Strides in personalized medicine


  • Carrie Printz

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Scientists continually report advances in personalized medicine for cancer. Among them are studies of several new treatments that were featured at the American Society of Clinical Oncology (ASCO) annual meeting, held earlier this year.

• The targeted drug afatinib delays the progression of advanced lung cancer. A multinational phase 3 trial found that initial single-agent oral therapy with afatinib prolongs progression-free survival in patients with lung adenocarcinoma with mutations in the epidermal growth factor receptor (EGFR) compared with standard chemotherapy. The drug was particularly effective (doubling progression-free survival) in the majority of patients with 1 of 2 EGFR mutations (deletion 19 or L858R) that comprise 90% of all EGFR mutations.

The trial, LUX-Lung 3, is of particular interest because researchers compared afatinib with a relatively new first-line therapy of combination chemotherapy with pemetrexed and cisplatin for the treatment of patients with advanced, previously untreated lung adenocarcinoma, which is a subtype of nonsmall cell lung cancer. EGFRmutated lung adenocarcinoma is often associated with never-smokers and patients of Asian descent.

Researchers randomized 345 patients to receive treatment with afatinib or standard combination chemotherapy. After a median follow-up of 8 months, they found that afatinib delayed disease progression by more than 4 months compared with standard chemotherapy (11.1 months vs 6.9 months). In the 308 patients with either the deletion 19 or L858R EGFR mutations, progression-free survival was found to be prolonged even further (13.6 months vs 6.9 months).

Principal investigator James Chih-Hsin Yang, MD, PhD, of National Taiwan University said that because the therapy is given orally, it may require fewer visits to the physician's office. It also slowed the development of common lung cancer-related symptoms such as cough and shortness of breath.

• A MEK inhibitor improves survival in patients with advanced melanoma. The oral investigational drug trametinib was found to delay tumor growth and extend survival in patients with advanced melanoma who have BRAF mutations. It demonstrated an advantage over chemotherapy in a phase 3 clinical trial, which to the authors' knowledge is the first to examine the effectiveness of a treatment that inhibits the MEK protein, part of the mitogen-activated protein (MAP) kinase signaling pathway. BRAF also is a component of that pathway. Trametinib is part of a new class of targeted drugs that may help patients diagnosed with melanoma with BRAF mutations. It may become another first-line treatment for patients with advanced melanoma, according to Caroline Robert, MD, PhD, head of dermatology at the Institut Gustave-Roussy in Paris, France.

The study, known as METRIC, randomly assigned patients who had received up to 1 chemotherapy regimen to treatment with trametinib or standard chemotherapy with either dacarbazine or paclitaxel. Findings demonstrated that approximately 22% of patients who received trametinib responded to treatment, compared with 8% of those who received chemotherapy.

Other results included a significantly greater median progression-free survival noted in the patients treated with trametinib (4.8 months) compared with those receiving chemotherapy (1.5 months), which was a 55% reduction in the risk of disease progression. In addition, approximately 81% of patients in the trametinib group were alive after 6 months of follow-up versus 67% in the standard chemotherapy group, and 47% of patients whose disease progressed while receiving chemotherapy were permitted to take trametinib. As a result, the overall survival advantage may prove to be greater if this “crossover effect” is considered, the researchers said.

• A new BRAF inhibitor delays disease progression in patients with advanced melanoma. The BRAF-targeted drug dabrafenib was found to reduce the risk of disease progression by 70% in patients with previously untreated advanced melanoma with mutations in the BRAF gene, according to results from a phase 3 multicenter trial. The drug was compared with standard dacarbazine chemotherapy. Researchers also found that there appeared to be fewer cases of serious skin toxicities associated with the drug (including squamous cell carcinoma) when compared with the current standard targeted drug, vemurafenib.

Lead author Alex Hauschild, MD, of the University Hospital in Kiel, Germany, said that no new therapies for metastatic melanoma had been available for the past 3 decades, but the scenario is changing with the approval of ipilimumab and vemurafenib and now possibly dabrafenib in the future. He said the drug next needs to be evaluated in combination with other drugs.

The study, BREAK-3, included patients with previously untreated, inoperable stage III or IV melanoma who were randomly assigned to receive dabrafenib (187 patients) or standard chemotherapy with dacarbazine (63 patients). Of those in the former group, 50% responded to therapy compared with 6% percent of the patients treated with dacarbazine. The estimated median progression-free survival was significantly longer in the group receiving dabrafenib (5.1 months vs 2.7 months). Overall survival data were not yet mature at the time the study results were reported, and patients whose disease progressed while receiving dacarbazine were allowed to cross over to the dabrafenib arm.

• Regorafenib can improve outcomes for gastrointestinal stromal tumors that resist targeted therapies. Patients with gastrointestinal stromal tumors who have exhausted other treatment options have a new possibility with the targeted oral drug regorafenib, said researchers who led an international phase 3 trial of the drug. They found that progression-free survival was 4 times longer among patients treated with regorafenib than those receiving a placebo. These patients' tumors had continued to progress after developing resistance to other treatment options, including imatinib and sunitinib (85% of patients eventually develop a resistance to these therapies).

Similar to these other approved targeted therapies, regorafenib targets abnormalities in cancer cell signaling pathways driven by an enzyme called KIT; however, it appears to inhibit the cancer-promoting signals in a unique way. The study randomized 199 patients with metastatic and/or inoperable gastrointestinal stromal tumors to treatment with either regorafenib or placebo. Progression-free survival was found to be significantly longer with the former (4.8 months vs 0.9 months.) There was no statistical difference noted with regard to overall survival between the 2 treatment arms due to the trial design.