approval of Tisagenlecleucel for Pediatric ALL

Catherine M. Bollard, MD

Citing “unprecedented clinical success” and calling the drug “potentially paradigm-changing,” the Oncologic Drugs Advisory Committee (ODAC) voted 10-0 today to recommend approval of a biologics license application (BLA) for tisagenlecleucel (CTL019) for the treatment of patients aged 25 or younger with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL).

Tisagenlecleucel is the first CAR T-cell therapy to enter regulatory review. The FDA granted a priority review designation in this patient population in March, when the treatment was still known as tisagenlecleucel-T.

The committee was asked to consider 4 issues:

• Manufacturing quality control with respect to identity, safety, purity and potency
• Strategies to address safety concerns including generation of replication-competent retrovirus (RCR) and insertional mutagenesis
• Risk mitigation measures for the serious risks of cytokine release syndrome and neurotoxicity
• The necessary duration patient follow-up and the type of assessments recommended

The FDA already requires 15 years of follow-up to monitor for subsequent malignant transformation for the tisagenlecleucel investigational new drug studies.

The committee eventually concluded that the strong efficacy data presented and Novartis’ long-term patient monitoring plan deserved approval. The application will now go to the full FDA for consideration.

“This is a very poor risk patient population, and there is an unmet need in pediatric population,” said Catherine M. Bollard, MD, professor of pediatrics and microbiology immunity at the George Washington University. “As we saw the with data today, the clinical responses are remarkable.”

“This is a major advance ushering in a new era in treating patients with ALL,” said Malcolm A. Smith, MD, PhD, associate branch chief for pediatrics in the clinical investigations branch at the National Cancer Institute.

All doses of tisagenlecleucel are manufactured in the United States by Novartis, the company developing the autologous T-cell therapy in conjunction with the University of Pennsylvania.

The primary efficacy analysis was based on phase II results from CCTL019B2202 (B2202), a single-arm, international trial of 63 patients who received a single dose of tisagenlecleucel. The targeted dose of each tisagenlecleucel-T infusion was 2.0 to 5.0 x 106 kg for patients ≤50 kg and 1.0 to 2.5 x 108 for those >50 kg.

Overall remission rate (ORR) was 82.5% (95% CI, 70.9-91.0) in treated subjects. Forty patients (63%) had complete remission (CR) and 12 (19%) had complete remission with incomplete hematologic recovery (CRi).

All patients who had CR or CRi were associated with negative minimal residual disease status (MRD) in the bone marrow.

Investigators concluded that tisagenlecleucel was associated with clinically meaningful remissions. Estimated relapse-free rate among responders at month 6 was 75.4% (95% CI, 57.2-86.7). Median duration of response (DOR) was not reached at a median follow-up of 4.8 months.

Eleven patients who had CR+ CRi relapsed after tisagenlecleucel prior to data cut-off and before any new cancer therapy. Two other patients relapsed after receiving both tisagenlecleucel and new cancer therapy. Of the 52 patients who had CR+ CRi, 29 were still in remission at the last assessment before the data cutoff.

Median event-free survival (EFS) has not been reached at a median follow-up of 5.6 months. Of 63 patients evalualuable for efficacy, 20 (31.7%) had an EFS event. At a median follow-up of 6.9 months, overall survival has not been reached.

Sixty-eight patients were included in the safety review.

The most common, >5%, serious adverse events (AEs) recorded in the study were cytokine release syndrome (CRS), febrile neutropenia, hypotension, acute kidney injury, fever, and hypoxia. Thirty-two patients (47%) experienced grade 3/4 CRS, and median duration was 8 days. There were no deaths associated with CRS.

Ten patients (15%) experienced grade 3 neurotoxicity, and 18 experienced grade 3/4 infections within 8 days of infusion. Three patients died within 60 days of infusion due to infections.