Assessing Long-term Treatment Benefits Using Complementary Statistical Approaches: An In Silico Analysis of the Phase III Keynote-045 and Checkmate-214 Immune Checkpoint Inhibitor Trials.

BACKGROUND: The Keynote-045 trial illustrates that the long-term benefit (LTB) of treatment does not always translate to improved progression-free survival (PFS). Milestone survival and flexible parametric survival model with cure (FPCM) have been proposed as complementary statistical approaches to more comprehensively evaluate LTBs of treatments. OBJECTIVE: The current study compares milestone survival and FPCM analyses to evaluate treatment effects of immune checkpoint inhibitor (ICI) phase III trials. DESIGN, SETTING, AND PARTICIPANTS: Individual patient data, from initial and follow-up analyses of Keynote-045 (urothelial cancer) and Checkmate-214 (advanced renal cell carcinoma), were reconstructed for PFS. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Each trial was reanalyzed using the Cox proportional hazard regression and two complementary methods (milestone survival and FPCM) to estimate treatment impact on the LTB. RESULTS AND LIMITATIONS: For each trial, there was evidence of nonproportional hazards. For the long-term analysis of the Keynote-045 trial, FPCM identified a time-dependent effect on PFS, but the Cox model found no statistical difference in PFS (hazard ratio, 0.90; 95% confidence interval, 0.75-1.08). Milestone survival and FPCM identified improvements in the LTB fractions. This was consistent with the results from the reanalysis of Keynote-045, based on the shorter follow-up, although the LTB fraction was not retained. The increase in PFS in Checkmate-214 was identified by both Cox model and FPCM. Experimental treatment-dependent improvement in the LTB fraction was demonstrated using milestone survival and FPCM. The LTB fraction estimated with FPCM was consistent with the results from the reanalysis of the shorter follow-up period. CONCLUSIONS: Although ICIs show substantial shifts toward LTBs in terms of PFS, based on a conventional Kaplan-Meier or Cox model analysis, our approach provides an alternative assessment of benefit-risk ratios for new therapeutics and facilitates communicating risk to patients. Kidney patients treated with ICIs can be counseled that they are potentially cured, but future work will need to definitively validate this conclusion. PATIENT SUMMARY: Although immune checkpoint inhibitor treatments show substantial shifts toward long-term benefits in terms of progression-free survival, a more rigorous attempt to quantify this shift, rather than simply using a Kaplan-Meier estimate or comparing progression-free survival curves using the classic Cox model, is warranted. Our results suggest that advanced renal cell carcinoma patients who had not received a previous treatment are functionally cured by nivolumab and ipilimumab, which is not the case for second-line urothelial carcinoma.

Asterics: a simple tool for the ExploRation and Integration of omiCS data.

BACKGROUND: The rapid development of omics acquisition techniques has induced the production of a large volume of heterogeneous and multi-level omics datasets, which require specific and sometimes complex analyses to obtain relevant biological information. Here, we present ASTERICS (version 2.5), a publicly available web interface for the analyses of omics datasets. RESULTS: ASTERICS is designed to make both standard and complex exploratory and integration analysis workflows easily available to biologists and to provide high quality interactive plots. Special care has been taken to provide a comprehensive documentation of the implemented analyses and to guide users toward sound analysis choices regarding some specific omics data. Data and analyses are organized in a comprehensive graphical workflow within ASTERICS workspace to facilitate the understanding of successive data editions and analyses leading to a given result. CONCLUSION: ASTERICS provides an easy to use platform for omics data exploration and integration. The modular organization of its open source code makes it easy to incorporate new workflows and analyses by external contributors. ASTERICS is available at https://asterics.miat.inrae.fr and can also be deployed using provided docker images.

Clinical reliability of pedicled perforator flaps in the management of adult limb and trunk soft tissue sarcomas: Experience of two French expert centres.

INTRODUCTION: Limb-sparing surgery combined with radiation has become the standard treatment for soft tissue sarcomas. Despite the many advantages of reconstruction procedures, such as muscle-sparing flap and local reconstruction, the use of pedicled perforator flaps remains non-consensual due to doubts about their reliability when associated with radiotherapy. This study evaluated their surgical reliability in reconstructive surgery for limb and trunk soft tissue sarcomas, in terms of healing time, wound disorders, and postoperative complications, regardless of radiation timing. PATIENTS AND METHODS: We realized a retrospective, observational, bi-center study (Cancer University Institute of Toulouse Oncopole, France and Bergonié Institute Bordeaux, France) and describes pedicled perforator flaps performed between January 2015 and January 2021. RESULTS: A total of 74 flaps were included. The median age of the population was 70-year-old. The group consisted of 68.8% (n = 51/74) propeller flaps. We found a partial necrosis rate of 28.4% (n = 21/74), scar disunion of 48.6% (n = 36/74), local infection of 10.8% (n = 8/74), and venous congestion of 13.5% (n = 10/74). Only 16.2% (n = 12/74) required secondary surgical repair to a local complication. The average length of stay was 7.3 days  [1.0-25.0]. The mean operating time of our flaps was 133.4 min [38.0-280.0]. CONCLUSIONS: Pedicled perforator flaps are a surgical technique that can be used in reconstructive surgery for limb and trunk soft tissue sarcomas in adults, regardless of radiation timing. However, these flaps carry a high rate of postoperative complications so they should be reserved for expert surgeons in referral centers.

Assessment of Treatment Effects and Long-term Benefits in Immune Checkpoint Inhibitor Trials Using the Flexible Parametric Cure Model: A Systematic Review.

Importance: Compared with standard cytotoxic therapies, randomized immune checkpoint inhibitor (ICI) phase 3 trials reveal delayed benefits in terms of patient survival and/or long-term response. Such outcomes generally violate the assumption of proportional hazards, and the classical Cox proportional hazards regression model is therefore unsuitable for these types of analyses. Objective: To evaluate the ability of the flexible parametric cure model (FPCM) to estimate treatment effects and long-term responder fractions (LRFs) independently of prespecified time points. Evidence Review: This systematic review used reconstructed individual patient data from ICI advanced or metastatic melanoma and lung cancer phase 3 trials extracted from the literature. Trials published between January 1, 2010, and October 1, 2019, with long-term follow-up periods (maximum follow-up, ≥36 months in first line and ≥30 months otherwise) were selected to identify LRFs. Individual patient data for progression-free survival were reconstructed from the published randomized ICI phase 3 trial results. The FPCM was applied to estimate treatment effects on the overall population and on the following components of the population: LRF and progression-free survival in non-long-term responders. Results obtained were compared with treatment effects estimated using the Cox proportional hazards regression model. Findings: In this systematic review, among the 23 comparisons studied using the FPCM, a statistically significant association between the time-to-event component and experimental treatment was observed in the main analyses and confirmed in the sensitivity analyses of 18 comparisons. Results were discordant for 4 comparisons that were not significant by the Cox proportional hazards regression model. The LRFs varied from 1.5% to 12.7% for the control arms and from 4.6% to 38.8% for the experimental arms. Differences in LRFs varied from 2% to 29% and were significantly increased in the experimental compared with the control arms, except for 4 comparisons. Conclusions and Relevance: This systematic review of reconstructed individual patient data found that the FPCM was a complementary approach that provided a comprehensive and pertinent evaluation of benefit and risk by assessing whether ICI treatment was associated with an increased probability of patients being long-term responders or with an improved progression-free survival in patients who were not long-term responders.