Relationship between Progression-Free Survival and Overall Survival in Chronic Lymphocytic Leukemia: A Literature-Based Analysis

Beauchemin, C.; Johnston, James B.; Lapierre, M.; Aïssa, F.; Lachaine, J.

doi:10.3747/co.22.2119

Cited by 26 publications

(19 citation statements)

References 48 publications

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“…Improvements in efficacy were instead measured through overall survival, which is universally taken to indicate clinical benefit in oncology trials. 26,27,28 However, if surrogate markers do in fact represent unique dimensions to the benefit that is derived from treatment, then their absence would mean that our analysis is incomplete. Surrogacy, however, implies that their value to patient health is at least in part captured by the three outcome measures-overall survival, quality of life, and safety-that are considered.…”

Section: Overall Therapeutic Benefitsmentioning

confidence: 99%

“…However, our approach was designed to reflect the system that is currently used in England to identify OS improvements that are large enough to justify additional expense in end-of-life care, 27 and used at times by Australian authorities to assess new health technologies. 28 Quality of life and safety benefits were categorized as improvement, reduction, mixed evidence, or no difference relative to the standards of care existing at time of evaluation. A hierarchical process was followed to generate a composite measure of the drug-related effect on OS, QoL, and safety.…”

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confidence: 99%

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Assessment of Overall Survival, Quality of Life, and Safety Benefits Associated With New Cancer Medicines

2017

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LSE has developed LSE Research Online so that users may access research output of the School. Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Users may download and/or print one copy of any article(s) in LSE Research Online to facilitate their private study or for non-commercial research. You may not engage in further distribution of the material or use it for any profit-making activities or any commercial gain. You may freely distribute the URL (http://eprints.lse.ac.uk) of the LSE Research Online website.Copyright 2016 American Medical Association. All rights reserved. Assessment of Overall Survival, Quality of Life, and Safety Benefits Associated With New Cancer MedicinesSebastian Salas-Vega, MSc; Othon Iliopoulos, MD; Elias Mossialos, MD, PhD IMPORTANCE There is a dearth of evidence examining the impact of newly licensed cancer medicines on therapy. This information could otherwise support clinical practice, and promote value-based decision-making in the cancer drug market. Of these 53 drugs, 23 (43%) increased OS by 3 months or longer, 6 (11%) by less than 3 months, and 8 (15%) by an unknown magnitude; there was no evidence to suggest that the remaining 16 (30%) increased OS over best alternative treatments. Where overall survival gains could be quantified, all new cancer drugs were associated with a mean (SE) total increase in OS of 3.43 (0.63) months over the treatments that were available in 2003. Drug-related improvements in OS were, however, widely distributed across therapeutic targets-ranging between 0 (thyroid, ascites) and 8.48 months (breast cancers)-and were sometimes based on modeled data, indirect or nonactive comparisons, or nonvalidated evidence. Although 22 (42%) of 53 new medicines were associated with an increase in QoL, 24 (45%) were also associated with reduced patient safety. Of the 53 new cancer drugs, 42 (79%) were associated with at least some improvement in OS, QoL, or safety.CONCLUSIONS AND RELEVANCE Although innovation in the oncology drug market has contributed to improvements in therapy, the magnitude and dimension of clinical benefits vary widely, and there may be reasons to doubt that claims of efficacy reflect real-world effectiveness exactly. These findings raise important questions for clinical decision-making and value-based policy. JAMA Oncol. doi:10.1001/jamaoncol.2016 Published online December 29, 2016. T here are growing questions about the value gained from spending on what seem to be ever more expensive cancer medicines. Rising expenditures may make it difficult for patients to access or remain compliant with lifeextending therapies. 1,2 Yet, some have argued that high prices may be justified if new and innovative treatments offer significant benefits to patients. 2,3 Even as studies point to gains in overall survival (OS) from innovative cancer medicines, 4 efforts to examine the value from spending on new cancer drugs remain stymied by a dearth of systematic evidence on their clinical ri...

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Section: Overall Therapeutic Benefitsmentioning

confidence: 99%

mentioning

confidence: 99%

Assessment of Overall Survival, Quality of Life, and Safety Benefits Associated With New Cancer Medicines

2017

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“…Since PFS is the primary end point for many clinical trials and also serves a surrogate end point for the overall survival (OS) (49), validation of the PK-PD model-predicted clinical response was performed by comparing the model generated PFS profiles with clinically observed profiles. One of the most important parameter for the clinical PK-PD model is the growth rate of the tumor.…”

Section: Discussionmentioning

confidence: 99%

Application of a PK-PD Modeling and Simulation-Based Strategy for Clinical Translation of Antibody-Drug Conjugates: a Case Study with Trastuzumab Emtansine (T-DM1)

Singh

Shah

2017

AAPS J

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Successful clinical translation of antibody-drug conjugates (ADCs) can be challenging due to complex pharmacokinetics and differences between preclinical and clinical tumors. To facilitate this translation, we have developed a general pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation (M&S)-based strategy for ADCs. Here we present the validation of this strategy using T-DM1 as a case study. A previously developed preclinical tumor disposition model for T-DM1 (Singh and Shah, AAPSJ. 2015; 18(4):861–875) was used to develop a PK-PD model that can characterize in vivo efficacy of T-DM1 in preclinical tumor models. The preclinical data was used to estimate the efficacy parameters for T-DM1. Human PK of T-DM1 was a priori predicted using allometric scaling of monkey PK parameters. The predicted human PK, preclinically estimated efficacy parameters, and clinically observed volume and growth parameters for breast cancer were combined to develop a translated clinical PK-PD model for T-DM1. Clinical trial simulations were performed using the translated PK-PD model to predict progression-free survival (PFS) and objective response rates (ORRs) for T-DM1. The model simulated PFS rates for HER2 1+ and 3+ populations were comparable to the rates observed in three different clinical trials. The model predicted only a modest improvement in ORR with an increase in clinically approved dose of T-DM1. However, the model suggested that a fractionated dosing regimen (e.g., front loading) may provide an improvement in the efficacy. In general, the PK-PD M&S-based strategy presented here is capable of a priori predicting the clinical efficacy of ADCs, and this strategy has been now retrospectively validated for all clinically approved ADCs.

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“…Moreover, it is possible that levels of CEACAM6 in lung lining fluid and/or the circulation will reflect the severity of lung disease in infants (and adults) as found for specific cancers (Beauchemin et al. ).…”

Section: Discussionmentioning

confidence: 99%

Expression of human carcinoembryonic antigen-related cell adhesion molecule 6 and alveolar progenitor cells in normal and injured lungs of transgenic mice

et al. 2015

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Carcinoembryonic antigen‐related cell adhesion molecule 6 (CEACAM6) is expressed in the epithelium of various primate tissues, including lung airway and alveoli. In human lung, CEACAM6 is developmentally and hormonally regulated, protects surfactant function, has anti‐apoptotic activity and is dysregulated in cancers. We hypothesized that alveolar CEACAM6 expression increases in lung injury and promotes cell proliferation during repair. Studies were performed in CEABAC transgenic mice‐containing human CEACAM genes. The level of CEACAM6 in adult CEABAC lung was comparable to that in human infants; expression occurred in epithelium of airways and of some alveoli but rarely co‐localized with markers of type I or type II cells. Ten days after bleomycin instillation, both the number of CEACAM6+ cells and immunostaining intensity were elevated in injured lung areas, and there was increased co‐localization with type I and II cell markers. To specifically address type II cells, we crossed CEABAC mice with animals expressing EGFP driven by the SP‐C promoter. After bleomycin injury, partially flattened, elongated epithelial cells were observed that expressed type I cell markers and were primarily either EGFP + or CEACAM6+. In cell cycle studies, mitosis was greater in CEACAM6+ non‐type II cells versus CEACAM6+/EGFP + cells. CEACAM6 epithelial expression was also increased after hyperoxic exposure and LPS instillation, suggesting a generalized response to acute lung injuries. We conclude that CEACAM6 expression is comparable in human lung and the CEABAC mouse. CEACAM6 in this model appears to be a marker of a progenitor cell population that contributes to alveolar epithelial cell replenishment after lung injury.

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Relationship between Progression-Free Survival and Overall Survival in Chronic Lymphocytic Leukemia: A Literature-Based Analysis

Abstract: BackgroundThe endpoints of progression-free survival (pfs) and time-to-progression (ttp) are frequently used to

Cited by 26 publications

References 48 publications

Assessment of Overall Survival, Quality of Life, and Safety Benefits Associated With New Cancer Medicines

Assessment of Overall Survival, Quality of Life, and Safety Benefits Associated With New Cancer Medicines

Application of a PK-PD Modeling and Simulation-Based Strategy for Clinical Translation of Antibody-Drug Conjugates: a Case Study with Trastuzumab Emtansine (T-DM1)

Expression of human carcinoembryonic antigen-related cell adhesion molecule 6 and alveolar progenitor cells in normal and injured lungs of transgenic mice

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