FDA Actions & Updates

The latest approvals, designations, and new indications from the U.S. Food and Drug Administration for oncology drugs.

Thursday, May 24, 2018

The FDA has approved dabrafenib in combination with trametinib for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection. The FDA granted the combination Breakthrough Therapy Designation for this indication in October 2017 and Priority Review in December 2017.

The melanoma approval is based on results from COMBI-AD, a phase III study of 870 patients with stage III BRAF V600E/K mutation-positive melanoma treated with dabrafenib + trametinib after complete surgical resection (N Engl J Med 2017;377:1813-1823). Patients received the dabrafenib (150 mg BID) + trametinib (2 mg QD) combination (n = 438) or matching placebos (n = 432). After a median follow-up of 2.8 years, the primary endpoint of relapse-free survival (RFS) was met.

Treatment with the combination therapy significantly reduced the risk of disease recurrence or death by 53 percent as compared to placebo (HR: 0.47 [95% CI: 0.39-0.58]; p<0.0001; median not reached with combination therapy vs. 16.6 months with placebo). The RFS benefit among the combination arm was observed across all patient subgroups, including disease sub-stage. Improvements were also observed in key secondary endpoints including overall survival (OS), distant metastasis-free survival (DMFS), and freedom from relapse (FFR).

Adverse events (AEs) were consistent with other dabrafenib + trametinib studies, and no new safety signals were reported. Of patients treated with the combination, 97 percent experienced an AE, 41 percent had grade 3/4 AEs and 26 percent had AEs leading to treatment discontinuation (vs. 88%, 14%, and 3%, respectively, with placebo).

"The purpose of adjuvant therapy is to improve recurrence-free and overall survival in our patients with melanoma. Adjuvant therapy options are crucial today because more than half of patients have a recurrence after surgery," said John M. Kirkwood, MD, Usher Professor of Medicine, Director of Melanoma and Skin Cancer, University of Pittsburgh. "We developed the first adjuvant therapy approved by the FDA 22 years ago, and now we have the first effective oral targeted therapy combination that prevents relapse among patients with BRAF-mutated melanoma that has spread to lymph nodes."

"Prevention and early detection are important safeguards from melanoma, but that's only half the picture. Melanoma is an aggressive cancer that can recur, particularly when it shows certain warning signs like increased depth, ulceration, or spread to the lymph nodes," noted Sancy Leachman, MD, PhD, Chair of the Department of Dermatology at OHSU School of Medicine. "With proven treatment options for these patients, it is important for dermatologists to assure that appropriate patients are offered adjuvant treatment options - a 'watch and wait' approach is no longer the standard of care. Collaborating with a multidisciplinary care team of surgeons, pathologists and oncologists, and determining the right treatment based on the patient's individual circumstances and mutational status is crucial to our patients' care plans."​

Thursday, May 24, 2018

The FDA recently alerted health care professionals, oncology clinical investigators, and the public about decreased survival associated with the use of pembrolizumab or atezolizumab monotherapy in clinical trials to treat patients with metastatic urothelial cancer who have not received prior therapy and who have low expression of PD-L1.

In two ongoing clinical trials (KEYNOTE-361 and IMVIGOR-130), the Data Monitoring Committees' (DMC) early reviews found patients in the monotherapy arms of both trials with PD-L1 low status had decreased survival compared to patients who received cisplatin- or carboplatin-based chemotherapy. There was no change in the adverse event profile of pembrolizumab or atezolizumab. Enrollment of patients whose tumors have PD-L1 low status to the pembrolizumab or atezolizumab monotherapy arms have stopped per the DMCs' recommendations.

The clinical trials compare platinum-based chemotherapy combined with pembrolizumab or atezolizumab to platinum-based chemotherapy alone. Both trials enrolled a third arm of monotherapy with pembrolizumab or atezolizumab to compare to platinum-based chemotherapy alone. The monotherapy arms remain open only to patients whose tumors have PD-L1 high status. The combination arms and the chemotherapy arms of both studies also remain open. The FDA is reviewing the findings of the ongoing clinical trials and will communicate new information as necessary.

Both pembrolizumab and atezolizumab are currently approved under accelerated approval for the treatment of locally advanced or metastatic urothelial carcinoma patients who are not eligible for cisplatin-containing chemotherapy, irrespective of PD-L1 status. Patients taking pembrolizumab or atezolizumab for other approved uses should continue to take their medication as directed by their health care professional.

Wednesday, May 9, 2018

The FDA approved dabrafenib and trametinib, administered together, for the treatment of anaplastic thyroid cancer (ATC) that cannot be removed by surgery or has spread to other parts of the body (metastatic), 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 with 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, fever that may be severe, 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.

Wednesday, May 9, 2018

The FDA has approved daratumumab in combination with bortezomib, a proteasome inhibitor (PI); 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 (ASCT).

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, Chicago, Illinois 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 (Hazard Ratio [HR] = 0.50; 95% CI [0.38-0.65], p<0.0001). The median progression-free survival (PFS) for daratumumab/VMP had not yet been reached, compared to a median PFS of 18.1 months for patients who received VMP alone.

Wednesday, May 2, 2018

The FDA has approved tisagenlecleucel suspension for intravenous 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.

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 (NHL) 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," said 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. "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."

Tisagenlecleucel is an innovative immunocellular therapy that is a one-time treatment manufactured individually for each patient using the patient's own T cells. It uses the 4-1BB costimulatory domain in its chimeric antigen receptor to enhance cellular expansion and persistence. In 2012, Penn entered into a global collaboration to further research, develop and commercialize CAR-T cell therapies, including tisagenlecleucel, for the investigational treatment of cancers.

To ensure all hospitals and their associated clinics are aware of how to manage the risks of cytokine release syndrome (CRS) 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 which are certified and fully operational to begin treatment of eligible patients with DLBCL.

To address the unique aspects of this therapy, various patient programs and resources are available to support safe and timely access for patients and address a range of needs.

JULIET Pivotal Study

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.

Tisagenlecleucel showed an overall response rate (ORR) of 50 percent (95% confidence interval [CI], 38% - 62%), with 32 percent of patients achieving a complete response (CR) and 18 percent achieving a partial response (PR) in 68 patients evaluated for efficacy. The median duration of response was not reached among these patients, indicating sustainability of response.

In all patients infused with tisagenlecleucel (n=106), severe or life-threatening (grade 3/4) CRS, defined by the Penn Grading Scale – a rigorous scale for grading this reaction –, occurred in 23 percent of patients. CRS is a known complication of CAR-T therapy that may occur when the engineered cells become activated in the patient's body. CRS was managed globally using prior site education on implementation of the CRS treatment algorithm.

Eighteen percent of all infused patients experienced grade 3/4 neurologic events, which were managed with supportive care. Encephalopathy, a distinctive neurotoxicity associated with CAR-T therapies, was seen as severe or life-threatening in 11 percent of patients. There were no deaths attributed to neurological events, and no fatal cases of cerebral edema have occurred.

Grade 3/4 cytopenias lasting more than 28 days included thrombocytopenia (40%) and neutropenia (25%), and grade 3/4 infections occurred in 25 percent. The most common (>20%) adverse events (AEs) in the JULIET study are CRS, infections, pyrexia, diarrhea, nausea, fatigue, hypotension, edema, and headache.​