The FDA was busy in 2017, with a number of notable approvals, including the first chimeric antigen receptor T-cell treatment. In a session at the 59th American Society of Hematology Annual Meeting and Exposition in Atlanta, Georgia, employees from the FDA presented data on 5 new drug approvals in leukemia and lymphoma in 2017.
The FDA was busy in 2017, with a number of notable approvals, including the first chimeric antigen receptor (CAR) T-cell treatment. In a session at the 59th American Society of Hematology Annual Meeting and Exposition in Atlanta, Georgia, employees from the FDA presented data on 5 new drug approvals in leukemia and lymphoma in 2017.
Tisagenlecleucel was the first CAR T therapy to be approved and its approval was for the treatment of patients age 25 or younger who have B-cell precursor acute lymphoblastic leukemia (ALL). The approval was based on a single-arm international trial in patients with CD19 B-cell ALL. More than half (59%) of the patients had prior ALL hematopoietic stem cell transplantation (HSCT). The population in the study was a highly refractory and treatment-resistant population, explained Emily Jen, MD, PhD, of FDA.
While 78 patients were enrolled in the study, not all eligible patients received treatment due to manufacturing failures, patients dying before infusion, and some patients having an adverse event that precluded infusion. Of those who did receive the infusion, 63% achieved a complete response (CR) and the median duration of response had not been reached.
The treatment’s efficacy showed a substantial improvement over available therapy, such as blinatumumab, said Jen.
“However, treatment with tisagenlecleucel is not without some major safety concerns,” she said. The box includes warnings for cytokine release syndrome (CRS) and neurologic toxicities.
Treatment with tisagenlecleucel will also not be widely available. It will only be available through a restricted program with a Risk Evaluation and Mitigation Strategy (REMS). Facilities must be specially certified, providers must be trained to manage the risk, and patients must be educated.
The second leukemia drug presented was inotuzumab ozogamicin, a CD22-directed antibody-drug conjugate. It was approved for adult patients with CD22 relapsed or refractory ALL based on a trial with 326 patients enrolled. The study found CR in 35.8% of patients, with a median response of 8 months. Tanya Wroblewski, MD, of FDA, noted that it was interesting overall survival did not reach statistical significance.
She added that hepatic veno-occlusive disease (VOD) developed in 14% of patients, overall, and in 23% of those who underwent subsequent HSCT.
“The rationale behind the decision for the approval of inotuzumab considered the population of patients—adults with relapsed or refractory ALL—as having a high unmet medical need,” Wroblewski said. “Secondly, the durable complete remission can be considered evidence of the direct clinical benefit in patients with relapsed or refractory acute leukemias.”
The presentations by the FDA reviewers was followed by an overview from Crystal L. Mackall, MD, professor of pediatrics and internal medicine at Stanford University. There has been substantial progress in ALL, but it still represents a common disease with a high morbidity and mortality in patients and for patients, the outcomes remain poor, explained Mackall.
While the results of the inotuzumab trial were impressive, the development of liver toxicity offset the promise of those results a little. This is not isolated to inotuzumab. A previous agent, gemtuzumab ozogamicin, also demonstrated similar activity in ALL but the risk of hepatic VOD diminished the benefits of the agent.
In pediatric ALL, the efforts of the medical community have led to steadily improved outcomes. Tisagenlecleucel exemplifies the promise of new agents, Mackall said. The story of Emily Whitehead, who received 1 infusion of cells in 2012 that continue to circulate in her show the novelty and promise of the CAR T therapy.
“I want to argue that these CARs, despite the complexities in production and the cost, and these issues, are still poised for major impact in B-cell ALL,” she said.
Adults with relapsed or refractory large B-cell lymphoma who have been on 2 or more lines of systemic therapy now have another therapeutic option: axicabtagene ciloleucel. The FDA approved axicabtagene based on the ZUMA1 trial, a single-arm, multi-phase study.
In the study, the objective response rate (ORR) was 72% and the CR was 52%. Most of the patients in the trial had diffuse large B-cell lymphoma with approximately 69% having failed 3 prior lines of therapy. Patients with a CR tended to have a durable response, explained Yvette Kasamon, MD, of FDA.
However, there were notably serious adverse reactions in 52% of patients. CRS was near universal with 94% of all patients experiencing it. More than half (55%) experienced grade 2 or higher CRS and 13% had grade 3 or higher CRS. The median time to onset of CRS was 2 days and the median duration was 7 days.
“It is vital to ensure the availability of 2 doses of tocilizumab before the CAR T infusion,” Kasamon noted.
In addition, central nervous system neurotoxicity occurred in the majority of patients. Any grade neurotoxicity occurred in 65% to 87% of patients, depending on definition. The median onset to neurotoxicity was 4 days and the median duration was 9 to 13 days.
The drug was approved with restricted distribution in order to reduce CRS and neurotoxicity. Kasamon also noted the exclusion criteria of ZUMA1, which included history of malignancy other than nonmelanoma skin cancer, carcinoma in situ, or follicular lymphoma unless disease free for at least 3 years; presence of fungal, bacterial, viral, or other infection that is uncontrolled; and a known history of infection with HIV or hepatitis B or C.
“These exclusion criteria were relatively stringent and not necessarily representative of many patients we see in the clinic with relapsed/refractory large B-cell lymphoma,” she said.
Copanlisib was granted accelerated approval in adult patients with relapsed follicular lymphoma who had failed on at least 2 prior systemic therapies. The agent is a phosphatidylinositol-3-kinase (PI3K) inhibitor. It was approved based on results of the CHROOS-1 trial, a multi-center single-arm trial with 104 patients.
The trial reported an ORR of 59% and a CR of 14%. The median duration of response was 12.2 months. During the trial, 21% of patients required a dose reduction and 16% discontinued treatment due to adverse reactions. Copanlisib caused infusion-related hyperglycemia and hypertension.
Overall, the trial demonstrated a magnitude of response and duration of response that predicts clinical benefit in these patients.
“The short-term safety profile of copanlisib is tolerable, yet due to limited exposure to copanlisib, long-term safety information is needed and a postmarketing requirement to prospectively characterize long-term safety was issued,” said Nicholas Richardson, DO, MPH, of FDA.
The last therapy presented was acalabrutinib, which was granted accelerated approval for the treatment of relapsed or refractory mantle cell lymphoma. While patients with mantle cell lymphoma tend to respond to initial therapy, most patients relapse.
“Although the therapeutic landscape for mantle cell lymphoma is changing, with chemo, immunotherapy, and targeted agents, prognosis remains poor in the setting of relapsed disease,” explained Margret Merino, MD, of FDA.
Acalabrutinib is a second-generation inhibitor with less inhibition than ibrutinib, which results in less off-target toxicity. Currently, ORR for approved therapies ranges from 31% to 66% and CR ranges from 8% to 17%. The ACE-LY-004 study, a multicenter, global, single-arm trial of 124 patients reported ORR of 81% and CR of 40%. Further, 73% of patients who responded maintained response at 12 months, and at the 15-month follow-up, median response hadn’t been met.
Acalabrutinib was generally well tolerated, Merino explained. There was a low rate of discontinuation (7%) and of dose reduction (3%). The most common adverse reactions, which were mostly low grade, were cytopenias, headache, diarrhea, fatigue, myalgia, and bruising. Lymphocytosis occurred in 31% of patients, occurred early, and resolved in the majority of patients.
“Additional analysis of safety data with longer follow-up is warranted and is planned as part of the postmarketing requirements,” Merino concluded.