New Drug Update

October 2013, Vol 3, No 6 - FDA News


As oncology practice managers assume higher levels of assistance to the medical oncology staff, it becomes critically important to stay abreast of the latest news and updates concerning the drug agents used in cancer treatment. The following drugs have been approved by the US Food and Drug Administration (FDA) since January 1, 2013, for the treatment of various cancers. For more information on any of these agents visit the FDA’s website at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm.


New Drug for Advanced Prostate Cancer
Xofigo approved 3 months ahead of schedule under priority review program.

The US Food and Drug Administration (FDA) has approved Xofigo (radium Ra 223 dichloride) to treat men with symptomatic late-stage (metastatic) castration-resistant prostate cancer that has spread to bones but not to other organs. It is intended for men whose cancer has spread after receiving medical or surgical therapy to lower testosterone.

According to the National Cancer Institute, an estimated 238,590 men will be diagnosed with prostate cancer and 29,720 will die from the disease in 2013.
Xofigo was approved more than 3 months ahead of the product’s prescription drug user fee goal date of August 14, 2013, the date the agency was scheduled to complete review of the drug application. The FDA reviewed Xofigo under the agency’s priority review program, which provides for an expedited review of drugs that appear to provide safe and effective therapy when no satisfactory alternative therapy exists, or offer significant improvement compared with marketed products.

In August 2012, the FDA approved Xtandi to treat men with metastatic castration-resistant prostate cancer that has spread or recurred, even with medical or surgical therapy to minimize testosterone. Xtandi is approved for patients who have previously been treated with the chemotherapy drug docetaxel.
Xofigo’s safety and effectiveness were evaluated in a single clinical trial of 809 men with symptomatic castration-resistant prostate cancer that spread to bones but not to other organs. Patients were randomly assigned to receive Xofigo or a placebo plus best standard of care.

The study was designed to measure overall survival. Results from a preplanned interim analysis showed that men who received Xofigo lived a median of 14 months compared with a median of 11.2 months for men who received placebo. An exploratory updated analysis conducted later in the trial confirmed Xofigo’s ability to extend overall survival.

The most common side effects reported during the clinical trials in men receiving Xofigo were nausea, diarrhea, vomiting, and swelling of the leg, ankle, or foot. The most common abnormalities detected during blood testing included low levels of red blood cells (anemia), lymphocytes (lymphocytopenia), white blood cells (leukopenia), platelets (thrombocytopenia), and infection-fighting white blood cells (neutropenia).

Source: US Food and Drug Administration


First Companion Diagnostic to Detect Gene Mutation Associated with a Type of Lung Cancer
New indication for Tarceva also approved.

The US Food and Drug Ad­­ministration (FDA) approved the cobas EGFR Mutation Test, a companion diagnostic for the cancer drug erlotinib (Tarceva). This is the first FDA-approved companion diagnostic that detects epidermal growth factor receptor (EGFR) gene mutations, which are present in approximately 10% of non–small-cell lung cancers (NSCLCs).

The test was approved with an expanded use for Tarceva as a first-line treatment for patients with NSCLC that has spread to other parts of the body (metastasized) and who have certain mutations in the EGFR gene.

Lung cancer is the leading cause of cancer-related death among both men and women. According to the National Cancer Institute, there will be an estimated 228,190 new cases of lung cancer this year, and 159,480 deaths. About 85% of lung cancers are NSCLC, making it the most common type of lung cancer.

The safety and effectiveness of the cobas EGFR Mutation Test was established with clinical data showing that, on average, patients with NSCLC with specific types of EGFR mutations (exon 19 deletions or exon 21 L858R substitution mutations) lived without their disease progressing for 10.4 months when they received Tarceva treatment, compared with 5.4 months for those who received a standard 2-drug chemotherapy regimen. Investigators used tumor samples from the clinical trial to validate the test’s use in this patient population.

The approval is Tarceva’s fourth indication and the third use for lung cancer. The FDA approved Tarceva in April 2010 for maintenance treatment of patients with locally advanced or metastatic NSCLC whose disease had not progressed after 4 cycles of platinum-based first-line chemotherapy. Tarceva was originally approved in November 2004 for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least 1 prior chemotherapy regimen.

Source: US Food and Drug Administration


Single-Agent Injection for HER2-Positive Metastatic Breast Cancer
Ado-trastuzumab emtansine showed longer progression-free survival and overall survival in clinical trials.

In February, the US Food and Drug Administration approved ado-trastuzumab emtansine (Kadcyla for injection), for use as a single agent for the treatment of patients with HER2-positive metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either received prior therapy for metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy.

The approval is based on a randomized, multicenter, open-label trial enrolling 991 patients with HER2-positive metastatic breast cancer. Patients must have received prior taxane and trastuzumab-based therapy before enrollment. Patients who received these therapies only in the adjuvant setting were required to have disease recurrence during or within 6 months of completing this therapy. Breast tumor specimens were required to show HER2 overexpression defined as 3+ immunohistochemistry or fluorscence in situ hybridization amplification ratio ?2 determined at a central laboratory.

Patients were randomly allocated (1:1) to receive ado-trastuzumab emtansine 3.6 mg/kg by intravenous infusion on day 1 every 21 days or lapatinib 1250 mg/day orally once daily for 21 days plus capecitabine 1000 mg/m2 orally twice daily for 14 days. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal.

The coprimary efficacy endpoints were progression-free survival (PFS), based on tumor response assessments by an independent review committee, and overall survival (OS).

The median PFS was 9.6 and 6.4 months for patients in the ado-trastuzumab emtansine and lapatinib plus capecitabine arms, respectively. The median OS was 30.9 and 25.1 months in the ado-trastuzumab emtansine and the lapatinib plus capecitabine arms, respectively.

The most common (>25%) ad­­verse reactions observed in patients receiving ado-trastuzumab emtansine were fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, increased transaminases, and constipation. The most common adverse events leading to ado-trastuzumab emtansine withdrawal were thrombocytopenia and increased transaminases. The most common (>2%) grade 3 or 4 adverse reactions were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy, and fatigue. Serious hepatobiliary disorders, including at least 2 fatal cases of severe drug-induced liver injury and associated hepatic encephalopathy, have been reported in clinical trials with ado-trastuzumab emtansine. Other significant adverse reactions include left ventricular dysfunction, interstitial lung disease, and infusion-associated reactions.

A Boxed Warning in product labeling describes the risk of hepatotoxicity, reduction in left ventricular ejection fraction, embryo-fetal toxicity and birth defects, and the need for effective contraception prior to starting ado-trastuzumab emtansine.

The recommended dose and schedule for ado-trastuzumab emtansine is 3.6 mg/kg administered as an intravenous infusion every 3 weeks (a 21-day cycle) until disease progression or unacceptable toxicity. Ado-trastuzumab emtansine should not be administered at doses greater than 3.6 mg/kg and should not be substituted for or with trastuzumab.

Source: US Food and Drug Administration


Pomalidomide Capules Approved for Multiple Myeloma
FDA granted accelerated approval for treatment of patients who have received at least 2 prior therapies.

In February, the US Food and Drug Administration (FDA) granted accelerated approval to pomalidomide (Pomalyst capsules) for the treatment of patients with multiple myeloma (MM) who have received at least 2 prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on or within 60 days of completion of the last therapy.

The approval was based on the results of clinical trial CC-4047-MM-002; a multicenter, randomized, open-label study in 221 pa­tients with relapsed and refractory MM who had previously received lenalidomide and bortezomib and were refractory to the last myeloma therapy. The treatment arms were pomalidomide alone or pomalidomide plus low-dose dexamethasone.

The efficacy results demonstrated an overall response rate of 7% in patients treated with pomalidomide alone, and 29% in those treated with pomalidomide plus low-dose dexamethasone. The median response duration was not evaluable in the pomalidomide alone arm and was 7.4 months in the pomalidomide plus low-dose dexamethasone arm.

The most common side effects reported in the clinical trial included fatigue and asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper respiratory tract infections, back pain, and pyrexia. Pomalidomide carries a Boxed Warning alerting patients and healthcare professionals that the drug can cause embryo-fetal toxicity and venous thromboembolism.

Because of this embryo-fetal risk, pomalidomide is available only through a restricted distribution program called the Pomalyst Risk Evaluation and Mitigation Strategy (REMS) Program. Pres­cribers must be certified with the Pomalyst REMS program by enrolling and complying with the REMS requirements. Patients must sign a Patient–Physician Agreement Form and comply with the REMS requirements. Female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements. Males must comply with contraception requirements.

Pharmacies must be certified with the Pomalyst REMS program, must only dispense to patients who are authorized to receive pomalidomide, and comply with REMS requirements.

As a condition of this accelerated approval, the FDA will require submission of the results of clinical trial CC-4047-MM-007, a randomized clinical trial of pomalidomide added to bortezomib and low-dose dexamethasone compared with bortezomib plus low-dose dexamethasone in patients with previously treated MM.

The recommended dose and schedule for pomalidomide is 4 mg taken orally on days 1 to 21 of repeated 28-day cycles. Cycles are repeated until disease progression.

Source: US Food and Drug Administration


Doxorubicin Hydrochloride Liposome Injection
FDA expedited review of generic application due to drug shortage.

In February 2013, the US Food and Drug Administration (FDA) approved doxorubicin hydrochloride liposome injection, a generic version of Doxil Injection (doxorubicin hydrochloride liposome) for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy and for AIDS-related Kaposi’s sarcoma after the failure of prior systemic chemotherapy or intolerance to such therapy.
The FDA’s Office of Generic Drugs expedited the review of this generic application because of the drug shortage for Doxil. As of April, Doxil was still under drug shortage because of manufacturing issues.

The FDA has been exercising regulatory discretion for alternative doxorubicin hydrochloride injection products to meet patient needs. Upon approval of the generic product, the FDA will stop enforcement discretion once approved product supply is sufficient to meet patient demand. The FDA will closely monitor the drug supply situation and continue to use enforcement discretion to allow importation of additional Lipodox or the release of additional lots of unapproved Doxil until supplies of commercially marketed lots of doxorubicin hydrochloride liposome injection in the United States are sufficient to meet patient demand.

Source: US Food and Drug Administration


Bevacizumab for Use in Combination with Fluoropyrimidine-Based Chemotherapy for Metastatic Colorectal Cancer
Drug will be used to treat patients whose disease progresses on a first-line bevacizumab-containing regimen.

In January 2013, the US Food and Drug Administration (FDA) approved bevacizumab (Avastin) for use in combination with fluor­opyrimidine-irinotecan or fluoro­pyrimidine-oxaliplatin– based chemo­therapy for the treatment of patients with metastatic colorectal cancer (mCRC) whose disease has progressed on a first-line bevacizumab-containing regimen. Bevacizumab is a recombinant humanized monoclonal immunoglobulin G1 antibody that binds to human vascular endothelial growth factor (VEGF), preventing the interaction of VEGF to its receptors on the surface of endothelial cells.

This approval is based on the results of a randomized, open-label, multinational trial enrolling patients with mCRC that progressed during or within 3 months of discontinuation of bevacizumab- based combination chemotherapy with fluoropyrimidine-oxaliplatin or fluoropyrimidine-irinotecan in the first line.
The primary efficacy end point was overall survival (OS). Treatment assignment was stratified by first-line treatment (irinotecan-based vs oxaliplatin-based), first-line progression-free survival (PFS) (>9 months vs ?9 months), time from last bevacizumab dose (>42 days vs ?42 days), and Eastern Cooperative Oncology Group (ECOG) performance status (0-1 vs 2).

The median age of the study population was 63 years, 64% were men, and 96% had an ECOG performance status of 0 or 1. A statistically significant OS improvement was observed in patients receiving crossover chemotherapy plus bevacizumab compared with those receiving crossover chemotherapy alone. Median OS was 11.2 and 9.8 months for patients on the crossover chemotherapy plus bevacizumab and crossover chemotherapy arms, respectively. PFS was also significantly improved in patients receiving crossover chemotherapy plus bevacizumab compared with those receiving chemotherapy alone. The median PFS times were 5.7 and 4 months, respectively.

No new safety signals were ob­served in this trial. The safety data were consistent with the known safety profile established in previously approved indications. The recommended dose and schedule in patients receiving bevacizumab in combination with fluoropyrimidine-irinotecan– or fluoropyrimidine-oxaliplatin–based chemotherapy after progression on a first-line bevacizumab-containing regimen is 5 mg/kg administered every 2 weeks or 7.5 mg/kg administered every 3 weeks as a 60-minute intravenous infusion.

Source: US Food and Drug Administration