The investigational CTL019, proposed for the treatment of relapsed or refractory (r/r) pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL),1 has demonstrated durable remission rates in its global phase II study.2,3 If FDA accepts the panel recommendation, CTL019 would receive the very first market approval for chimeric antigen receptor (CAR) T cell therapy.
Currently, the Berlin–Frankfurt–Münster regimen is arguably the core of most contemporary treatment regimens for ALL, leading to a remarkable result in cure rates exceeding 85%.4 Nonetheless, relapse and refractory ALL remain a therapeutic challenge.5 A limited number of treatment options are available for patients with r/r B-cell ALL, and these are associated with poor efficacy and safety outcomes.6
CTL019, also known as tisagenlecleucel, is an autologous and immunocellular cancer therapy which involves reprogramming a patient’s own T cells with a transgene encoding a CAR to identify and eliminate CD19-expressing malignant and non-malignant cells (Figure 1).6
The concept of CAR T cell therapy represents an emerging and novel immunotherapeutic tool, with the CTL019 receiving an FDA-designated breakthrough therapy status in 2014 for r/r B-cell ALL in pediatric and young adult patients, and in 2017 for r/r diffuse large B-cell lymphoma (DLBCL) who have failed two or more prior therapies.7
The unanimous (10-0) recommendation by ODAC is based on the review of three studies involving pediatric and young adult patients with r/r B-cell ALL.6 Encouraging data were initially coming from a US single site trial at the Children’s Hospital of Philadelphia, which led to the initiation of a US multicentre study to confirm the efficacy and safety of CTL019, and followed by the Novartis-led ELIANA trial.6
“We’re very proud to be expanding new frontiers in cancer treatment by advancing immunocellular therapy for children and young adults with r/r B-cell ALL and other critically ill patients who have limited options. We look forward to working with the FDA as they complete their review.” said Bruno Strigini, Chief Executive Officer of Novartis Oncology.1
The single-arm, open-label, multicenter, global phase 2 ELIANA study is the first pediatric global CAR T cell therapy registration trial, in which the interim results were presented at the 2017 European Hematology Association (EHA) Annual Meeting in Spain.2,3
Among 63 evaluable patients, the overall remission rate was 83% (95% CI: 71% to 91%).3 Furthermore, the interim analysis of ELIANA has also showed that the relapse-free probability was 75% (95% CI: 57% to 87%) at 6 months and 64% (95% CI: 42% to 79%) at 12 months among responders.2,3
Cytokine release syndrome (CRS), a commonly observed toxicity due to the activation of bystander innate immune cells, occurred in 78% of patients.3,8 However, no CRS-associated deaths and no incidents of cerebral edema were reported.3
“The updated CTL019 ELIANA data illustrating early observed response rates that have held steady over 6 months’ time are exciting findings. Durability is an important measure for children and young adults with relapsed or refractory B-cell ALL, and we are truly encouraged by the results of this study,” said lead investigator Stephan Grupp, the Yetta Deitch Novotny Professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania (Penn), and Director of the Cancer Immunotherapy Frontier Program at the Children’s Hospital of Philadelphia (CHOP).2
Novartis is not alone in its efforts to secure the landmark approval in the CAR T cell market. In May 2017, the FDA has also granted a priority review to Kite Pharma’s KTE-C19 (axicabtagene ciloleucel) for transplant-ineligible patients with relapsed or refractory non-Hodgkin lymphoma (NHL).
“Patients with refractory aggressive NHL face a dire prognosis with only a 50 percent chance of surviving six months. This underscores the urgent medical need for these patients and why every day matters, from development to manufacturing to clinical experience,” said Dr. David Chang, Executive Vice President of Research and Development and Chief Medical Officer of Kite. “We firmly believe in the potential for axicabtagene ciloleucel to address this need and forge a new path for the future of cell therapy.”10
*As of August 30, 2017, the FDA has finally approved CTL019 (tisagenlecleucel) for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.11