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A phase II trial of Salirasib in patients with lung adenocarcinomas with KRAS mutations
Gregory J Riely1, Melissa L Johnson, Chanoa Medina
1Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York City, New York, USA. rielyg@mskcc.org
Introduction:
KRAS mutations are present in 30% of lung adenocarcinomas. Salirasib prevents Ras membrane binding thereby blocking the function of all Ras isoforms. This phase II study determined the activity of salirasib in patients with advanced lung adenocarcinomas with KRAS mutations.
Methods:
Two cohorts of patients with stage IIIB/IV lung adenocarcinoma were eligible: patients with tumors with KRAS mutations who were previously treated with chemotherapy and patients receiving initial therapy who had ≥15 pack-year smoking history. Salirasib was given orally from days 1 to 28 of a 35-day cycle. The primary end point was the rate of nonprogression at 10 weeks.
Results:
Thirty-three patients were enrolled. Thirty patients had KRAS mutations (23 patients who were previously treated and 7/10 patients who had no prior therapy). Of the previously treated patients, 7 of 23 (30%) had stable disease at 10 weeks, and 4 of 10 (40%) previously untreated patients had stable disease at 10 weeks. No patient had a radiographic partial response (0% observed rate, 95% confidence interval 0-12%). The median overall survival was not reached (>9 months) for previously untreated patients and it was 15 months for patients who received prior chemotherapy. Diarrhea, nausea, and fatigue were the most common toxicities.
Conclusions:
Salirasib at the current dose and schedule has insufficient activity in the treatment of KRAS mutant lung adenocarcinoma to warrant further evaluation. The successful enrollment of 30 patients with tumors with KRAS mutant lung adenocarcinoma over 15 months at a single site demonstrates that drug trials directed at a KRAS-specific genotype in lung cancer are feasible.
Insights
Salirasib showed insufficient activity in treating KRAS mutant lung adenocarcinoma. However, the study successfully demonstrated the feasibility of KRAS-targeted lung cancer clinical trials.
Area of Science:
- Oncology
- Molecular Biology
- Clinical Trials
Background:
- KRAS mutations are common in lung adenocarcinoma (30%).
- Salirasib inhibits Ras signaling by preventing membrane binding.
Purpose of the Study:
- To determine the activity of salirasib in advanced KRAS-mutant lung adenocarcinoma.
- To assess salirasib's efficacy in previously treated and untreated patients.
Main Methods:
- Phase II study of oral salirasib in two cohorts of stage IIIB/IV lung adenocarcinoma patients.
- Cohort 1: KRAS-mutant tumors, previously treated with chemotherapy.
- Cohort 2: Initial therapy, KRAS wild-type, and ≥15 pack-year smoking history. Primary endpoint: nonprogression rate at 10 weeks.
Main Results:
- 33 patients enrolled; 30 had KRAS mutations.
- Stable disease at 10 weeks: 30% in previously treated (7/23) and 40% in untreated (4/10).
- No partial responses observed (0%). Median overall survival: 15 months (prior chemo) and >9 months (untreated).
Conclusions:
- Salirasib demonstrated insufficient activity at the tested dose and schedule for KRAS-mutant lung adenocarcinoma.
- The study confirmed the feasibility of conducting genotype-directed clinical trials in lung cancer.
