Phase II trial of single-agent sorafenib in patients with advanced non-small cell lung carcinoma

Abstract

7002 Background: Sorafenib, an oral multi-kinase inhibitor, targets the Raf/MEK/ERK pathway at the level of Raf kinase and receptor tyrosine kinases, and has shown efficacy against several tumor types in phase I/II trials. Non-small-cell lung cancer (NSCLC) is associated with mutations in k-ras, upstream of Raf/MEK/ERK. Methods: This multi-center, uncontrolled, phase II trial evaluated efficacy (every 8 weeks using RECIST) and safety of sorafenib (400 mg bid, continuous) in patients with relapsed or refractory advanced NSCLC. Plasma for proteomic biomarker analysis (ELISA [n=44]; mass-spectrometry [n=43]) was taken at screening, Day 21 of Cycle 1, and Day 1 of Cycle 3. Results: Fifty-two of 54 patients enrolled received sorafenib. Most (49/52) patients who received sorafenib had stage IV NSCLC. Thirty patients (59%) out of 51 evaluable for efficacy had SD. Although there were no confirmed PRs, tumor shrinkage was observed in 15 (29%) patients (four had ≥30% shrinkage). Patients with SD had a median progression-free survival (PFS) of 23.7 weeks, while all evaluable patients (n=51) had a median PFS of 11.9 weeks and median overall survival of 29.3 weeks. The most frequent drug-related adverse events observed in 52 patients were diarrhea (21 [40%] patients), hand-foot skin reaction (HFS; 19 [37%]), fatigue (14 [27%]), and nausea (13 [25%]). Frequent drug-related adverse events ≥ grade 3 included HFS (n=5 [10%]) and hypertension (n=2 [4%]). Three patients discontinued due to adverse events (HFS, elevated lipase, and myocardial infarction). There were nine deaths within 30 days of discontinuation of sorafenib (n=5 PD; n=2 cardiopulmonary arrest; n=1 hemoptysis; and n=1 unknown cause). The levels of five proteins measured by ELISA, either at screening or change over treatment duration, correlated significantly with time to progression (TTP) or maximum tumor shrinkage. Levels of five additional proteins, identified by mass-spectrometry, also correlated with TTP. Conclusions: Identified biomarkers may help assess efficacy of sorafenib in NSCLC patients. Sorafenib 400 mg bid is generally well tolerated and shows promising efficacy in patients with advanced, progressive NSCLC, with approximately 60% of pts achieving disease stabilization. [Table: see text]

Cutaneous adverse effects in patients treated with the multitargeted kinase inhibitors sorafenib and sunitinib

“…1,2 Sorafenib is approved for use in the treatment of metastatic renal cell carcinoma (RCC) and has been found to have significant clinical activity against hepatocellular carcinoma (HCC). 3 Sunitinib (SU011248; Sutent Ò ; Pfizer, New York, NY, U.S.A.) is also an oral MKI that targets VEGFRs 1-3, PDGFR-a, c-Kit, Flt-3, colony-stimulating factor receptor 1, and the glial cell line-derived neurotrophic factor receptor. Although sunitinib is approved for use in the treatment of gastrointestinal stromal tumour (GIST) and advanced RCC, the drug has also been shown to be efficacious in treating colon and breast cancers.…”

Meta-analysis of dermatological toxicities associated with sorafenib

“…Clinical benefits for sorafenib were initially seen in randomized trials, which found longer progression‐free survival with sorafenib than with placebo in patients with metastatic renal‐cell carcinoma and advanced hepatocellular carcinom 3–5 . In addition, clinical efficacy was also found for sorafenib in phase II clinical trials for other malignant diseases such as advanced melanoma, breast cancer, non‐small‐cell lung cancer, urothelial cancer, prostate cancer, carcinoma of the head and neck, gastrointestinal stromal tumours and thyroid cancer 6–14 …”

Shortcomings of current therapies for non-small-cell lung cancer: unmet medical needs

“…The most commonly reported adverse events were diarrhea, hand-foot syndrome, fatigue and nausea. Grade 3-4 hypertension was also reported in 4% of the patients (Gatzemeier et al, 2006). Results from a planned interim analysis of a large phase III trial (n ¼ 926) of sorafenib plus chemotherapy (carboplatin/ paclitaxel) in patients with NSCLC showed no benefit.…”