Abstract
The targeted therapies dabrafenib and neratinib are being tested separately in subsets of patients with BRAF- and HER2-mutant non–small cell lung cancer. While dabrafenib shows some promise, the preliminary results for neratinib with or without temsirolimus are insufficient to determine whether patients may benefit.
Therapies targeting oncogenic gene alterations have proven effective in non–small cell lung cancer (NSCLC), particularly in adenocarcinomas, with drugs like erlotinib (Tarceva; Roche) and gefitinib (Iressa; AstraZeneca) for EGFR-mutant disease, and crizotinib (Xalkori; Pfizer) for ALK-rearranged NSCLC, altering patient care. Interest has now surged in pitting targeted therapies against other molecularly defined subsets of this disease.
Two such therapies were highlighted at the recent 2014 European Society for Medical Oncology Congress in Madrid, Spain. David Planchard, MD, PhD, a pulmonary oncologist at the Institut Gustave Roussy in Villejuif, France, reported data from ongoing phase II trials targeting BRAF-mutant NSCLC with dabrafenib (Tafinlar; GlaxoSmithKline). His colleague, Benjamin Besse, MD, PhD, presented results of a trial testing neratinib (Puma) alone or combined with temsirolimus (Torisel; Pfizer) in patients with HER2-mutant NSCLC, which occurs in 2% to 4% of cases.
Planchard's team reported on the efficacy of dabrafenib, a BRAF inhibitor, in 78 NSCLC patients with the BRAF V600E mutation, which occurs in 1.5% of cases. All had advanced disease and had received at least one line of prior therapy. The investigator-assessed overall response rate (ORR) was 32%, with a median duration of 11.8 months. Common side effects included fever and some skin toxicities—notably cutaneous squamous-cell carcinomas, thought to be a result of compensatory cell signaling through CRAF.
“It seems that nonsmoker patients and those who received only one previous line of treatment had better response rates,” Planchard says, “but we're still verifying this observation.”
Currently approved for V600E-mutant metastatic melanoma, dabrafenib has also received Breakthrough Therapy designation from the FDA for V600E-mutant advanced NSCLC.
“The results [of this study] are encouraging enough that we should consider BRAF testing for patients with advanced lung adenocarcinomas,” says Gregory Masters, MD, a lung cancer specialist at the Helen F. Graham Cancer Center in Newark, DE.
Besse reported an ORR of 21% for 14 NSCLC patients with somatic HER2 mutations who received neratinib, a pan HER inhibitor, plus temsirolimus, an mTOR inhibitor. Their median progression-free survival was 4 months. Thirteen other patients with HER2 mutations who received neratinib alone experienced some tumor regression, but the predefined threshold for “activity”—an ORR of at least 15%—was not achieved.
“It probably reflects a certain level of [neratinib] activity, just not as high as one might expect,” Besse says, adding that “this was also a very preliminary analysis.”
Neratinib has shown promise in clinical trials for HER2-positive breast cancer, but it is not yet approved.
“Right now, there is insufficient evidence to recommend routine HER2 testing in lung cancer, or treating patients with this drug,” Masters says. “The same gene mutation may not drive different cancers, so blocking its product is not necessarily effective.”
Despite the small size of these studies, Masters believes they can still yield valuable information. “To me,” he says, “it's about narrowing our focus so we're better able to match the appropriate patients with more accurate and less toxic treatments.”
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