FDA Approves Afatinib Plus Companion Diagnostic for Late Stage Non-Small Cell Lung Cancer

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The FDA has approved the pan-HER inhibitor afatinib (Gilotrif), along with a companion diagnostic, to treat patients with metastatic non-small cell lung cancer who express specific types of EGFR mutations.

Approximately 10% of all cases of NSCLC have mutations of EGFR, and about 90% of these mutations are either an exon 19 deletion or an exon 21 L858R substitution. These specific mutations are targeted by afatinib and can be detected by the therascreen EGFR RGQ PCR Kit that was approved as a companion diagnostic. Similarly, earlier this year, the FDA expanded the approval of erlotinib (Tarceva) to include this same group of patients, along with a companion diagnostic, the cobas EGFR Mutation Test.

“The approval of companion diagnostic tests and drugs are important developments in oncology, as they help us bring safe and effective treatments to patients who need them,” said Alberto Gutierrez, PhD, director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health, in a statement.

Afatinib targets the entire ErbB/HER family of receptors, which includes EGFR (ErbB1) and HER2 (ErbB2). Each of these tyrosine kinases is implicated in varying ways among different cancers, so the drug is being investigated in numerous tumor types in addition to lung cancer.

The agency based its afatinib approval on the results of the phase III LUX-Lung 3 trial, the results of which were first presented at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO) and recently published in theJournal of Clinical Oncology. In that trial, 345 patients with stage IIIB/IV lung adenocarcinoma were randomly assigned to treatment with either afatinib or a combination of cisplatin and pemetrexed. The primary endpoint was progression-free survival (PFS).

In that trial, 345 patients with stage IIIB/IV lung adenocarcinoma were randomly assigned to treatment with either afatinib or a combination of cisplatin and pemetrexed. The primary endpoint was progression-free survival (PFS). The study found that patients in the afatinib arm of the study experienced a median PFS of 11.1 months compared with 6.9 months in the cisplatin and pemetrexed arm (hazard ratio [HR] = 0.58; 95% CI, 0.43-0.78;P= .001). Patients with either an exon 19 deletion or an exon 21 L858R substitution who received afatinib experienced a median PFS of 13.6 months compared with 6.9 months in the cisplatin and pemetrexed arm (HR = 0.47; 95% CI, 0.34-0.65;P= .001).

The most common treatment-related adverse events experienced by patients in the study who received afatinib were diarrhea, rash or acne, and stomatitis. Overall, many of the adverse events experienced with afatinib were consistent with those seen in other EGFR inhibitors. Of note, the occurrence of these side effects was higher than with pemetrexed/cisplatin but was manageable. The most common side effect with the chemotherapy regimen was nausea.

“Today’s approvals further illustrate how a greater understanding of the underlying molecular pathways of a disease can lead to the development of targeted treatments,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, in a statement. “Gilotrif is the second drug approved this year for patients with untreated metastatic NSCLC whose tumors have the EGFR exon 19 deletions or exon 21 L858R substitution mutations.”

Afatinib is marketed by Boehringer Ingelheim Pharmaceuticals, Inc., based on Ridgefield, Connecticut, and the therascreen EGFR RGQ PCR Kit is manufactured by QIAGEN Manchester Ltd. in the United Kingdom.

Sequist LV, Yang J C-H, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma withEGFRmutations [published online ahead of print July 1, 2013].J Clin Oncol