Glenn J Hanna1, Jeffrey P Guenette2, Nicole G Chau3, Cyrus M Sayehli4, Christian Wilhelm5, Robert Metcalf6, Deborah J Wong7, Marcia Brose8, Mohammad Razaq9, Elisabeth Pérez-Ruiz10, Ezra E W Cohen11, Rahul Aggarwal12, Catherine Scholz13, Antonio Gualberto13, Alan L Ho14,15. 1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. 2. Division of Neuroradiology, Brigham & Women's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts. 3. Department of Medical Oncology, BC Cancer Vancouver Centre, Vancouver, British Columbia, Canada. 4. Department of Internal Medicine II, Early Clinical Trial Unit, University Hospital Wurzburg, Wurzburg, Germany. 5. Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, Wuerzburg, Germany. 6. Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom. 7. Division of Hematology and Oncology, Department of Medicine, Ronald Reagan University of California at Los Angeles Medical Center, Los Angeles, California. 8. Department of Otorhinolaryngology, Head and Neck Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. 9. Department of Hematology/Oncology, Stephenson Cancer Center, The University of Oklahoma, Oklahoma City, Oklahoma. 10. Department of Medical Oncology, Institute of Biomedical Research of Malaga, Costa del Sol Health Agency, Marbella, Spain. 11. Division of Hematology-Oncology, Moores Cancer Center, University of California at San Diego Health, San Diego, California. 12. Division of Hematology/Oncology, University of California at San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California. 13. Kura Oncology, San Diego, California. 14. Department of Hematology/Oncology, Memorial Sloan Kettering Cancer Center, New York City, New York. 15. Department of Medicine, Weill Cornell Medical College, New York City, New York.
Abstract
BACKGROUND: To the authors' knowledge, there are no approved therapies for recurrent, metastatic (R/M) salivary gland carcinoma (SGC), but molecularly targeted therapies warrant ongoing investigation. In the current study, the authors have reported on the efficacy of tipifarnib in patients with aggressive HRAS-mutant, R/M SGC. METHODS: The current prospective, nonrandomized, multicenter, international cohort study involved 8 centers and was conducted from May 2015 to June 2019. The median follow-up was 22 months (range, 6-55 months). Subjects with HRAS-mutant R/M SGC (any histology) and disease progression within the last 6 months were enrolled. Tipifarnib was dosed orally twice daily. The authors determined the objective response rate using Response Evaluation Criteria in Solid Tumors (version 1.1), duration of response, and molecular predictors of response. RESULTS: A total of 13 patients with R/M SGC were enrolled; all had received prior systemic therapy (1-3 regimens). One objective response was observed; an additional 7 of 12 evaluable patients (58%) had stable disease as their best response with a median duration of 9 months (range, 3-14 months). Five of 7 patients had >10% tumor regression and 6 of 7 had stable disease lasting >6 months. Q61R was the most frequent activating HRAS mutation noted (7 of 13 patients; 54%), but gene variant and allele frequency did not correlate with outcomes. The median progression-free survival was 7 months (95% confidence interval, 5.9-10.1 months), and the median overall survival was 18 months (95% confidence interval, 9.6-22.4 months) with approximately 58.6% of patients alive at 1 year. Survival was similar regardless of HRAS mutant variant or co-occurring PIK3CA alterations. No participant discontinued treatment because of toxicity. CONCLUSIONS: Tipifarnib resulted in modest clinical activity with a promising disease control rate among patients with HRAS-mutant, R/M SGC who developed disease progression within the last 6 months.
BACKGROUND: To the authors' knowledge, there are no approved therapies for recurrent, metastatic (R/M) salivary gland carcinoma (SGC), but molecularly targeted therapies warrant ongoing investigation. In the current study, the authors have reported on the efficacy of tipifarnib in patients with aggressive HRAS-mutant, R/M SGC. METHODS: The current prospective, nonrandomized, multicenter, international cohort study involved 8 centers and was conducted from May 2015 to June 2019. The median follow-up was 22 months (range, 6-55 months). Subjects with HRAS-mutant R/M SGC (any histology) and disease progression within the last 6 months were enrolled. Tipifarnib was dosed orally twice daily. The authors determined the objective response rate using Response Evaluation Criteria in Solid Tumors (version 1.1), duration of response, and molecular predictors of response. RESULTS: A total of 13 patients with R/M SGC were enrolled; all had received prior systemic therapy (1-3 regimens). One objective response was observed; an additional 7 of 12 evaluable patients (58%) had stable disease as their best response with a median duration of 9 months (range, 3-14 months). Five of 7 patients had >10% tumor regression and 6 of 7 had stable disease lasting >6 months. Q61R was the most frequent activating HRAS mutation noted (7 of 13 patients; 54%), but gene variant and allele frequency did not correlate with outcomes. The median progression-free survival was 7 months (95% confidence interval, 5.9-10.1 months), and the median overall survival was 18 months (95% confidence interval, 9.6-22.4 months) with approximately 58.6% of patients alive at 1 year. Survival was similar regardless of HRAS mutant variant or co-occurring PIK3CA alterations. No participant discontinued treatment because of toxicity. CONCLUSIONS:Tipifarnib resulted in modest clinical activity with a promising disease control rate among patients with HRAS-mutant, R/M SGC who developed disease progression within the last 6 months.
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