wo products based on chimeric antigen receptor (CAR) T cell technology are now racing against each other to reach the market: Novartis's tisagenlecleucel-T (CTL019) for leukemia and Kite's axicabtagene ciloleucel (KTE-C19) for lymphoma.
As previously reported by Medscape Medical News, CAR T cells have shown tremendous results in clinical trials in patients with relapsed/refractory hematologic cancers, who have few — if any — therapeutic options. In some cases, one dose of the treatment has eradicated the disease.
However, "these therapies are not for the fainthearted," as an expert commented recently, because they can be associated with serious toxicity, and treatment-related deaths have occurred in clinical trials.
At one stage, it looked as if this approach would never make it out of an academic setting. Personalized for each patient, the treatment involves taking T cells from an individual, genetically modifying them, and then reinfusing them back into the patient, who in the meantime has undergone chemotherapy.
Then, a number of companies became involved in commercializing the technology.
Now two of the products have reached the registration stage, and as they have been granted priority review (to be completed within 6 months), they could both be approved before the end of the year.
Novartis Product for Leukemia
Novartis announced on March 29 that it has filed for approval in the United States for tisagenlecleucel-T, developed in partnership with University of Pennsylvania researchers, for use in children and young adults with B cell acute lymphoblastic leukemia. The company is also preparing to file for registration of this product in Europe.
This filing is based on data from the ELIANA global registration study, details of which were presented at the American Society of Hematology annual meeting in December 2016, as reported at the time by Medscape Medical News.
This phase 2 study was conducted across 25 centers in the United States, the European Union, Canada, Australia, and Japan. Results showed that 82% (41 of 50) of patients infused with the CAR T cells achieved complete remission or complete remission with incomplete blood count recovery at 3 months after infusion.
Lead investigator of the clinical trials, Stephan Grupp, MD, PhD, from the Children's Hospital of Philadelphia, Pennsylvania, said, "Even if a patient has difficult-to-treat relapsed/refractory leukemia, we have seen treatment with CTL019 in clinical trials put cancer into remission."
In this trial, 48% of patients experienced grade 3 or 4 cytokine release syndrome (CRS), and 15% of patients experienced grade 3 neurologic and psychiatric events, including confusion, delirium, encephalopathy, agitation, and seizure. Both are typical adverse events seen with CAR T cells and can be severe. In this trial, no deaths and no cerebral edema were reported
This treatment offers "a potential new paradigm in the treatment of blood cancers that have not responded to standard therapies," Carl June, MD, leader of the team that developed the technology at the University of Pennsylvania, Philadelphia, commented in the press announcement.
Kite Product for Lymphoma
Meanwhile, Kite announced on March 31 that it has completed the rolling submission with the US Food and Drug Administration for axicabtagene ciloleucel (previously known as KTE-C19) as a treatment for patients with relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL) who are ineligible for autologous stem cell transplant. The company also plans to file in Europe.
This filing is based on data from the ZUMA-1 pivotal trial for axicabtagene ciloleucel, conducted in 101 patients with aggressive NHL, in collaboration with the National Cancer Institute. The company released final results in February 2017, which showed an overall response rate (ORR) in 82% of patients and a complete response (CR) in 54%.
At 6 months, these were maintained as follows: ORR in 41% of patients and CR in 36%.
Five of the 101 patients (5%) continue to experience highly significant and durable partial responses (PRs) with minimal abnormalities on positron emission tomography scans. One of these PRs converted to a CR at month 9, the company noted.
The most common grade 3 or higher adverse events included anemia (43%), neutropenia (39%), decreased neutrophil count (32%), febrile neutropenia (31%), decreased white blood cell count (29%), thrombocytopenia (24%), encephalopathy (21%), and decreased lymphocyte count (20%). Grade 3 or higher CRS was seen in 13% of patients and neurologic events in 28%. There were no cases of cerebral edema.
Three patients died in the early part of this trial. Two deaths — one from hemophagocytic lymphohistiocytosis and one from cardiac arrest in the setting of CRS — were deemed related to axicabtagene ciloleucel. The third death, from a pulmonary embolism, was deemed unrelated to the treatment, the company noted.
Kite senior vice-president of clinical development, Jeff Wiezorek, MD, said these results "suggest that more than a third of patients with refractory aggressive NHL could potentially be cured after a single infusion of axicabtagene ciloleucel."
"We know as clinicians that patients with aggressive lymphoma who do not respond to their previous treatments have a very poor prognosis. In fact, we know from the SCHOLAR-1 study, these patients have only an eight percent chance of achieving a complete response with current therapies," said Frederick L. Locke, MD, ZUMA-1 co-lead investigator, and director of research for the Immune Cell Therapy Program at Moffitt Cancer Center in Tampa, Florida. He noted that several of the patients treated at their center "experienced a rapid and durable complete response with this first-of-its-kind therapy. The ZUMA-1 study results suggest that axicabtagene ciloleucel could become a new standard of care for patients with refractory aggressive lymphoma."