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FDA Actions & Updates

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

Monday, January 21, 2019

The FDA recently approved cabozantinib tablets for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

This approval was based on results from the CELESTIAL phase III pivotal trial of cabozantinib for patients with advanced HCC who received prior sorafenib. Cabozantinib demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) versus placebo. On November 15, 2018, Exelixis' partner Ipsen received approval from the European Commission for CABOMETYX tablets as a monotherapy for HCC in adults who have previously been treated with sorafenib.

"Patients with this form of advanced liver cancer have few treatment options, particularly once their disease progresses following treatment with sorafenib," said Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center, New York and lead investigator on CELESTIAL. "Physicians are eager for new options for these patients, and the results of the CELESTIAL trial demonstrate that [cabozantinib] has the efficacy and safety profile to become an important new therapy in our efforts to slow disease progression and improve treatment outcomes."

In the pivotal CELESTIAL trial, median OS was 10.2 months with cabozantinib versus 8.0 months with placebo (HR 0.76, 95% CI 0.63-0.92; p=0.0049). Median progression-free survival (PFS) was more than doubled, at 5.2 months with cabozantinib and 1.9 months with placebo (HR 0.44, 95% CI 0.36-0.52; p<0.0001). Objective response rates per RECIST 1.1 were 4 percent with cabozantinib and 0.4 percent with placebo (p=0.0086). Disease control (partial response or stable disease) was achieved by 64 percent of patients in the cabozantinib group compared with 33 percent of patients in the placebo group.

Adverse events in CELESTIAL were consistent with the known safety profile of cabozantinib. The most common (≥10 percent) grade 3 or 4 adverse events in the cabozantinib group compared to the placebo group were palmar-plantar erythrodysesthesia (17% vs. 0%), hypertension (16% vs. 2%), increased aspartate aminotransferase (12% vs. 7%), fatigue (10% vs. 4%) and diarrhea (10% vs. 2%).

Treatment-related grade 5 adverse events occurred in six patients in the cabozantinib group (hepatic failure, esophagobronchial fistula, portal vein thrombosis, upper gastrointestinal hemorrhage, pulmonary embolism and hepatorenal syndrome) and in one patient in the placebo group (hepatic failure). Sixteen percent of patients in the cabozantinib arm and three percent of patients in the placebo arm discontinued treatment due to treatment-related adverse events.

"While we've seen some progress in the treatment of primary liver cancer in recent years, the patient community still needs new and better options," said Andrea Wilson, President and Founder of Blue Faery: The Adrienne Wilson Liver Cancer Association. "The approval of [cabozantinib] has been eagerly anticipated, making this an important day for patients diagnosed with this devastating disease."

In December 2018, the initiation of COSMIC-312, a phase III pivotal trial of cabozantinib in combination with atezolizumab versus sorafenib in previously untreated advanced HCC, was announced. The trial will also explore single-agent activity of cabozantinib in the first-line setting.

Friday, January 4, 2019

The FDA has expanded the indication for dasatinib tablets to include the treatment of pediatric patients 1 year of age and older with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in combination with chemotherapy.

Dasatinib is the only second-generation tyrosine kinase inhibitor approved for this patient population. The approval, which was granted following priority review by the FDA, is based on data from the phase II study, CA180-372 (NCT01460160).

Dasatinib is associated with the following warnings and precautions: myelosuppression, bleeding-related events, fluid retention, cardiovascular events, pulmonary arterial hypertension, QT prolongation, severe dermatologic reactions, tumor lysis syndrome, embryo-fetal toxicity, and effects on growth and development in pediatric patients.

The efficacy of dasatinib tablets in combination with chemotherapy was evaluated in a single cohort of the phase II, multicenter, single-arm CA180-372 study, which included 78 pediatric patients with newly diagnosed B-cell precursor Ph+ ALL. At 3 years, the study demonstrated an event-free survival (EFS) binary rate of 64.1 percent (95% confidence interval [CI]: 52.4 to 74.7). Event-free survival is defined as the time from the start of dasatinib to lack of complete response at the end of the third high-risk block, relapse, secondary malignancy, or death from any cause.

Of the 81 patients evaluated for safety, fatal adverse reactions occurred in three patients (4%), and eight (10%) experienced adverse reactions leading to treatment discontinuation, including fungal sepsis, hepatotoxicity of graft versus host disease, thrombocytopenia, CMV infection, pneumonia, nausea, enteritis, and drug hypersensitivity. The most common serious adverse reactions (incidence ≥10%) were pyrexia, febrile neutropenia, mucositis, diarrhea, sepsis, hypotension, infections (bacterial, viral, and fungal), hypersensitivity, vomiting, renal insufficiency, abdominal pain, and musculoskeletal pain.

"As treatments have advanced in recent years, we've seen improvements in outcomes for pediatric patients with Ph+ ALL overall, but there remains a need for additional options," said Stephen Hunger, MD, lead study author, Chief of the Division of Oncology and Director of the Center for Childhood Cancer Research at Children's Hospital of Philadelphia. "The phase II CA180-372 trial was particularly informative because it was designed to limit the use of cranial irradiation and stem cell transplant. In the study, dasatinib plus chemotherapy demonstrated a 3-year event-free survival benefit. These results show that dasatinib is an effective medication for physicians to consider for children and adolescents with Ph+ ALL."

In the CA180-372 trial, the 78 patients evaluated for efficacy in cohort 1 received dasatinib at a daily dose of 60 mg/m2 for up to 24 months, in combination with chemotherapy. The backbone chemotherapy regimen was the AIEOP-BFM ALL 2000 multi-agent chemotherapy protocol. Efficacy was established based on 3-year EFS, defined as the time from the start of dasatinib to lack of complete response at the end of the third high-risk block, relapse, secondary malignancy, or death from any cause. The trial was designed such that patients with central nervous system 3 disease receive cranial irradiation. Patients were assigned to receive stem cell transplant (SCT) based on minimal residual disease if they were considered high-risk. 

The recommended starting dosage for dasatinib in pediatric patients with Ph+ ALL is based on body weight. The recommended dose should be administered orally once daily, and the dose should be recalculated every 3 months based on changes in body weight, or more often if necessary. For pediatric patients with Ph+ ALL, dasatinib therapy should begin on or before day 15 of induction chemotherapy, when diagnosis is confirmed, and continue for 2 years.

Sunday, December 23, 2018

The FDA approved tagraxofusp-erzs infusion for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and in pediatric patients, 2 years of age and older.

"Prior to [this] approval, there had been no FDA approved therapies for BPDCN. The standard of care has been intensive chemotherapy followed by bone marrow transplantation. Many patients with BPDCN are unable to tolerate this intensive therapy, so there is an urgent need for alternative treatment options," 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.

The efficacy of tagraxofusp-erzs was studied in two cohorts of patients in a single-arm clinical trial. The first trial cohort enrolled 13 patients with untreated BPDCN, and seven patients (54%) achieved complete remission (CR) or CR with a skin abnormality not indicative of active disease (CRc). The second cohort included 15 patients with relapsed or refractory BPDCN. One patient achieved CR and one patient achieved CRc.

Common side effects reported by patients in clinical trials were capillary leak syndrome, nausea, fatigue, peripheral edema, pyrexia, chills. and weight increase. Most common laboratory abnormalities were decreases in lymphocytes, albumin, platelets, hemoglobin and calcium, and increases in glucose and liver enzymes (ALT and AST). Health care providers are advised to monitor liver enzyme levels and for signs of intolerance to the infusion. Women who are pregnant or breastfeeding should not take tagraxofusp-erzs because it may cause harm to a developing fetus or newborn baby.

The labeling for tagraxofusp-erzs contains a Boxed Warning to alert health care professionals and patients about the increased risk of capillary leak syndrome which may be life-threatening or fatal to patients in treatment.

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

Thursday, December 6, 2018

​The FDA recently approved glasdegib tablets to be used in combination with low-dose cytarabine (LDAC) for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are 75 years of age or older or who have comorbidities that may preclude the use of intensive chemotherapy.

"Intensive chemotherapy is usually used to control AML, but many adults with AML are unable to have intensive chemotherapy because of its toxicities. [This] approval gives health care providers another tool to use in the treatment of AML patients with various, unique needs. Clinical trials showed that overall survival was improved using glasdegib in combination with LDAC compared to LDAC alone for patients who would not tolerate intensive chemotherapy," 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.

NCI estimates that in 2018, approximately 19,520 people will be diagnosed with AML and approximately 10,670 patients with AML will die of the disease. Almost half of the adults diagnosed with AML are not treated with intensive chemotherapy because of comorbidities and chemotherapy related toxicities.

The efficacy of glasdegib was studied in a randomized clinical trial in which 111 adult patients with newly diagnosed AML were treated with either glasdegib in combination with LDAC or LDAC alone. The trial measured overall survival (OS) from the date of randomization to death from any cause. Results demonstrated a significant improvement in OS in patients treated with glasdegib. The median OS was 8.3 months for patients treated with glasdegib plus LDAC compared with 4.3 months for patients treated with LDAC only.

Common side effects reported by patients receiving glasdegib in clinical trials include anemia, fatigue, hemorrhage, febrile neutropenia, muscle pain, nausea, edema, thrombocytopenia, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash.

The prescribing information for glasdegib includes a Boxed Warning to advise health care professionals and patients about the risk of embryo-fetal death or severe birth defects. It should not be used during pregnancy or while breastfeeding. Pregnancy testing should be conducted in females of reproductive age prior to initiation of glasdegib treatment and effective contraception should be used during treatment and for at least 30 days after the last dose.

Glasdegib must be dispensed with a patient Medication Guide that describes important information about the drug's uses and risks. Patients should also be advised not to donate blood or blood products during treatment. Health care providers should also monitor patients for changes in the electrical activity of the heart, called QT prolongation.

The FDA granted this application Priority Review designation. Glasdegib also received Orphan Drug designation.

Tuesday, November 27, 2018

The FDA granted accelerated approval to larotrectinib, a treatment for adult and pediatric patients whose cancers have a specific biomarker.

This is the second time the agency has approved a cancer treatment based on a common biomarker across different types of tumors rather than the location in the body where the tumor originated. The approval marks a new paradigm in the development of cancer drugs that are "tissue agnostic." It follows the policies that the FDA developed in a guidance document released earlier this year.

Larotrectinib is indicated for the treatment of adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity and have no satisfactory alternative treatments or that have progressed following treatment.

"[This] approval marks another step in an important shift toward treating cancers based on their tumor genetics rather than their site of origin in the body," said FDA Commissioner Scott Gottlieb, MD. "This new site-agnostic oncology therapy isn't specific to a cancer arising in a particular body organ, such as breast or colon cancer. Its approval reflects advances in the use of biomarkers to guide drug development and the more targeted delivery of medicine.

"We now have the ability to make sure that the right patients get the right treatment at the right time. This type of drug development program, which enrolled patients with different tumors but a common gene mutation, wouldn't have been possible a decade ago because we knew a lot less about such cancer mutations," he continued. "Using our breakthrough therapy designation and accelerated approval processes, we support innovation in precision oncology drug development and the evolution of more targeted and effective treatments for cancer patients. This is especially true when it comes to pediatric cancers.

"We're committed to continuing to advance a more modern framework of clinical trial designs that support more targeted innovations across disease types based on our growing understanding of the underlying biology of diseases like cancer."

Research has shown that the NTRK genes, which encode for TRK proteins, can become fused to other genes abnormally, resulting in growth signals that support the growth of tumors. NTRK fusions are rare but occur in cancers arising in many sites of the body. Prior to this approval, there had been no treatment for cancers that frequently express this mutation, like mammary analogue secretory carcinoma, cellular or mixed congenital mesoblastic nephroma and infantile fibrosarcoma.

The efficacy of larotrectinib was studied in three clinical trials that included 55 pediatric and adult patients with solid tumors that had an identified NTRK gene fusion without a resistance mutation and were metastatic or where surgical resection was likely to result in severe morbidity. These patients had no satisfactory alternative treatments or had cancer that progressed following treatment.

Larotrectinib demonstrated a 75 percent overall response rate across different types of solid tumors. These responses were durable, with 73 percent of responses lasting at least 6 months, and 39 percent lasting a year or more at the time results were analyzed. Examples of tumor types with an NTRK fusion that responded to larotrectinib include soft tissue sarcoma, salivary gland cancer, infantile fibrosarcoma, thyroid cancer, and lung cancer.

Larotrectinib received an accelerated approval, which enables the FDA to approve drugs for serious conditions to fill an unmet medical need using clinical trial data that is thought to predict a clinical benefit to patients. Further clinical trials are required to confirm larotrectinib's clinical benefit and the sponsor is conducting or plans to conduct these studies.

Common side effects reported by patients receiving larotrectinib in clinical trials include fatigue, nausea, cough, constipation, diarrhea, dizziness, vomiting, and increased AST and ALT enzyme blood levels in the liver. Health care providers are advised to monitor patient ALT and AST liver tests every 2 weeks during the first month of treatment, then monthly and as clinically indicated. Women who are pregnant or breastfeeding should not take larotrectinib because it may cause harm to a developing fetus or newborn baby. Patients should report signs of neurologic reactions such as dizziness.

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