KRAS G12C Inhibition with Sotorasib in Advanced Solid Tumors

Background: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C. Methods: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Results: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma. Conclusions: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.)

Energy metabolism and thermoregulation in old age

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Comparative vs ontogenetic paradigms for tests of the intrinsic mutagenesis hypothesis of aging

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Analytical approaches to and interpretations of data on time, rate, and cause of death of mice exposed to external gamma irradiation

Young adult male and female mice of inbred strains, A, BALB/c, C57BL/6, and C57L, and B6CF/sub 1/ and F/sub 2/ hybrids were exposed to daily duration-of-life external /sup 60/Co ..gamma.. irradiation. Age at death was recorded, and most decedents were necropsied to ascertain occurrence of major types of tumors. Age- and cause-specific mortality or incidence rates were derived, and their regressions on age were fitted with polynomial equations by least-squares procedures. Age-specific and age-adjusted integrated lifetime risk in excess of the control population was expressed as the mortality ratio (irradiated/control). Linear and nonlinear functions and widely different life expectancies can be accommodated by this technique. These basic actuarial statistics provide a means for comparative analysis of dose-response functions, sex and genetic variables, relative vs. absolute risk, protraction or dose-rate factors, and major contributing causes of excess risk. They also provide a basis for extrapolation to man. As examples, life shortening in days per rad (4 days/100 rads accumulated) is generally independent of sex, genotype, and daily dose rate. The integrated average lifetime risk of death related to all tumors (0.025%/rad) is largely independent of sex, genotype and dose-rates <12 rads/day, despite the fact that tumor incidence varies by a factor of 2 to 3 among genotypes. At low exposure rates, tumor-related mortality accounts for 80% of the excess risk, and life shortening is a function only of accumulated dose, independent of dose rate below 12 rads/day. The radiobiological effectiveness for low daily exposure levels is less than that for single exposures by a factor of 5 to 10. Life shortening following low daily exposure rates is induced at the rate of .03 to .06 days/R for the mouse, which extrapolates to about 1 to 2 days/R for man