A single-arm, multicenter, phase II trial of osimertinib in patients with epidermal growth factor receptor exon 18 G719X, exon 20 S768I, or exon 21 L861Q mutations.

BACKGROUND: For patients with stage IV non-small-cell lung cancer with epidermal growth factor receptor (EGFR) exon 19 deletions and exon 21 L858R mutations, osimertinib is the standard of care. Investigating the activity and safety of osimertinib in patients with EGFR exon 18 G719X, exon 20 S768I, or exon 21 L861Q mutations is of clinical interest. PATIENTS AND METHODS: Patients with stage IV non-small-cell lung cancer with confirmed EGFR exon 18 G719X, exon 20 S768I, or exon 21 L861Q mutations were eligible. Patients were required to have measurable disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Patients were required to be EGFR tyrosine kinase inhibitor-naive. The primary objective was objective response rate, and secondary objectives were progression-free survival, safety, and overall survival. The study used a two-stage design with a plan to enroll 17 patients in the first stage, and the study was terminated after the first stage due to slow accrual. RESULTS: Between May 2018 and March 2020, 17 patients were enrolled and received study therapy. The median age of patients was 70 years (interquartile range 62-76), the majority were female (n = 11), had a performance status of 1 (n = 10), and five patients had brain metastases at baseline. The objective response rate was 47% [95% confidence interval (CI) 23% to 72%], and the radiographic responses observed were partial response (n = 8), stable disease (n = 8), and progressive disease (n = 1). The median progression-free survival was 10.5 months (95% CI 5.0-15.2 months), and the median OS was 13.8 months (95% CI 7.3-29.2 months). The median duration on treatment was 6.1 months (range 3.6-11.9 months), and the most common adverse events (regardless of attribution) were diarrhea, fatigue, anorexia, weight loss, and dyspnea. CONCLUSIONS: This trial suggests osimertinib has activity in patients with these uncommon EGFR mutations.

Erlotinib in African Americans with advanced non-small cell lung cancer: a prospective randomized study with genetic and pharmacokinetic analyses.

Prospective studies on epidermal growth factor receptor (EGFR) inhibitors in African Americans with non-small cell lung cancer (NSCLC) have not previously been performed. In this phase II randomized study, 55 African Americans with NSCLC received 150 mg/day erlotinib or a body weight-adjusted dose with subsequent escalations to the maximum-allowable dose, 200 mg/day, to achieve rash. Erlotinib and OSI-420 exposures were lower than those observed in previous studies, consistent with CYP3A pharmacogenetics implying higher metabolic activity. Tumor genetics showed only two EGFR mutations, EGFR amplification in 17/47 samples, eight KRAS mutations, and five EML4-ALK translocations. Although absence of rash was associated with shorter time to progression (TTP), disease-control rate, TTP, and 1-year survival were not different between the two dose groups, indicating the dose-to-rash strategy failed to increase clinical benefit. Low incidence of toxicity and low erlotinib exposure suggest standardized and maximum-allowable dosing may be suboptimal in African Americans.

Bevacizumab in the treatment of non-small-cell lung cancer.

Lung cancer is the leading cause of cancer death in the United States. The majority of patients present with advanced disease, and treatment with standard cytotoxic chemotherapy improves survival and quality of life in patients with a preserved functional status. However, the prognosis is poor with the majority of patients dying in less than a year. Treatment with standard cytotoxic chemotherapy has reached a therapeutic plateau, and new therapeutic approaches have investigated therapies that target the specific molecular pathways involved in carcinogenesis and angiogenesis. The most promising strategy for inhibiting angiogenesis involves agents that either target the proangiogenesis growth factor, vascular endothelial growth factor A (VEGF) by preventing binding to the receptor or inhibiting the downstream signaling of the vascular endothelial growth factor receptor. The only therapeutic agent approved for the treatment of lung cancer is bevacizumab, a monoclonal antibody that binds to VEGF. A recent phase III trial revealed a statistically significant improvement in response rate, progression free and overall survival with combination of bevacizumab with chemotherapy over chemotherapy alone. Attempts to identify surrogate markers of antiangiogenesis activity are currently ongoing, and may assist in the selection of patients for antiangiogenesis therapy and the development of this class of agents.

Renal cell carcinoma.

In addition to the known risk factors for renal cell carcinoma, hypertension, obesity, and tobacco use, a diet high in consumption of fried or sautéed meat and the frequent consumption of poultry may increase the risk for renal cell carcinoma. A diet high in consumption of fruits and vegetables appears to have a protective effect. Molecular markers, in particular markers of cell proliferation, may have prognostic value and be of assistance in identifying patients who would benefit from more aggressive therapy. Surgery continues to the mainstay of treatment of localized disease, and may be the optimal treatment for patients with isolated solitary metastatic disease. Response rates to systemic therapy with cytokines vary from 5% to 20% with significant adverse effects.