In 2017, the U.S. Food and Drug Administration (FDA) approved several therapies for the treatment of hematologic malignancies, marking the first chimeric antigen receptor (CAR) T-cell therapies for any indication and the first antibody-drug conjugate for acute lymphocytic leukemia (ALL). As the number of treatment options for ALL and non-Hodgkin lymphoma (NHL) expands, so do questions about how these new agents should be incorporated into clinical practice.
At the 2017 ASH Annual Meeting, experts discussed the clinical applications of five newly approved treatments in the ASH-FDA Joint Symposium on New Drug Approvals in Acute Lymphocytic Leukemia and Non-Hodgkin Lymphoma:
- tisagenlecleucel – approved August 30, 2017, for the treatment of pediatric and young adult patients with B-cell precursor ALL that is refractory or in second or later relapse
- inotuzumab ozogamicin – approved August 17, 2017, for the treatment of adults with relapsed or refractory B-cell precursor ALL
- axicabtagene ciloleucel – approved October 18, 2017, for the treatment of patients with large B-cell lymphoma
- copanlisib – approved September 14, 2017, for the treatment of adult patients with relapsed follicular lymphoma (FL)
- acalabrutinib – approved October 31, 2017, for the treatment of relapsed or refractory mantle cell lymphoma (MCL)
The session, chaired by 2017 ASH President Kenneth C. Anderson, MD, was adapted from ASH’s webinar series on newly approved drugs. The webinars feature FDA reviewers discussing the approval decisions and clinicians with significant experience with the agents commenting on treatment challenges, including identification of the appropriate population, dosing, adverse events (AEs), and off-label use. “There has been incredible progress over the last few years in all of the hematologic malignancies,” Dr. Anderson said, citing the seven FDA approvals for myeloma treatments in the last two years. “In the last year, we’ve had paradigm changes in ALL and NHL, as well.”
The FDA’s approval of the CAR T-cell therapy tisagenlecleucel to treat young patients (≤25 years old) with B-cell precursor ALL that is refractory or is in second or later relapse made history as the first gene therapy available in the U.S. The decision was based on complete remission (CR) rates in the U.S. population, explained Emily Jen, MD, PhD, clinical reviewer with the FDA. “Within three months of tisagenlecleucel infusion, 63 percent achieved CR, and all patients with a CR or CR with incomplete count recovery also achieved minimal residual disease (MRD) negativity,” she added. “From an efficacy standpoint, tisagenlecleucel showed a substantial improvement over available therapy.”
Fatal adverse events (AEs) included infection (4%) and intracerebral hemorrhage (1%), and other common AEs (reported in >30% of patients) included cytokine release syndrome (CRS), hypogammaglobulinemia, infections, pyrexia, headache, encephalopathy, hypotension, and bleeding. The therapy carries boxed warnings for CRS and neurologic toxicities, and the treatment is only available under a Risk Evaluation and Mitigation Strategy (REMS).
As the first gene therapy approved in the U.S., the approval of tisagenlecleucel represented “a watershed moment in cancer immunotherapy,” said Crystal L. Mackall, MD, professor of Pediatrics and Medicine at Stanford University in California, who discussed approvals in ALL. “To me, the exciting point is that, in all the studies of anti-CD19 CAR T-cell therapy in ALL, the highest-risk patients continually saw high rates of remission,” she added. “Despite the complexities in production and cost and [toxicity] issues, these therapies are still poised for a major impact in B-cell ALL.”
Dr. Mackall expressed concerns about CRS and neurotoxicities associated with these therapies, which may be unfamiliar to many hospitals. She noted that the observed toxicities are “not a deal breaker.” The interleukin-6 receptor tocilizumab, which was approved simultaneously with tisagenlecleucel to manage CRS, has improved outcomes for patients who develop this AE. Researchers also are developing treatment algorithms, grading scales, and early predictors that can identify patients who would benefit from prophylactic treatment.
Early clinical trials with tisagenlecleucel were marred by challenges in manufacturing; in the pivotal ELIANA trial, only 76 percent of children enrolled in the trial received the manufactured cells. “It simply took too long to get these cells to the children,” Dr. Mackall said. “Accounting for these manufacturing failures, the response rate drops to 67 percent.”
However, she noted, progress in cell manufacturing suggests that CAR products could be generated for nearly all patients who need them. At the National Cancer Institute, for example, 94 percent of patients were able to receive manufactured cell products. “We will find a time where, at least from a technical standpoint, this product could be made for every child who would need it. The economics of it, I think, will still need to be demonstrated,” Dr. Mackall said.
Inotuzumab ozogamicin, a CD22-directed antibody-drug conjugate, was approved as the first antibody-drug conjugate for adult patients with CD22-positive relapsed or refractory ALL. The decision was based on results from the phase III INO-VATE 1022 trial, reported Tanya Wroblewski, MD, clinical reviewer at the FDA. The CR rate in the inotuzumab arm was 36 percent, versus 17 percent in the investigator choice of chemotherapy arm. Duration of CR also was longer in the inotuzumab arm, at 8.0 months versus 4.9 months in the control arm.
However, overall survival in the total number of patients enrolled and treated in the INO-VATE ALL study did not reach statistical significance, “which is surprising given the CR rate, MRD-negativity rate, and the number of patients who proceeded to subsequent transplantation in the inotuzumab arm,” Dr. Wroblewski added.
“The antibody drug conjugate class of therapeutics embodies the principle of Ehrlich’s magic bullet – something that cancer researchers have been working toward for many, many years,” Dr. Mackall said during her discussion of this anti-CD22 therapy. “There have been substantial technological improvements in engineering antibodies and in refining the chemistry needed to link the chemotherapy agent to the antibody,” she noted, which is resulting in more of these agents entering clinical trials.
While inotuzumab ozogamicin showed “impressive” remission rates in adults with relapsed or refractory B-cell ALL, Dr. Mackall mentioned that her excitement over the new agent is tempered by toxicity concerns. The drug carries a boxed warning for hepatotoxicity, including hepatic veno-occlusive disease (VOD). In patients who received inotuzumab ozogamicin in the INO-VATE trial, 14 percent developed VOD overall, and 23 percent who underwent subsequent allogeneic hematopoietic cell transplantation (alloHCT) developed VOD.
Previous experiences with a related compound, gemtuzumab ozogamicin, also raise concerns, she said. “[Gemtuzumab ozogamicin] previously similarly demonstrated activity in acute myeloid leukemia, but clinical benefit was diminished by the risk of VOD in those patients, many of whom go on to get alloHCT,” she said.
Axicabtagene ciloleucel was the second CAR T-cell therapy approved by the FDA in 2017, and it is indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. This includes adults with diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from FL, but is not indicated for primary central nervous system (CNS) lymphoma, said Yvette Kasamon, MD, clinical reviewer at the FDA.
Approval was based on results from the single-arm, multicenter ZUMA-1 trial, which enrolled more than 100 adult patients with aggressive B-cell NHL. Following conditioning with low-dose cytarabine and fludarabine, 72 percent of patients responded to axicabtagene ciloleucel, with a CR rate of 51 percent.
“Only patients who achieved CR tended to have durable remissions. In patients with the best overall response of CR, the median duration of response was not reached after approximately eight months of follow-up,” Dr. Kasamon said. “In contrast, in patients who achieved only partial remission, the median duration of response was two months.”
The overall risk-benefit ratio is favorable in the approved population, she added. However, as with tisagenlecleucel, this CAR T-cell therapy carries boxed warnings for CRS and CNS neurotoxicity, and is only available through a REMs. In ZUMA-1, 52 percent of patients experienced a serious AE, the most common of which (occurring in ≥10% of patients) included febrile neutropenia CRS, encephalopathy, and infections.
“This is a ‘living drug’ with significant side effects,” noted Helen Heslop, MD, DSc (Hon), Dan L. Duncan Chair at the Baylor College of Medicine in Houston, Texas, who discussed the approvals for NHL. Familiarity with toxicities will play a role in how these side effects are managed, and understanding of the manufacturing of the CAR T cells will affect access to this treatment approach.
“[Centers] need a significant infrastructure to access this therapy,” Dr. Heslop explained. “You need to have an apheresis center and tertiary hospital that can care for these complex patients, a local cell processing facility to assist with handling, a contract with the pharmaceutical company and an agreement with insurers, expertise in handling complications, and prescribers that are REMS-trained and -approved.”
Dr. Heslop also mentioned that there are other operational issues, including billing and insurance coverage. In the pivotal ZUMA trial, she added, patients received axicabtagene in an inpatient setting, meaning there is little experience with administering the approved product in an outpatient infusion setting.
“Because this is a complex product, there are many ways … [it] can be optimized,” said Dr. Heslop, noting ongoing investigations into targeting multiple antigens, modifying CAR to increase persistence and reduce toxicity, and optimizing manufacturing conditions.
“As with tisagenlecleucel in ALL, axicabtagene ciloleucel is being evaluated earlier in the course of disease,” she added, “and the important question is, ‘Will CAR T-cell products enable or replace HCT in patients with DLBCL?’”
The phosphatidylinositol 3-kinase (PI3K) inhibitor copanlisib received accelerated approval for the treatment of adult patients with relapsed FL who have received at least two prior systemic therapies. “PI3K is linked to cellular proliferation, motility, and survival of malignant B-cells in NHL,” explained Nicholas Richardson, DO, MPH, clinical reviewer at the FDA.
In the multicenter, single-arm CHRONOS-1 trial, which evaluated the drug’s safety and efficacy in patients with relapsed or refractory FL (grade 1-2 or 3a), 59 percent of patients responded to treatment. The median duration of response was 12.2 months.
The most common AEs (≥20%) were hyperglycemia, diarrhea, fatigue, hypertension, neutropenia, nausea, lower respiratory tract infection, and thrombocytopenia. However, “most AEs were of low severity and resolved with dose interruption, dose reduction, or discontinuation,” Dr. Richardson said. It is important to note that patient exposure to copanlisib was limited, with a median of 22 weeks or 5.6 cycles administered (ranges not provided).
“So far, there have been fewer autoimmune and infectious toxicities than idelalisib, but this will need to be confirmed with longer-term follow-up,” Dr. Heslop added. “Because there are still some side effects, it would be nice to have some sort of biomarkers to protect which patients may benefit, and which patients may be more susceptible to side effects.”
“[Copanlisib] is a useful option to have for thirdline therapy,” Dr. Heslop commented. “The question is, ‘How do we integrate it in a population where many patients may have more indolent disease and with other potential therapeutic options?’”
Margret Merino, MD, clinical reviewer at the FDA, discussed the agency’s approval of the second-generation Bruton tyrosine kinase (BTK) inhibitor acalabrutinib for the treatment of adult patients with MCL who have received at least one prior therapy. The approval was based on results from the phase II, single-arm ACE-LY-004 trial, in which 81 percent of patients responded to acalabrutinib monotherapy. “Of note, 72 percent of patients who responded maintained this response for 12 months,” Dr. Merino said.
“[Acalabrutinib] is a more selective BTK inhibitor than ibrutinib,” Dr. Heslop commented, “and there was a high response rate and duration in MCL.” Because patients with MCL are often older, “there is an unmet need, with comorbidities often precluding more intensive therapies,” she said.
Acalabrutinib was generally well tolerated, with only 7 percent of patients discontinuing the drug and only 3 percent of patients requiring a dose reduction, she added. The most common AEs (occurring in ≥20% of patients), were anemia, thrombocytopenia, headache, neutropenia, diarrhea, fatigue, myalgia, and bruising, and these were noted as low grade. Neutropenia (11%), anemia (9%), and pneumonia (6%) were the most common grade ≥3 treatment-emergent AEs.
“Lymphocytosis, which has been associated with BTK-inhibitor therapy in MCL, occurred in 31 percent of patients, occurred early, and was not associated with clinical symptoms and resolved in the majority of patients,” Dr. Merino said.
“Importantly, with the studies so far, there appears to be a lower rate of hemorrhage and atrial fibrillation than with ibrutinib, which is often a concern in this older population,” Dr. Heslop added.
She noted several questions that will need to be answered with larger, longer-term studies. “[The pivotal trial] was done in patients who had not received other BTK therapy, so we don’t know what [acalabrutinib’s] activity will be in [disease] that failed ibrutinib.” Researchers are also evaluating acalabrutinib in combination with other agents, such as bendamustine and CAR T-cell therapies.