Yescarta (axicabtagene ciloleucel), formerly known as KTE-C19, is a chimeric antigen receptor (CAR) T-cell therapy developed by Kite Pharma for adults with large B-cell non-Hodgkin lymphoma (NHL) that either relapsed or did not improve after treatment with at least two other therapeutics.
Kite Pharma is now a part of Gilead Sciences.
In October 2017, the U.S. Food and Drug Administration (FDA) approved the use of Yescarta in the U.S. The European Commission (EC) followed suit in August 2018, authorizing the use of Yescarta in 28 countries of the E.U., Liechtenstein, Iceland, and Norway.
How Yescarta works
NHL is a group of closely related blood cancers that are caused by the abnormal behavior and fast growth of white blood cells, or lymphocytes. There are many different types of NHL that are classified based on the type of lymphocyte in which cancer originates, the behavior of cancer, and whether specific proteins are expressed on the surface of tumor cells. Large B-cell NHL is an aggressive type of cancer originating in the B-cells, a type of lymphocyte. It is the most common type of NHL.
Yescarta is a cell-based immunotherapy; it triggers the body’s immune system to fight cancer. Normally, a type of immune system cell called T-cells can detect and destroy abnormal cells to protect the body. However, in cancer, the immune system often is unable to recognize the cancer cells or is too weak to have an effect.
Yescarta is made using the patient’s own T-cells that are isolated from blood. A gene carrying instructions to make a special receptor called the chimeric antigen receptor (CAR) is introduced into the isolated T-cells in the laboratory. These modified T-cells are propagated and re-introduced into the patient’s body through a vein (intravenous infusion). The receptor binds to CD19, which is a protein present on the surface of most cancer cells causing their breakdown by the CAR producing T-cells (CAR T-cells).
Yescarta in clinical trials
The safety and effectiveness of Yescarta are being evaluated in several types of non-Hodgkin lymphomas.
An ongoing Phase 1/2 trial (NCT02348216) called ZUMA-1 is assessing the safety, efficacy, and dosage of Yescarta in patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), and transformed follicular lymphoma (TFL) who have relapsed or did not respond to treatment with standard therapies (refractory).
This study is being conducted in three phases:
- Phase 1 evaluates the safety of Yescarta treatment;
- Pivotal Phase 2 assesses the efficacy (effectiveness) of the treatment;
- Management Phase 2 examines the incidence and severity of side effects such as cytokine release syndrome (CRS) and neurologic toxicity.
Results from seven DLBCL patients treated in the Phase 1 portion of ZUMA-1 were published in the journal Molecular Therapy in January 2017. Of the seven patients, four (57%) achieved complete remission, where there are no symptoms of cancer. Three of these patients were still in complete remission after 12 months. Among them, Yescarta was still present in the body at the time of follow-up.
Topline primary results ZUMA-1’s second phase were announced in February 2017. A total of 77 DLBCL patients and 24 TFL or PMBCL patients were treated. At six months, 31% of DLBCL patients and 54% of TFL/PMBCL patients achieved complete remission. The study met its primary endpoint (goal) with an overall response rate of 82% after a single Yescarta infusion. The researchers reported that three deaths occurred during the study, but they were not related to Yescarta treatment.
The two-year follow-up data from ZUMA-1 were published in the journal The Lancet in January 2019. At the median period of 27.1 months, 101 of 108 patients who received treatment at the start of the study were available for the pivotal Phase 2 follow-up. The study reported that 83% (84) of the patients showed some level of reduction in tumor burden (objective response). Complete response was achieved by 58% (59) of the patients. Cancer did not worsen for a median of 5.9 months after the treatment, an interval known as progression-free survival).
Phase 1 and 2 safety data were available for 108 patients. Serious side effects were reported in 48% (52) of the patients. Neurologic events and CRS were recorded in 32% (35) and 11% (12) of all the patients, respectively. No new Yescarta-related deaths occurred since the previous follow-up.
ZUMA-2 (NCT02601313) is an ongoing Phase 2 clinical trial investigating the safety and efficacy of Yescarta in an estimated 70 patients with relapsed/refractory mantle cell lymphoma (MCL). This study will evaluate the efficacy of two different doses of Yescarta. The trial is recruiting participants at sites in the U.S., France, Germany, and The Netherlands.
The Phase 1/2 ZUMA-3 (NCT02614066) trial investigating Yescarta in patients, ages 18 and older with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL) is also underway. According to the preliminary results published in the journal Blood, a single dose of Yescarta was able to cause a high remission rate in the population tested. At the median follow-up of 11 months, 32 of the 35 patients dosed at the start of the study could be evaluated for treatment response. Among those 32 patients, the treatment efficiently cleared the tumor as suggested by the overall rate of undetectable minimal residual disease of 78%. Complete remission was reported in 72% (23) of the group. In the 35 patients who were treated, 46 percent (16) had serious neurological side effects while CRS occurred in 26% (nine) of the patients. Low blood pressure was the most common adverse side effect, followed by fever, low platelet count, and anemia.
ZUMA-4 (NCT02625480) is a Phase 1/2 clinical trial to test Yescarta in 75 pediatric/adolescent patients, ages 2 to 21, with relapsed/refractory ALL. An update for the first four treated patients was presented at the 22nd Congress of the European Hematology Association in May 2017 showing a favorable safety profile. The study is still enrolling patients at sites in the U.S. and in Canada, France, and The Netherlands.
The Phase 2 ZUMA-5 trial (NCT03105336) aims to assess Yescarta as a treatment for indolent B-cell NHL that has relapsed or is resistant to standard therapy. The first patient of an estimated 50 received Yescarta in August 2017.
The Phase 1/2 ZUMA-6 trial (NCT02926833) is investigating the safety and efficacy of Yescarta in combination with Tecentriq (atezolizumab) in 31 DLBCL patients.
ZUMA-9 (NCT03153462) is an expanded access study, allowing potential access to Yescarta to those patients who could not enroll in previous ZUMA trials.
Additional information
According to the manufacturer, side effects are common with the use of Yescarta, as they are with other anti-cancer therapies. That’s why patients should consult their physicians and discuss the treatment and its adverse effects, the most common of which include:
- Fever
- Severe nausea and vomiting
- Diarrhea
- Low blood cell count
- Difficulty breathing
- Chills
- Confusion
- Dizziness, headache, and fatigue
- Low blood pressure
- Heart arrhythmia
- Slurred speech
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