A new dawn is breaking in the field of hematologic malignancies, as the first product based on chimeric antigen receptor (CAR) T cells was scrutinized today by a panel of experts and unanimously recommended for approval.
All 10 panel members at today's US Food and Drug Administration (FDA) Oncology Drugs Advisory Committee meeting voted "yes" — there were no abstentions, and no one voted against recommending for approval.
The product is tisagenlecleucel-T (previously known as CTL019; developed by Novartis), and the "yes" vote was in answer to this question: "Considering the efficacy and safety results of Study B2202, is the benefit-risk profile of tisagenlecleucel favorable for treatment of pediatric and young adult patients (age 3-25 years) with relapsed (second or later relapse) or refractory (failed to achieve remission to initial induction or reinduction chemotherapy) B cell precursor acute lymphoblastic leukemia (ALL)? "
Commenting after the vote, panel members emphasized the "clear" efficacy of the product and the fact that there is a strong unmet need for new therapies for relapsed/refractory ALL. One panel member, Alan Rein, PhD, from the National Cancer Institute, Bethesda, Maryland, highlighted the "remarkable clinical successes." However, he also said that there are unanswered questions about long-term safety, so he was glad to see discussion of follow-up for 15 years.
Similar Products Not Far Behind
This product is made individually for each patient.
Blood is collected from the patient, and then autologous T cells are separated out and genetically engineered. The process involves inserting a CAR that targets CD19, an antigen expressed on B cells and tumors derived from B cells. These CAR T cells are then infused back into the patient, who has undergone chemotherapy, and in the body the product homes in on B-cell leukemic cells and destroys them.
Several similar products are in late stages of development. Coming up soon for review by the FDA is Kite Pharma's axicabtagene ciloleucel (KTE-C19) for lymphoma, while further back are CAR T-cell products from Juno.
Although they have been pitched as rivals in the race for the market, Kite's chief executive officer, Arie Belldegrun, said, "I will be Novartis' biggest cheerleader today."
"I am amused by the horse-race metaphors that are used to frame the various companies developing CAR-T therapies," Dr Belldegrun wrote in a blog post. "Today is not about competition," he continued. "Today is about advancing an exciting technology that has the potential to transform cancer."
Today is about advancing an exciting technology that has the potential to transform cancer. Arie Belldegrun
The main efficacy and safety data come from the phase 2 study CCTL019B2202 (B2202), which began on April 2015 and had data cutoff for efficacy analysis in November 2016.
"This was the first global study of a CAR T cell therapy, and more importantly it was the first with a global supply chain of this product," commented principal investigator, Stephan Grubb, MD, PhD, from Children's Hospital in Philadelphia, Pennsylvania. He also ran some of the earlier trials with this product and treated the first pediatric patient with a CAR T cell. This was a 6-year old girl, who remains in remission 5 years later, he said.
In the public part of the meeting, this patient, Emily Whitehead (now 12 years old), accompanied her father, who gave a moving account of how the therapy had saved her life. Another father also described the experience of his son, who underwent 6 years of chemotherapy for ALL, along with many procedures (including spinal taps and surgeries), before finally being treated with tisagenlecleucel and cured of the disease.
The B2202 study enrolled 88 patients (median age, 12 years; range, 3 to 27 years). These patients had received a median of three prior therapies, and just over half these patients had previously undergone stem cell transplantation.
However, 16 patients did not receive the product: 7 because of manufacturing failure, 6 because they died, and 3 because of adverse events.
The results show an overall remission rate of 82.5% (52 of 63 patients).
Of these 52 responders, 40 patients (63%) had a complete response within the first 3 months after infusion, and 12 (19%) had a complete remission with incomplete blood count recovery. All of these were associated with minimum residual disease–negative status in the bone marrow.
In its briefing document, the FDA describes these results as representing "clinically meaningful remission."
The median follow-up time for duration of response (DOR) was 4.8 months
(range, 1.2 to 14.1 months). The median DOR was not reached, and 75% of patients were relapse free at 6 months.
Seven patients went on to undergo hematological stem cell transplantation (HSCT) while they were in remission, and 14 went on to receive other chemotherapy without HSCT.
Eleven patients (17.5%) died after tisagenlecleucel infusion.
In the discussion period at the meeting, Novartis presented data to show that the overall survival seen with tisagenlecleucel is double that seen with other available therapies. The company noted that the 12-month survival rates in the B2202 study were 79% with tisagenlecleucel, compared with previous studies showing rates of 40% with blinatumomab and 20% with clofarabine monotherapy; the median overall survival durations were 16.6 months, 7.5 months, and 3 months, respectively.
The safety analysis population consisted of 68 patients, the FDA noted.
The agency noted that the main serious adverse events include life-threatening cytokine release syndrome (CRS, which consists of fever, hypotension, acute kidney injury, and hypoxia) and hemophagocytic lymphohistiocytosis, as well as neurologic events that occurred with CRS or were delayed after the resolution of the CRS, coagulopathies with CRS, and life-threatening infections.
Grade 3 or 4 CRS occurred in 32 (47%) patients, but no patients died of CRS.
Neurologic toxicities, reported in 30 (44%) patients, included encephalopathy, delirium, hallucinations, somnolence, cognitive disorder, seizure, depressed level of consciousness, mental status changes, dysphagia, mental status changes, muscular weakness, and dysarthria. All were reversible.
CRS is treated with the intereleukin-6 antagonist tocilizumab, and the neurologic symptoms are treated with corticosteroids, in addition to supportive measures.
These adverse reactions can be severe, and even life-threatening, but clinicians who have been involved in clinical trials with CAR T cells say that they are "manageable."
One of these clinicians is Elizabeth Budde, MD, PhD, assistant professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope Hospital in Duarte, California, who noted in a recent interview with Medscape Medical News that these patients need close monitoring with an experienced eye because " these patients can crash at any time."
Novartis said at the FDA meeting that the product would be restricted for use only by certified specialists, and only at certain selected treatment sites. In addition, it recommends that patients receiving this product stay close to the site for 3 to 4 weeks after receiving the infusion because of the risk for these severe adverse events. The company also proposed that the product have a Risk Evaluation and Mitigation Strategy for these two serious adverse events (CRS and neurologic toxicity).
In summarizing the Novartis experience with tisagenlecleucel, head of the CAR T Cell Global Program, David Lebwohl, MD, said that he had been involved in hematologic drug development for 20 years but has "never seen anything like this before."
The product achieves a consistent high overall rate of remission and has "the potential to be a definitive therapy — many patients do not require further therapy…. This is truly a paradigm shift in a setting of enormous medical need," he told the meeting attendees.
Theoretical Long-term Toxicity Concerns
In addition to the short-term safety issues mentioned above, the FDA noted in its briefing document that potential long-term safety concerns with tisagenlecleucel include the potential for generation of replication-competent retrovirus and the potential for insertional mutagenesis to cause new malignancies (genotoxicity).
However, these are theoretical concerns — the FDA also noted that clinical follow-up has not raised any concerns for tisagenlecleucel. The B2202 study did not identify risks from clonal outgrowth and vector-mediated delayed adverse events (eg, secondary leukemias), the agency noted. "However, most study subjects have not been followed for very long, thus limiting the ability to assess the risk of delayed events," it added.
The FDA said that it requires 15 years of follow-up to monitor for subsequent malignant transformation.
Dr Grubb reports receiving research funding (institutional) from Novartis.