Tumor growth inhibition‐overall survival modeling in non‐small cell lung cancer: A case study from GEMSTONE‐302

Abstract Overall survival is vital for approving new anticancer drugs but is often impractical for early‐phase studies. The tumor growth inhibition‐overall survival (TGI‐OS) model could bridge the gap between early‐ and late‐stage development. This study aimed to identify an appropriate TGI‐OS model for patients with non‐small cell lung cancer from the GEMSTONE‐302 study of sugemalimab. We used three TGI models to delineate tumor trajectories and investigated three OS model for linking TGI metric to OS. All three TGI models accurately captured tumor profiles at the individual level. The published atezolizumab‐based TGI‐OS model predicted survival time satisfactorily through simulation‐based evaluation, whereas the other published model built from multi‐treatment underestimated OS. Our study‐specific TGI‐OS model identified time‐to‐growth as the most significant metric with the number of metastatic sites and neutrophil‐to‐lymphocyte ratio at baseline as covariates and exhibited robust OS predictability. Our findings demonstrated the effectiveness of the TGI‐OS models in predicting phase III outcomes, which underpins their value as a powerful tool for antitumor drug development

90-kDa Heat Shock Protein Inhibition Abrogates the Topoisomerase I Poison-Induced G2/M Checkpoint in p53-Null Tumor Cells by Depleting Chk1 and Wee1S⃞

The G2/M cell cycle checkpoint is regulated by a multitude of signaling pathways after genotoxic stress. Herein, we report that treatment with the 90-kDa heat shock protein (Hsp90) molecular chaperone inhibitor 17-allylamino-17-demethoxygeldanamycin (17AAG) selectively abrogates the G2/M checkpoint induced by 7-ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of irinotecan, in p53-null compared with p53-intact HCT116 colon cancer cells. The basis for this selectivity can be explained in part by the lack of p21 induction in p53-null cells. In accord with published results, we could show that treatment with 17AAG resulted in depletion of Chk1, a known Hsp90 client protein. In addition, we observed a time- and dose-dependent decrease in Wee1 kinase level, a negative regulator of mitosis, after 17AAG treatment in gastrointestinal cancer cells. Depletion of Wee1 protein preceded mitotic entry induced by 17AAG, and this decrease could be partially rescued by cotreatment with a proteasome inhibitor. Coimmunoprecipitation experiments showed that Hsp90 and Wee1 interacted in whole cells, and 17AAG treatment decreased the degradative half-life of Wee1, indicating that Wee1 is another Hsp90 client in mammalian cells. Knockdown of Chk1 and Wee1 by short interfering RNA each resulted in abrogation of the G2/M checkpoint induced by SN-38. The combination of SN-38 and 17AAG was shown to be synergistic in p53-null but not in parental HCT116 cells by median effect/combination index analysis. Taken together, 17AAG specifically inhibits the G2/M checkpoint in p53-defective cells by down-regulation of two critical checkpoint kinases, Chk1 and Wee1

Can a propensity score matching method be applied to assessing efficacy from single‐arm proof‐of‐concept trials in oncology?

Abstract As a result of the escalating number of new cancer treatments being developed and competition among pharmaceutical companies, decisions regarding how to proceed with phase III trials are frequently based on findings from either single‐arm phase I expansion cohorts or phase II studies that compare the efficacy of the study drug to a standard‐of‐care benchmark derived from historical data. However, even when eligibility criteria are matched, differences in the distribution of baseline patient features may influence the outcome of single‐arm trials in real‐world scenarios. Therefore, novel methods are needed to enhance the accuracy of efficacy prediction from current cohorts relative to historical data. In this study, we demonstrated the feasibility of using the propensity score matching (PSM) method to improve decision making by matching relevant baseline features between current and historical cohorts. According to our findings, utilizing the PSM method may provide a less biased means of comparing outcomes between current and historical cohorts relative to a naïve approach, which relies solely on differences in average outcomes between the cohorts

Approximation, torsion, and amodally-completed surfaces

3In a stereo display simulating two rectangles, the lower frontoparallel and the upper slanted around the vertical axis, amodally completed behind a frontoparallel surface, either real or illusory, relative slant is underestimated with respect to a separate-rectangle condition. We compared with- vs. without-occluder displays. In Exps. 1 and 2 we found slant assimilation in with-occluder displays and slant contrast in without-occluder displays. In Exp. 3 we evaluated the effect of the mere presence of the occluder. Twist classification was impaired even when edge geometry hindered amodal completion, but the performance loss was larger when the patches were amodally completed. To minimize torsion, fragments are misperceived, indicating that in limiting conditions completion is mediated by approximation rather than interpolation. Slant assimilation decreases as twist increases, up to the limit for the formation of a smooth surface with torsion.nonemixedFANTONI C.; GERBINO W.; KELLMAN P.J.Fantoni, Carlo; Gerbino, Walter; Kellman, P. J