Authors: Wing Han Wu, Future Science Group
Data presented at the 2014 European Society for Medical Oncology Congress (26–30 September, Madrid, Spain) has demonstrated the antitumor potential of the BRAF inhibitor dabrafenib in the treatment of advanced BRAF V600E mutant non-small-cell lung cancer (NSCLC) that has progressed after chemotherapy.
“Reports of lung cancers bearing mutations in BRAF have generated considerable interest because these mutations may be associated with increased sensitivity to BRAF tyrosine-kinase inhibiting agents,” explained David Planchard of the Gustav-Roussy Cancer Campus (Paris, France).
The study was an open-label Phase II study that investigated the use of dabrafenib alone (150 mg twice daily) in patients with BRAF V600E mutant NSCLC. The primary end point was response rate as assessed by the investigators, while the secondary end points included progression-free survival, duration of response, overall survival, safety and tolerability, and population pharmacokinetics.
Data collected from the 78 patients enrolled after 12 weeks of treatment demonstrated an overall response rate of 32% in patients who had already received one or more prior treatments. In addition to this, the researchers were able to demonstrate a disease control rate of 56% after the same period of therapy. It was determined that the median duration of response was 11.8 months and three of the six first-line patients were described as having a partial response to the treatment.
Safety data for dabrafenib were observed to be similar to that of previous studies investigating its use in melanoma. The most common side effect was fever, which 36% of the enrolled patients suffered from. Other adverse effects included asthenia (30%), hyperkeratosis (30%), loss of appetite (29%), nausea (27%), cough (26%), fatigue (26%), and skin papilloma (26%). Cutaneous squamous-cell carcinomas, including keratoacanthoma, were also reported in 18% of patients.
Planchard explained: “These findings establish dabrafenib as an effective treatment option for patients with previously treated advanced BRAF V600E NSCLC.”
An additional group of researchers from Gustav-Roussy presented data highlighting their work in HER2 inhibition in NSCLC at the conference. They demonstrated that HER2 inhibition in the HER2-positive subset of NSCLC patients could represent a potential treatment strategy.
“HER2-mutated NSCLC patients are a small subset of NSCLC patients – around 1–2% – but it seems important to inhibit HER2 for these patients,” explained lead author Benjamin Besse (Gustave Roussy).
In this randomized two-stage study involving 27 patients with HER2-positive advanced metastatic NSCLC, the researchers investigated use of both neratinib, which inhibits the HER2 receptor, and temsirolimus, which inhibits mTOR. Patients were randomized to one of two groups either to treatment with oral neratinib (240 mg od continuously) alone, or in combination with intravenous temsirolimus (8 mg / week, dose escalation to 15 mg / week after one 3-week cycle if tolerated, at the discretion of the researcher).
The preliminary data generated from the ongoing study demonstrate that the combination of both neratinib and temsirolimus has a 21% overall response rate in 14 patients, and a median progression-free survival of 4 months. In addition, the researchers have observed that more side effects were associated with the combination therapy. Patients in the combination study group were more likely to report gastrointestinal effects such as diarrhea, which were managed with prophylactic loperamide and not defined as limiting toxicities.
Besse explained: “HER2-mutated NSCLC represents a very small number of patients, but it reflects the new face of NSCLC it is not a single homogeneous disease, but a lot of different molecularly defined subsets of patients with potential ‘druggable targets’, for which specific strategies should be addressed.”
Fiona Blackhall of The University of Manchester (Manchester, UK) explained that the results of the studies reinforce that diagnosis of the molecular subtype of lung cancer is central to identification of more effective treatments.
“Studies of targeted approaches in molecularly defined subsets of non-small-cell lung cancer are consistently yielding better response rates and survivals than historical studies conducted in non- molecularly selected populations,” Blackhall explained. “The principles of precision medicine are proven for non-small-cell lung cancer, and now efforts must intensify to ensure equitable access to molecular diagnostics for patients with this disease.”