On July 13, 2015 The U.S. Food and Drug Administration reported it approved Iressa (gefitinib) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors harbor specific types of epidermal growth factor receptor (EGFR) gene mutations, as detected by an FDA-approved test (FDA.gov, Press release, JUL 13, 2015, View Source [SID:1234506325]).

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Lung cancer is the leading cause of cancer-related death among men and women in the U.S. and, though more common in men, the number of deaths from lung cancer in women is increasing. According to the National Cancer Institute, an estimated 221,200 Americans will be diagnosed with lung cancer, and 158,040 will die from the disease this year. NSCLC is the most common type of lung cancer. Mutations in the EGFR gene are present in about 10 percent of NSCLC tumors.

Iressa is a kinase inhibitor that blocks proteins that promote the development of cancerous cells with certain EGFR mutations. It is intended for the treatment of patients whose tumors express the most common types of EGFR mutations in NSCLC (exon 19 deletions or exon 21 L858R substitution gene mutations). The therascreen EGFR RGQ PCR Kit was approved as a companion diagnostic test to identify patients with tumors having the EGFR gene mutations in order to determine which patients would be appropriate for treatment with Iressa.

"Iressa offers another effective first-line therapy option for selected lung cancer patients. This approval provides further support for a highly targeted approach to treating cancer," said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

The FDA granted Iressa orphan product designation for the treatment of EGFR mutation-positive metastatic NSCLC. Orphan product designation is given to drugs intended to treat rare diseases, which provides financial incentives – like tax credits, user fee waivers, and eligibility for market exclusivity – to promote their development.

"The approval of the therascreen EGFR RGQ PCR Kit will allow physicians to identify non-small cell lung cancer patients who are candidates for receiving Iressa as first-line therapy," said Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health. "Companion diagnostics provide information that is essential for the safe and effective use of important medications."

The efficacy and safety of Iressa for this use was demonstrated in a multi-center, single-arm clinical trial of 106 patients with previously untreated, EGFR mutation-positive metastatic NSCLC. The study’s primary endpoint was objective response rate, or the percentage of patients who experienced complete and partial shrinkage or disappearance of the tumors after treatment. Participants received Iressa 250 mg once daily. Results showed that tumors shrank in about 50 percent of patients after treatment and this effect lasted an average of six months. The response rates were similar in patients whether their tumors had EGFR exon 19 deletions or exon 21 L858R substitution mutations.

These results were supported by a retrospective analysis of another clinical trial, which identified a subgroup of 186 patients with EGFR mutation-positive metastatic NSCLC receiving first-line treatment. Patients were randomized to receive Iressa or up to six cycles of carboplatin/paclitaxel. The results from this subgroup suggested an improvement in progression-free survival with Iressa compared to carboplatin/paclitaxel.

Iressa may cause serious side effects including interstitial lung disease, liver damage, gastrointestinal perforation, severe diarrhea and ocular disorders. The most common side effects of Iressa are diarrhea and skin reactions (including rash, acne, dry skin and pruritus, or itching).

Iressa originally received accelerated approval in 2003 for the treatment of patients with advanced NSCLC after progression on platinum doublet chemotherapy and docetaxel. Iressa was voluntarily withdrawn from the market after subsequent confirmatory trials failed to verify clinical benefit. This current approval is for a different patient population (EGFR mutation-positive, previously untreated) than the 2003 approval.

Iressa is marketed by Wilmington, Delaware-based AstraZeneca Pharmaceuticals. The therascreen EGR RGQ PCR Kit is manufactured by QIAGEN Manchester Ltd., based in the United Kingdom.

The FDA, an agency within the U.S. Department of Health and Human Services, promotes and protects the public health by, among other things, assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

On July 13, 2015 Exelixis reported the initiation of a phase 1 trial of cabozantinib in combination with nivolumab alone or in combination with nivolumab plus ipilimumab in patients with advanced/metastatic urothelial (bladder) and other genitourinary tumors (Press release, Exelixis, JUL 13, 2015, View Source [SID:1234506322]).

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The primary endpoint of the trial is the determination of dose-limiting toxicities (DLT) and a recommended phase 2 dose (RP2D) for the combination of cabozantinib and nivolumab, and separately, for the combination of cabozantinib, nivolumab and ipilimumab, in patients with genitourinary solid tumors. Secondary endpoints include evaluating the activity of the two combinations by objective response rate, as well as progression-free survival (PFS) and overall survival (OS), in cohorts of patients with urothelial carcinoma of the bladder, urethra, ureter or renal pelvis.

The trial is sponsored by the U.S. National Cancer Institute (NCI) through Cooperative Research and Development Agreements between the NCI’s Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment and Diagnosis, and both Bristol-Myers Squibb and Exelixis. Andrea Apolo, M.D., of the NCI’s Genitourinary Malignancies Branch, is the principal investigator. The trial will be conducted by the NCI and includes centers from its Experimental Therapeutics Clinical Trials Network.

"In the United States, bladder cancer is one of the ten most common malignancies for men and women alike, and there are no drugs approved for use in the second-line setting," said Dr. Apolo. "In a previous study, single-agent cabozantinib demonstrated intriguing clinical activity in bladder cancer. Now, with this trial, we’ll explore the safety and tolerability, and the antitumor activity of the combination of cabozantinib with the immune checkpoint inhibitor nivolumab, alone or together with ipilimumab, in this and other important genitourinary cancer settings."

This open label, non-randomized phase 1 trial will enroll a maximum of 66 patients. The trial is divided into two parts: a dose-escalation phase and an expansion cohort phase. The dose-escalation phase will enroll patients with metastatic genitourinary solid tumors including renal cell carcinoma, urothelial cancer and castration-resistant prostate cancer who have progressed following treatment with at least one standard therapy. Up to 24 patients will be treated with the combination of cabozantinib plus nivolumab (CaboNivo), and up to 18 patients will receive the combination of cabozantinib, nivolumab, and ipilimumab (CaboNivoIpi). The starting dose of cabozantinib will be 40 mg daily for each combination and can increase up to 60 mg daily. Depending upon the cohort, dose levels for nivolumab will range from 1 to 3 mg/kg administered on an every two or every three week schedule, and ipilimumab will be administered at a dose level of 1 mg/kg every three weeks for a maximum of 4 doses.

Once the RP2Ds are determined for the combinations of CaboNivo and CaboNivoIpi, the trial will enroll expansion cohorts of up to 12 eligible patients for each combination, for up to 24 patients total in the expansion cohort. To be eligible for the expansion cohort, patients must have histologically confirmed metastatic, progressive urothelial cancer of the bladder, urethra, ureter, or renal pelvis. Patients in the expansion cohort will be evaluated for objective response rate, PFS and OS: all secondary endpoints of the trial.

"There is a strong rationale for combining cabozantinib with immunoncology agents, including clinical evidence of the compound’s ability to create a more immune-permissive environment, as well as preclinical data that suggest cabozantinib increases T-cell infiltration into tumors," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "In addition to bladder cancer, we believe that data on the tolerability and activity of the therapy combinations studied in this trial could have relevance in other disease settings, including non-small cell lung cancer and kidney cancer."

Dr. Morrissey continued: "Our collaboration with NCI-CTEP allows researchers to evaluate cabozantinib’s potential in diverse cancers while Exelixis focuses its internal resources on late-stage development, including the METEOR phase 3 pivotal trial in metastatic renal cell cancer expected to read out early this quarter. We look forward to following the progress of Dr. Apolo’s trial, which is one of more than 45 studies of cabozantinib either planned or ongoing under the CTEP collaboration and our investigator-sponsored trial program."

More information about this trial will be available at ClinicalTrials.gov shortly.

About Cabozantinib

Cabozantinib inhibits the activity of tyrosine kinases including MET, VEGFRs and RET. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.

COMETRIQ (cabozantinib) is currently approved by the U.S. Food and Drug Administration for the treatment of progressive, metastatic medullary thyroid cancer (MTC).

The European Commission granted COMETRIQ conditional approval for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. Similar to another drug approved in this setting, the approved indication states that for patients in whom Rearranged during Transfection (RET) mutation status is not known or is negative, a possible lower benefit should be taken into account before individual treatment decisions.

Important Safety Information, including Boxed WARNINGS

WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE

Serious and sometimes fatal gastrointestinal perforations and fistulas occur in COMETRIQ-treated patients.
Severe and sometimes fatal hemorrhage occurs in COMETRIQ-treated patients.
COMETRIQ treatment results in an increase in thrombotic events, such as heart attacks.
Wound complications have been reported with COMETRIQ.
COMETRIQ treatment results in an increase in hypertension.
Osteonecrosis of the jaw has been observed in COMETRIQ-treated patients.
Palmar-Plantar Erythrodysesthesia Syndrome (PPES) occurs in patients treated with COMETRIQ.
The kidneys can be adversely affected by COMETRIQ. Proteinuria and nephrotic syndrome have been reported in patients receiving COMETRIQ.
Reversible Posterior Leukoencephalopathy Syndrome has been observed with COMETRIQ.
Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.
COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.
COMETRIQ can cause fetal harm when administered to a pregnant woman.
Adverse Reactions – The most commonly reported adverse drug reactions (≥25%) are diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (≥25%) are increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.

Please see full U.S. prescribing information, including Boxed WARNINGS, at www.COMETRIQ.com/downloads/Cometriq_Full_Prescribing_Information.pdf. Please refer to the full European Summary of Product Characteristics for full European Union prescribing information, including contraindication, special warnings and precautions for use at www.sobi.com once posted.