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FDA advisory committee supports three oncology products
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An FDA advisory committee expressed its support for gemtuzumab ozogamicin as part of combination therapy for acute myeloid leukemia; ABP 215, a biosimilar candidate to bevacizumab; and chimeric antigen receptor T-cell product tisagenlecleucel-T suspension for relapsed/refractory B-cell acute lymphoblastic leukemia.
The FDA often follows the guidance of the Oncologic Drugs Advisory Committee (ODAC) when making its final decision on an agent’s approval, but the agency is not obligated to do so.
Gemtuzumab ozogamicin
Gemtuzumab ozogamicin (Mylotarg, Pfizer) is a recombinant, humanized anti-CD33 antibody-drug conjugate.
The FDA approved the product via accelerated review in May 2000 for monotherapy of elderly individuals with relapsed AML. However, Pfizer voluntarily withdrew the agent from the market in June 2010 after results of a postmarketing clinical trial showed the drug increased risk for death but conferred no additional benefit compared with other conventional therapies.
Pfizer resubmitted a biologics license application that sought approval of gemtuzumab ozogamicin in combination with daunorubicin and cytarabine for treatment of adults with treatment-naive CD33-positive AML.
ODAC voted 6-1 that the combination has a favorable risk-benefit profile.
“We are extremely pleased with the committee’s recommendation and believe this is an important step toward our goal of making Mylotarg available to patients with newly diagnosed AML,” Mace Rothenberg, MD, chief development officer for oncology with Pfizer Global Product Development, said in a press release. “We look forward to working closely with the FDA as we continue the regulatory process. We are grateful to both the investigators who led Mylotarg clinical trials and the patients who participated.”
The FDA is scheduled to make a decision on the application by Sept. 27.
Pfizer’s application included data from the randomized phase 3 ALFA-0701 study, which evaluated gemtuzumab ozogamicin in combination with standard induction chemotherapy administered in an alternative fractionated dosing schedule. The analysis included 278 adults (age range, 50 to 70 years) with de novo AML.
The final analysis showed gemtuzumab ozogamicin-treated patients achieved significantly higher rates of 3-year EFS (31% vs. 19%; HR = 0.66; 95% CI, 0.5-0.87) and 3-year RFS (38% vs. 25%; P = .006). Researchers also observed a 3-year OS benefit with gemtuzumab ozogamicin (44% vs. 36%; HR = 0.82; 95% CI, 0.6-1.1), but the difference did not reach statistical significance.
The application also included data from Pfizer-sponsored studies from the original new drug application, as well as a meta-analysis of more than 3,000 patients who participated in five randomized phase 3 studies, including ALFA-0701.
“Clinical studies investigating Mylotarg have provided a significant body of evidence supporting the risk-benefit profile of Mylotarg in AML,” Jorge E. Cortes, MD, deputy department chair of the department of leukemia at The University of Texas MD Anderson Cancer Center, said in the release. “Based on the totality of the efficacy and safety data, Mylotarg — if approved — has the potential to be an important treatment option for adult patients with AML.”
ABP 215
ODAC voted 17-0 that the risk-benefit profile of ABP 215 (Amgen/Allergan) — the first biosimilar candidate to bevacizumab (Avastin, Genentech) considered by FDA — supports its approval for treatment of a variety of solid tumors.
“If approved, ABP 215 has the potential to provide another high-quality treatment option for [patients with cancer] and pave the way for additional high-quality oncology biosimilars from Allergan and Amgen,” David Nicholson, chief of research and development at Allergan, said in a press release.
Bevacizumab, a recombinant immunoglobulin G1 monoclonal antibody, binds to vascular endothelial growth factor and inhibits the interaction of VEGF with its receptors. An angiogenesis inhibitor, it prevents the establishment of new blood vessels that solid tumors need survive and grow.
Bevacizumab is indicated for treatment of certain patients with metastatic colorectal cancer, advanced nonsquamous non-small cell lung cancer, platinum-resistant ovarian cancer, advanced cervical cancer, metastatic renal cell carcinoma or recurrent glioblastoma.
Amgen’s presentation included clinical, pharmacokinetic and analytical data designed to show that ABP 215 and bevacizumab are highly similar. The data showed no clinically meaningful differences in efficacy, safety or immunogenicity between the two agents, according to the press release.
The data package included results of a phase 3 study that met its primary endpoint, showing clinical equivalence between ABP 215 and bevacizumab as treatment for patients with nonsquamous NSCLC.
Tisagenlecleucel-T suspension
ODAC 10-0 in support of the favorability of tisagenlecleucel-T suspension’s benefit-risk profile for patients aged 3 to 25 years with relapsed/refractory B-cell acute lymphoblastic leukemia.
Tisagenlecleucel-T suspension (Novartis) — also known as CTL019 — is comprised of genetically modified T cells that target CD19, an antigen expressed on the surface of B cells.
Results of the phase 2 ELIANA study formed the basis of Novartis’ application. Among 63 patients who received a single infusion of tisagenlecleucel, researchers reported an overall response rate of 82.5% (95% CI, 70.9-91). All responding patients showed no minimal residual disease.
Several committee members expressed concern that heterogeneity of T-cell subpopulations in the final product could lead to varying safety and efficacy outcomes.
“I have concerns that you are not getting 100% CD3 T cells in your final product,” Catherine M. Bollard, MBChB, MD, chief of division of allergy and immunology, director of program for cell enhancement and technologies for immunotherapy at Children’s National Medical Center at The George Washington University, and voting member of ODAC, said during the committee discussion. “[Although] there are clearly some [natural killer] cells, what are the other cells remaining? What you’re starting with is a very heterogenous material. How can we increase that purity in terms of absolute T-cell numbers to 100%, if possible?”
All 68 patients infused with tisagenlecleucel were included in the safety analysis of ELIANA. Grade 3 or grade 4 cytokine release syndrome occurred in 32 patients (47%), but no deaths occurred due to cytokine release syndrome.
Thirty patients experienced neurological toxicities, which included encephalopathy, delirium, hallucinations, somnolence, cognitive disorder, seizure, depressed level of consciousness, mental status changes, dysphagia, muscular weakness and dysarthria.
The conduct of this trial demonstrated that tisagenlecleucel can safely and effectively be used beyond just a single trial site, after additional centers have been trained on proper handling of the product and adverse event management, according to Stephan A. Grupp, MD, PhD, director of the cancer immunotherapy program, director of translational research for the Center for Childhood Cancer Research and medical director of the stem cell laboratory at Children’s Hospital of Philadelphia.
“We’ve treated so many patients at this point that we have a pretty good understanding of the adverse events,” he said.
Upon approval, Novartis would introduce tisagenlecleucel in 30 to 35 sites across the United States. The company plans to train each center on processes for cell collection, cryopreservation, transport, safety management and logistics.
Safety management would involve an algorithm for infusion reactions and cytokine release syndrome management — developed and refined during the trials of tisagenlecleucel — which involves risk mitigation measures and close monitoring to allow early intervention and use of supportive care measures.
Patients and caregivers would be required to stay within 2 to 3 hours of the treatment center for several weeks after treatment.
Novartis also is planning to conduct a long-term postmarketing study with an observational registry, and to collect and evaluate tissue samples from patients who develop a secondary malignancy.
If the FDA follows the committee’s guidance, tisagenlecleucel would become the first approved chimeric antigen receptor T-cell therapy.
“This is the most exciting advance I’ve seen in my lifetime, and since multiagent care — as it was once called — for childhood leukemia in the 1950s,” Timothy P. Cripe, MD, PhD, FAAP, CPI, voting member of ODAC and professor and chief in the division of hematology/oncology/bone marrow transplantation at Nationwide Children’s Hospital at The Ohio State University, said after the vote. – by Mark Leiser and Alexandra Todak
Reference:
Castaigne S, et al. Abstract #376. Presented at: ASH Annual Meeting and Exposition; Dec. 6-9, 2014; San Francisco.
Disclosures: HemOnc Today could not confirm the committee members’ financial disclosures at the time of reporting.