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CHICAGO -- A drug developed for melanoma has demonstrated activity in a subgroup of patients with non-small cell lung cancer (NSCLC), a preliminary clinical study showed.
Eight of 20 patients had objective responses to treatment with dabrafenib (Tafinlar), an inhibitor of the BRAF V600E mutation. The study provided the first evidence that BRAF V600E is a viable therapeutic target in NSCLC, as it is in melanoma.
The drug's safety profile was consistent with expectations based on clinical experience in melanoma, David Planchard, MD, PhD, of Gustave Roussy Institute in Villejuif, France, reported here at the American Society of Clinical Oncology meeting.
"The preliminary efficacy data from the first 20 patients is the first demonstration of clinical activity of a BRAF inhibitor in BRAF V600E non-small cell lung cancer," said Planchard. "The study has expanded the sample size and now allows enrollment of first-line patients."
The discovery that the BRAF V600E mutation occurs in at least half of all melanomas spurred development of several agents that inhibit the gene protein. BRAF V600E also occurs in NSCLC, but with an estimated frequency of 2% or fewer tumors.
In a phase III study of patients with BRAF V600E-mutant metastatic melanoma, treatment with dabrafenib induced tumor regression in almost all of the 187 patients who received the drug. Half of the patients had confirmed objective responses, and the dabrafenib-treated group had a median progression-free survival almost double that of the control group (Lancet. 2012; 380: 358-365).
To evaluate dabrafenib activity in BRAF V600E NSCLC, investigators in 12 countries enrolled patients with stage IV BRAF-mutant tumors treated with one or more prior systemic regimens.
The ongoing trial comprised two stages of investigation: If as many as three of the first 20 patients achieved investigator-assessed responses, the trial would continue to stage 2, which would expand by an additional 20 patients, including patients with previously untreated melanoma.
Planchard presented results for 25 enrolled patients, including 20 evaluable for efficacy. He said 13 of the 25 patients had discontinued, primarily because of disease progression (10 of 13). Two patients stopped treatment because of adverse events.
Review of baseline characteristics showed that eight patients were nonsmokers, 12 a smoking history ≤40 pack years, and five had a history exceeding 40 pack years. All 25 patients had adenocarcinoma, and treatment history consisted of one prior therapy in 17 patients, four patients each who had received two prior regimens or three or more.
The median time from initial diagnosis was 12 months, and the median time since first-line treatment for metastatic disease was 8.9 months.
Planchard reported that all but three of the first 20 patients had some degree of tumor regression, including eight who had at least 50% tumor shrinkage (partial response). All of the responses occurred in nonsmokers and patients with a smoking history ≤40 pack years. The three patients who had no tumor regression all had smoking histories >40 pack years.
Response duration ranged from 4 to 16 months
Four additional patients had stable disease, resulting in a disease control rate of 60%.
Adverse events have occurred in 24 of the 25 patients enrolled thus far, and 23 of the 24 were considered treatment related. Planchard said 11 patients had grade 3 adverse events, and none had grade 4. One adverse event was fatal. Serious adverse events occurred in 10 patients.
Five patients had adverse events that required dose reductions, and 10 patients had dose interruptions related to adverse events.
The most common adverse event was fatigue (10 patients), followed by decreased appetite (eight), and asthenia, rash, nausea, and anemia (six each). No type of grade 3 adverse event occurred more than once, with the exception of hypophosphatemia (two patients).
The results clearly demonstrate that BRAF V600E is "an actionable target beyond melanoma," said invited discussant Pasi A. Janne, MD, PhD, of Dana-Farber Cancer Institute in Boston.
The potential role of BRAF inhibitors in the treatment of NSCLC remains unclear, Janne continued. Durability of responses has yet to be determined, as the progression-free survival data with dabrafenib are immature. Experience with crizotinib (Xalkori) in NSCLC has shown a median PFS of less than 8 months.
Future studies are needed to determine whether the combination of a BRAF inhibitor and another targeted agent, such as a MEK inhibitor, has greater efficacy compared with either drug alone. Preclinical studies of BRAF V600E-mutant colorectal cancer have suggested synergistic activity with the combination of an anti-BRAF agent and an inhibitor of epidermal growth factor receptor.
The study was supported by GlaxoSmithKline, and investigators included employees of GlaxoSmithKline.
Planchard had no relevant disclosures. One or more coinvestigators disclosed relationships with ARIAD, Celgene, Chugai Pharma, Daiichi Sankyo, Foundation Medicine, Noartis, Tragara Pharmaceuticals, Bristol-Myers Squibb, Concodia Pharmaceuticals, GlaxoSmithKline, Infinity, Merck, Millennium, Novartis, Pfizer, AVEO, Lilly, Oncothyreon, Acceleron, KEW Group, Transgenomic, and Response Genetics.
Janne disclosed relationships with AstraZeneca, Boehringer Ingelheim, Chugai Pharma, Genentech, Pfizer, Quintiles, Roche, Sanofi, Syndax, LabCorp, and GATEKEEPER Pharmaceuticals.
- Reviewed by Zalman S. Agus, MD Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania
American Society of Clinical OncologySource Reference: Planchard, D et al "Interim results of phase II study BRF113928 of dabrafenib in BRAF V600E mutation-positive non-small cell lung cancer patients" ASCO 2013; Abstract 8009.