First CAR T-cell therapy approvals bolster booming immunotherapy market

There were a number of landmark approvals by the US Food and Drug Administration (FDA) in 2017 for cancer therapies, among them, the approval of the first two chimeric antigen receptor (CAR) T-cell therapies for cancer: tisagenlecleucel (in August) and axicabtagene ciloluecel (in October).¹ CAR T-cells are a type of adoptive cell therapy or immunotherapy, in which the patient’s own immune cells are genetically engineered to target a tumor-associated antigen, in this case CD19. In tisagenlecleucel, CD19 proteins on B cells are targeted in the treatment of B-cell precursor acute lymphoblastic leukemia. Axicabtagene ciloluecel, the second anti-CD19 CAR T-cell therapy, was approved for the treatment of refractory, aggressive B-cell non-Hodgkin lymphoma.

Tisagenlecleucel

Tisagenlecleucel was approved for the treatment of pediatric patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) whose disease is refractory to treatment or who have relapsed after second-line therapy or beyond.² Approval was based on the pivotal ELIANA trial, a single-arm, global phase 2 trial conducted at 25 centers worldwide during April 2015 through April 2017. Patients were eligible for enrollment if they had relapsed or refractory B-cell ALL and were at least 3 years of age at screening and no older than 21 years of age at diagnosis, had at least 5% lymphoblasts in the bone marrow at screening, had tumor expression of CD19, had adequate organ function, and a Karnofsky (adult) or Lansky (child) Performance Status of ≥50 (with the worst allowable score, 50, indicating a patient who requires considerable assistance and frequent medical care [Karnofsky] and lying around much of the day, but gets dressed; no active playing but participates in all quiet play and activities [Lansky]). Exclusion criteria included previous receipt of anti-CD19 therapy, concomitant genetic syndromes associated with bone marrow failure, previous malignancy, and/or active or latent hepatitis B or C virus (HBV/HCV) infection.

The overall remission rate (ORR) was evaluated in 75 patients who were given a single dose of tisagenlecleucel (a median weight-adjusted dose of 3.1 x 10⁶ transduced viable T cells per kg of body weight) within 14 days of completing a lymphodepleting chemotherapy regimen. The confirmed ORR after at least 3 months of follow-up, as assessed by independent central review, was 81%, which included 60% of patients in complete remission (CR) and 21% in complete remission with incomplete hematologic recovery, all of whom were negative for minimal residual disease.

The most common adverse events (AEs) associated with tisagenlecleucel treatment were cytokine release syndrome (CRS), hypogammaglobulinemia, infection, pyrexia, decreased appetite, headache, encephalopathy, hypotension, bleeding episodes, tachycardia, nausea, diarrhea, vomiting, viral infectious disorders, hypoxia, fatigue, acute kidney injury, and delirium. AEs were of grade 3/4 severity in 84% of patients.³

To combat serious safety issues, including CRS and neurologic toxicities, the FDA approved tisagenlecleucel with a Risk Evaluation and Mitigation Strategy (REMS) that, in part, requires health care providers who administer the drug to be trained in their management. It also requires the facility where treatment is administered to have immediate, onsite access to the drug tocilizumab, which was approved in conjunction with tisagenlecleucel for the treatment of patients who experience CRS.

In addition to information about the REMS, the prescribing information details warnings and precautions relating to several other common toxicities. These include hypersensitivity reactions, serious infections, prolonged cytopenias, and hypogammaglobulinemia.

Patients should be monitored for signs and symptoms of infection and treated appropriately. Viral reactivation can occur after tisagenlecleucel treatment, so patients should be screened for HBV, HCV, and human immunodeficiency virus before collection of cells.

The administration of myeloid growth factors is not recommended during the first 3 weeks after infusion or until CRS has resolved. Immunoglobulin levels should be monitored after treatment and hypogammaglobulinemia managed using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement according to standard guidelines.

Patients treated with tisagenlecleucel should also be monitored for life for secondary malignancies, should not be treated with live vaccines from 2 weeks before the start of lymphodepleting chemotherapy until immune recovery after tisagenlecleucel infusion, and should be aware of the potential for neurological events to impact their ability to drive and use dangerous machinery.⁴

Tisagenlecleucel is marketed as Kymriah by Novartis Pharmaceuticals. The recommended dose is 1 infusion of 0.2-5 x 10⁶ CAR-positive viable T cells per kilogram of body weight intravenously (for patients ≤50kg) and 0.1-2.5 x 10⁸ cells/kg (for patients >50kg), administered 2-14 days after lymphodepleting chemotherapy.

Axicabtagene ciloleucel

Axicabtagene ciloleucel was approved for the treatment of adult patients with certain types of relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.⁵ It is not indicated for the treatment of patients with primary central nervous system lymphoma.