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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.

Friday, May 6, 2016

The FDA has granted Priority Review for the biologics license application (BLA) for olaratumab, a PDGFRα antagonist, in combination with doxorubicin, for the potential treatment of people with advanced soft tissue sarcoma (STS) not amenable to curative treatment with radiotherapy or surgery.

Eli Lilly has received additional designations for olaratumab from the FDA, including Breakthrough Therapy, Fast Track and Orphan Drug, for this indication. According to the FDA, Breakthrough Therapy designation is a process designed to expedite the development of a potential medicine that is intended to treat a serious condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint.

Providing Priority Review status for olaratumab reinforces that olaratumab is a potential medicine that treats a serious condition and can provide significant improvement in the treatment of people with advanced STS. Submission was completed in the first quarter of 2016.

The BLA submission for olaratumab was based upon the results from a pivotal Phase II trial, JGDG, an open-label, randomized study that compared olaratumab in combination with doxorubicin chemotherapy to doxorubicin alone in patients with advanced STS not amenable to curative treatment with surgery or radiotherapy. Results from JGDG were presented at the 2015 American Society of Clinical Oncology annual meeting and the 2015 Connective Tissue Oncology Society annual meeting.

Eli Lilly also submitted olaratumab to the European Medicines Agency (EMA) in the first quarter of 2016, and the application is currently being reviewed under an accelerated assessment schedule.


Friday, May 6, 2016

On April 25, 2016, the FDA approved cabozantinib (Cabometyx) for the treatment of advanced renal cell carcinoma in patients who have received prior anti-angiogenic therapy. 

The approval was based on a randomized study in which patients with advanced renal cell carcinoma who had received prior anti-angiogenic therapy received either cabozantinib 60 mg orally once daily (N=330) or everolimus 10 mg orally once daily (N=328). 

The primary endpoint was progression-free survival among the first 375 randomized subjects. Median progression-free survival in this group was 7.4 and 3.8 months in the cabozantinib and everolimus arms, respectively [HR 0.58 (95% CI: 0.45, 0.74); p<0.0001]. Median overall survival in the intent-to-treat population was 21.4 and 16.5 months in the cabozantinib and everolimus arms, respectively [HR 0.66 (95% CI: 0.53, 0.83); p=0.0003]. Confirmed response rate was 17 percent (95% CI: 13, 22) in the cabozantinib arm and 3 percent (95% CI: 2, 6) in the everolimus arm.

Safety was evaluated in 331 patients treated with cabozantinib. The most common (greater than or equal to 25%) adverse reactions included diarrhea, fatigue, nausea, decreased appetite, palmar-plantar erythrodysesthesia syndrome, hypertension, vomiting, weight decreased, and constipation. Sixty percent of patients treated with cabozantinib had at least one dose reduction while on study. Serious adverse events were reported in 40 percent of patients. The most common serious adverse events (greater than or equal to 2%) were abdominal pain, pleural effusion, diarrhea, and nausea.

The recommended dose and schedule for cabozantinib is 60 mg orally daily. 

This application was granted Breakthrough Therapy Designation, Fast Track, and Priority Review. It was approved prior to the Priority Review deadline of June 22, 2016.


Wednesday, May 4, 2016

The FDA approved venetoclax (Venclexta tablets) for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy.

The approval was based on the results of a phase II, single-arm trial of venetoclax for the treatment of patients with CLL harboring the 17p deletion who had received at least one prior therapy. The major efficacy outcome measure was overall response rate (ORR) according to the 2008 Modified IWCLL NCI-WG Guidelines for Tumor Response as evaluated by an independent review committee (IRC). Duration of response (DOR) was an additional outcome measure.

The trial enrolled 106 patients who had received at least one prior therapy with 17p deletion, as detected by an FDA-approved CLL fluorescence in situ hybridization probe kit. Patients had a median of 2.5 prior treatments (range 1-10). The ORR by IRC was 80 percent (95% CI: 71%, 87%) with 8 percent complete remission (including 2 percent complete remission with incomplete marrow recovery). Minimal residual disease (MRD) was evaluated in peripheral blood and bone marrow for patients who achieved CR or CRi, following treatment with venetoclax. Three percent of the patients in the intent-to-treat population achieved a complete remission (CR or CRi) and were also negative for MRD in the bone marrow and peripheral blood. The median time to first response was 0.8 months (range: 0.1 to 8.1 months). Median DOR has not been reached with approximately 12 months median follow-up. The DOR ranged from 2.9 to more than 19.0 months.

 Safety data were evaluated in 240 patients with previously-treated CLL who were treated with single-agent venetoclax at a target dose of 400 mg orally daily. The most common (greater than or equal to 20%) adverse reactions of any grade were neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue. Serious adverse reactions were reported in 44 percent of patients, and the most common (greater than or equal to 2%) serious adverse reactions were pneumonia, febrile neutropenia, pyrexia, autoimmune hemolytic anemia, anemia, and tumor lysis syndrome (TLS). 

 Due to a rapid reduction in tumor volume, TLS is an important identified risk when initiating venetoclax. The risk of TLS is reduced with stratification by tumor burden, prophylaxis with hydration and anti-hyperuricemics, frequent blood chemistry monitoring, and correction of electrolyte abnormalities. In patients with higher risk features, hospitalization for IV hydration, electrolyte monitoring, and aggressive correction of electrolyte abnormalities may be required. In 66 patients with CLL starting with a daily dose of 20 mg and increasing over five weeks to a daily dose of 400 mg, the rate of TLS was 6 percent with no clinical events. All events were laboratory TLS and occurred in patients who had a lymph node(s) greater than or equal to 5 cm or ALC greater than or equal to 25 x 109/L.

 The recommended dose and schedule for venetoclax for the approved indication is a ramp-up schedule over five weeks. Dosing is initiated at 20 mg for 1 week, followed by 1 week at each dose level of 50 mg, 100 mg, and 200 mg, then the recommended daily dose of 400 mg until disease progression or unacceptable toxicity. 


Wednesday, May 4, 2016

The FDA approved Xalkori (crizotinib) to treat people with advanced (metastatic) non-small cell lung cancer (NSCLC) whose tumors have an ROS-1 gene alteration. Xalkori is the first and only FDA-approved treatment for patients with ROS-1 positive NSCLC.

Lung cancer is the leading cause of cancer-related deaths in the U.S., with an estimated 221,200 new diagnoses and 158,040 deaths in 2015, according to the National Cancer Institute. ROS-1 gene alterations, thought to lead to abnormal cells, have been identified in various cancers, including NSCLC. ROS-1 gene alterations are present in approximately 1 percent of patients with NSCLC. The overall patient and disease characteristics of NSCLC with ROS-1 gene alterations appear similar to NSCLC with anaplastic lymphoma kinase (ALK) gene alterations, for which crizotinib use was previously approved. Xalkori was approved to treat certain patients with late-stage NSCLC that expresses an abnormal ALK gene in 2011.

"Lung cancer is difficult to treat, in part, because patients have different mutations, some of which are rare," said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research. "The expanded use of Xalkori will provide a valuable treatment option for patients with the rare and difficult to treat ROS-1 gene mutation by giving health care practitioners a more personalized way of targeting ROS-1 positive NSCLC."

Xalkori is an oral medication that blocks the activity of the ROS-1 protein in tumors that have ROS-1 gene alterations. This effect on ROS-1 may prevent NSCLC from growing and spreading.

The safety and efficacy of Xalkori for the treatment of patients with ROS-1 positive tumors were evaluated in a multi-center, single-arm study of 50 patients with ROS-1 positive metastatic NSCLC. Patients received Xalkori twice daily to measure the drug's effect on their lung cancer tumors. The studies were designed to measure overall response rate, the percentage of patients who experienced complete or partial shrinkage of their tumors. Results showed 66 percent of participants experienced a complete or partial shrinkage of their NSCLC tumors, an effect that lasted a median of 18.3 months.

The safety results of this study were generally consistent with the safety profile of Xalkori evaluated in 1,669 patients with ALK-positive metastatic NSCLC. 

The most common side effects of Xalkori are vision disorders, nausea, diarrhea, vomiting, swelling (edema), constipation, liver problems (elevated transaminases), fatigue, decreased appetite, upper respiratory infection, and dizziness and numbness or tingling in the hands or feet (neuropathy). Xalkori may cause serious side effects, including liver problems, life-threatening or fatal inflammation of the lungs, abnormal heartbeats, and partial or complete loss of vision in one or both eyes.

The FDA granted the Xalkori expanded use application breakthrough therapy designation and priority review status. These are distinct programs intended to facilitate and expedite the development and review of certain new drugs in light of their potential to benefit patients with serious or life-threatening conditions. Xalkori also received orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for exclusivity to assist and encourage the development of drugs for rare diseases.

Xalkori is marketed by Pfizer, based in New York, N.Y.


Thursday, March 17, 2016

The U.S. Food and Drug Administration has granted priority review designation to artezolizumab (MPDL3280A) for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who had disease progression during or following platinum-based chemotherapy in the metastatic setting, or whose disease worsened within 12 months of receiving platinum-based chemotherapy before surgery or after surgery.

The FDA's priority review designation shortens the time to complete a drug's review and aims to deliver a decision on marketing approval designation for drugs that may offer major advances in treatment or provide a treatment where no adequate therapy exists within six months under the Prescription Drug User Fee Act (PDUFA). The FDA action date for artezolizumab for this indication is September 12.

Previous FDA Actions for Artezolizumab
Artezolizumab has previously received breakthrough therapy designation for the treatment of patients with metastatic bladder cancer that expresses the protein PD-L1 (OT 6/25/14 issue). The drug has also previously received breakthrough therapy designation for the treatment of patients with PD-L1 positive non-small cell lung cancer whose disease has progressed during or after platinum-based chemotherapy (OT 2/25/15 issue).

Phase II and III Trials
This designation for artezolizumab is based on data from the open-label, multicenter, single-arm Phase II IMvigor 210 study that evaluated the safety and efficacy of artezolizumab in patients with locally advanced or metastatic urothelial cancer, regardless of PD-L1 expression. In an updated analysis based on 11.7 months of median follow up, treatment with artezolizumab shrank tumors in 15 percent of the patients show disease progressed after platinum-based chemotherapy. Atezolizumab shrank tumors in 26 percent of patients whose disease had medium and high levels of PD-L1 expression. And median duration of response was not reached at the time of analysis.

The most common grade 3 to 4 treatment-related adverse events included: fatigue, decreased appetite, pyrexia, anemia, enzymes in the blood, arthralgia, dyspnea, pneumonitis, colitis, hypertension, and hypotension. There were no treatment-related grade 5 adverse events.

A confirmatory Phase III study (IMvigor 211) is also ongoing in patients with bladder cancer that has progressed on at least one prior platinum-containing regimen. The trial is comparing treatment with artezolizumab with treatment with chemotherapy.

The drug is being developed by Genentech.

About the Author

Sarah DiGiulio
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