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Tisagenlecleucel Submitted for European Approval for ALL, DLBCL

Jason Harris
Published: Monday, Nov 06, 2017

Gilles A. Salles, MD, PhD
Gilles A. Salles, MD, PhD
The European Medicines Agency (EMA) has received a Marketing Authorization Application (MAA) for tisagenlecleucel (Kymriah) for 2 forms of advanced lymphoma.

Novartis is seeking approval to market tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell therapy, for the treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and for adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are ineligible for autologous stem cell transplant (ASCT).

“For patients in the EU living with these aggressive forms of blood cancer, we have very limited options to improve their chances of sustained remission after their disease has relapsed or become refractory to initial treatment,” Gilles Salles, MD, PhD, head of Hematology, Hospices Civils de Lyon, Lyon, France, said in a press release. “The data for tisagenlecleucel has provided an optimistic look at the potential to achieve durable responses in two distinct and difficult-to-treat patient populations, helping to address a dire unmet need for patients.”

The MAA submission is based on results from the global phase II ELIANA and JULIET trials. ELIANA is the first pediatric global CAR-T cell therapy registration trial while JULIET is the first multicenter global registration study for CTL019 in adult patients with relapsed/refractory DLBCL and the largest study examining a CAR-T therapy exclusively in DLBCL.

Researchers are scheduled to present data from the 6-month primary analysis of JULIET at the ASH Annual Meeting in December.

In August, the FDA approved tisagenlecleucel as the first CAR T-cell therapy authorized in the United States, based on results from a 6-month follow-up of 63 patients who received a single dose of tisagenlecleucel in ELIANA.1

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

All patients who had CR or CRi also had negative minimal residual disease status in the bone marrow.

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

Eleven patients who had CR or CRi relapsed after tisagenlecleucel prior to data cutoff 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 or CRi, 29 were still in remission at the last assessment before the data cutoff.

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

The FDA's safety review included 68 patients. 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.

“When tisagenlecleucel became a reality for certain patients and their families in the United States after approval by the FDA for patients with relapsed or refractory ALL this year, I believe it forever changed the face of cancer treatment,” Stephen J. Schuster, MD, the Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research in Penn's Perelman School of Medicine and director of the Lymphoma Program at the Abramson Cancer Center, said in a press release. “The data show this is a groundbreaking immunocellular therapy that has the potential to alter outcomes in patients who have limited options. This submission brings us closer to realizing that potential for more patients with fatal blood cancers.”

Novartis submitted a supplemental biologics license application (sBLA) with the FDA in October 2017 to expand the indication for tisagenlecleucel to include adults with relapsed/refractory DLBCL who are ineligible for ASCT, based on results from the JULIET trial presented in June at the 2017 International Conference on Malignant Lymphoma biennial meeting in Lugano, Switzerland.2

Tisagenlecleucel was associated with an objective response rate of 59% (95% CI, 44.2%-72.4%; P <.0001) in 51 patients with DLBCL at a median follow-up of 3.7 months.

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