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FDA Approves Tisagenlecleucel for Adults With R/R Large B-Cell Lymphoma

The FDA has approved tisagenlecleucel suspension for IV infusion for its second indication-the treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL), high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

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Tisagenlecleucel is not indicated for the treatment of patients with primary central nervous system lymphoma. The treatment, developed in collaboration with the University of Pennsylvania, became the first chimeric antigen receptor T-cell (CAR-T) therapy to receive regulatory approval in August 2017 for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. It is now the only CAR T-cell therapy to receive FDA approval for two distinct indications in non-Hodgkin lymphoma and B-cell ALL.


"The goal of [tisagenlecleucel] is to provide physicians with a therapy that has demonstrated durable response rates in relapsed or refractory DLBCL patients, a patient population that has endured multiple rounds of chemotherapy with many having experienced unsuccessful stem cell transplants," explained Stephen J. Schuster, MD, the Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research in Penn's Perelman School of Medicine, and Director of the Lymphoma Program at the Abramson Cancer Center, Philadelphia. "With this approval, physicians now have a meaningful therapeutic option that can achieve and maintain a sustained response without stem cell transplant along with a consistent safety profile."


The FDA approval of tisagenlecleucel in adult patients with r/r DLBCL is based on the pivotal phase II JULIET clinical trial, the first multi-center global registration study for tisagenlecleucel in adult patients with r/r DLBCL.


JULIET was conducted in collaboration with Penn and is the largest study examining a CAR-T therapy in DLBCL, enrolling patients from 27 sites in 10 countries across the U.S., Canada, Australia, Japan, and Europe, including Austria, France, Germany, Italy, Norway, and the Netherlands. In the JULIET trial, patients were infused in the inpatient and outpatient setting.


To ensure all hospitals and their associated clinics are aware of how to manage the risks of cytokine release syndrome and neurological toxicities, tisagenlecleucel is available through a Risk Evaluation and Mitigation Strategy (REMS) program. The REMS program serves to inform and educate health care professionals about the risks that may be associated with the treatment. To support safe patient access, a network of certified treatment centers throughout the country has been established, which are fully trained on the use of tisagenlecleucel and appropriate patient care, and there are currently treatment centers that are certified and fully operational to begin treatment of eligible patients with DLBCL.


Daratumumab Approved for Transplant-Ineligible Multiple Myeloma Patients

The FDA has approved daratumumab in combination with bortezomib, a proteasome inhibitor; melphalan, an alkylating agent; and prednisone (VMP) for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.


Daratumumab is the first monoclonal antibody approved for newly diagnosed patients with this disease. Clinical trial results showed daratumumab in combination with VMP reduced the risk of disease progression or death by 50 percent compared to treatment with VMP alone.


"This approval is significant as we now have the first antibody-based regimen for treating newly diagnosed multiple myeloma patients who are not eligible for a stem cell transplant," said Andrzej Jakubowiak, MD, PhD, Director of the Multiple Myeloma Program at University of Chicago Medical Center, and a daratumumab clinical study investigator. "In clinical studies, patients who received treatment with daratumumab experienced a lower risk of disease progression and higher rates of response."


The FDA approval of daratumumab in combination with VMP is supported by data from the randomized, open-label, multicenter, phase III ALCYONE (MMY3007) study (N Engl J Med 2018;378:518-528). The combination of daratumumab with VMP reduced the risk of disease progression or death by 50 percent, compared to treatment with VMP alone (HR=0.50; 95% CI [0.38-0.65], p<0.0001). The median progression-free survival for daratumumab/VMP had not yet been reached, compared to a median PFS of 18.1 months for patients who received VMP alone.


Dabrafenib/Trametinib Approved for BRAF-Positive Anaplastic Thyroid Cancer

The FDA approved dabrafenib and trametinib, administered together, for the treatment of anaplastic thyroid cancer (ATC) that cannot be removed by surgery, has spread to other parts of the body, and has a type of abnormal gene, BRAF V600E (BRAF V600E mutation-positive).


"This is the first FDA-approved treatment for patients with this aggressive form of thyroid cancer, and the third cancer with this specific gene mutation that this drug combination has been approved to treat," said Richard Pazdur, MD, Director of the FDA's Oncology Center of Excellence and Acting Director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research. "This approval demonstrates that targeting the same molecular pathway in diverse diseases is an effective way to expedite the development of treatments that may help more patients."


Both dabrafenib and trametinib are also approved for use, alone or in combination, to treat BRAF V600 mutation-positive metastatic melanoma. Additionally, dabrafenib and trametinib are approved for use in combination to treat BRAF V600E mutation-positive, metastatic non-small cell lung cancer.


The efficacy of dabrafenib and trametinib in treating ATC was shown in an open-label clinical trial of patients with rare cancers having the BRAF V600E mutation. Data from trials in BRAF V600E mutation-positive, metastatic melanoma or lung cancer and results in other BRAF V600E mutation-positive rare cancers provided confidence in the results seen in patients with ATC. The trial measured the percent of patients with a complete or partial reduction in tumor size. Of 23 evaluable patients, 57 percent experienced a partial response and 4 percent experienced a complete response; in nine (64%) of the 14 patients with responses, there were no significant tumor growths for 6 months or longer.


The side effects of dabrafenib and trametinib in patients with ATC are consistent with those seen in other cancers when the two drugs are used together. Common side effects include pyrexia, rash, chills, headache, arthralgia, cough, fatigue, nausea, vomiting, diarrhea, myalgia, dry skin, decreased appetite, edema, hemorrhage, hypertension, and dyspnea.


Severe side effects of dabrafenib include the development of new cancers, growth of tumors in patients with BRAF wild-type tumors, serious bleeding problems, heart problems, severe eye problems, severe fever, serious skin reactions, high blood sugar or worsening diabetes, and serious anemia.


Severe side effects of trametinib include the development of new cancers; serious bleeding problems; inflammation of intestines and perforation of the intestines; blood clots in the arms, legs or lungs; heart problems; severe eye problems; lung or breathing problems; fever that may be severe; serious skin reactions; and high blood sugar or worsening diabetes.


The FDA granted Priority Review and Breakthrough Therapy designation for this indication. Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases, was also granted for this indication.