Plasma biomarker signature associated with improved survival in advanced non-small cell lung cancer patients on linifanib

McKeegan, Evelyn; Ansell, Peter; Davis, Gerard; Chan, Sabrina S.; Chandran, Raj; Gawel, Susan H.; Dowell, Barry L.; Bhathena, Anahita; Chakravartty, Arunava; McKee, Mark D.; Ricker, Justin L.; Carlson, Dawn M.; Ramalingam, Suresh S.; Devanarayan, Viswanath

doi:10.1016/j.lungcan.2015.09.011

Cited by 14 publications

(12 citation statements)

References 30 publications

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“…2 and File S1; see Supporting Information). 21,22 The resulting population combined the week-12 HiSCR responders with patients who did not achieve HiSCR at week 12, but did achieve a partial response at week 12, i.e. ≥ 25% reduction in AN count relative to baseline (week-12 partial responders) to form the week-12 partial responders plus HiSCR responders (PRR) population (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…An additional population was defined post hoc to identify the most clinically appropriate patient group for continued treatment of ADAew (continued from Period A to Period B) over the medium term vs. adalimumab discontinuation (ADAew/pbo) (Fig. and File S1; see Supporting Information) . The resulting population combined the week‐12 HiSCR responders with patients who did not achieve HiSCR at week 12, but did achieve a partial response at week 12, i.e.…”

Section: Methodsmentioning

confidence: 99%

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Adalimumab medium-term dosing strategy in moderate-to-severe hidradenitis suppurativa: integrated results from the phase III randomized placebo-controlled PIONEER trials

Jemec

Okun

Forman³

et al. 2019

British Journal of Dermatology

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SummaryBackgroundWeekly adalimumab (Humira®) is approved for the treatment of hidradenitis suppurativa (HS) based on the 12‐week placebo‐controlled periods of the two phase III PIONEER trials.ObjectivesUsing PIONEER integrated trial results, we aimed to evaluate the optimal medium‐term adalimumab maintenance dosing strategy for moderate‐to‐severe HS.MethodsEach trial had two double‐blind periods; 12‐week Period A and 24‐week Period B. Patients randomized to adalimumab 40 mg every week (ADAew) (Period A), were rerandomized in Period B to ADAew (ADAew/ew), ADA every other week (ADAew/eow), or placebo (ADAew/pbo). Placebo‐randomized patients were reassigned in Period B to ADAew (PIONEER I) or placebo (PIONEER II). The primary outcome was HS Clinical Response (HiSCR). Patients who lost response during Period B were discontinued from the study and offered an option to enter the open‐label extension (OLE) to receive ADAew. Results are reported across the two study periods, and data were combined from the two study periods and the OLE.ResultsFor week‐12 HiSCR achievers, the HiSCR week‐36 rate was 48·1% (ADAew/ew) vs. 46·2% (ADAew/eow) and 32·1% (ADAew/pbo). Combining (post hoc) these patients with week‐12 partial responders further differentiated outcomes in Period B (ADAew/ew 55·7% vs. ADAew/eow 40·0% and ADAew/pbo 30·1%). Period‐B adverse‐event rates were ADAew/ew 59·6% vs. ADAew/eow 57·4% and ADAew/pbo 65·0%. One patient (ADAew/ew) reported a serious infection.ConclusionsWeekly adalimumab treatment, effective throughout 36 weeks, was the optimal maintenance medium‐term dosing regimen for this population. At least partial response after 12 weeks with continued weekly dosing had better outcomes than dose reduction or interruption. Patients who do not show at least a partial response to weekly adalimumab by week 12 are unlikely to benefit from continued therapy. No new safety risks were identified. What's already known about this topic? Hidradenitis suppurativa (HS) is a chronic inflammatory disease, commonly misinterpreted as an infection and treated with long‐term antibiotic regimens or surgical incisions.Based on the chronicity of HS and the lack of evidence for efficacious and safe long‐term HS treatments, it is important to evaluate medium‐ to long‐term therapies for HS.Weekly adalimumab (Humira®) is approved for the treatment of moderate‐to‐severe HS based on the two phase III PIONEER trials. What does this study add? This study pooled data from the two PIONEER trials, providing a more robust assessment of outcomes.After at least partial treatment success with weekly adalimumab short‐term therapy (12 weeks), continuing weekly dosing during the subsequent 24 weeks had better outcomes than dose reduction or treatment interruption.Patients who do not show at least a partial response to weekly adalimumab by week 12 are unlikely to benefit from continued therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Adalimumab medium-term dosing strategy in moderate-to-severe hidradenitis suppurativa: integrated results from the phase III randomized placebo-controlled PIONEER trials

Jemec

Okun

Forman³

et al. 2019

British Journal of Dermatology

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“…In Section 2, we describe two methods for subgroup identification: (i) sequential‐BATTing, a multivariate extension of the bootstrapping and aggregating of thresholds from trees (BATTing) and (ii) AIM‐RULE, a multiplicative rules‐based modification of the adaptive index model (AIM) . The application of sequential‐BATTing method has been described in McKeegan et al , and here we provide the formal statistical description of this algorithm. We present these subgroup identification methods under a unified regression framework while incorporating other methods such as BATTing and AIM to search for the optimal stratification.…”

Section: Introductionmentioning

confidence: 99%

Patient subgroup identification for clinical drug development

Huang

Sun

Trow

et al. 2017

Statistics in Medicine

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Causal mechanism of relationship between the clinical outcome (efficacy or safety endpoints) and putative biomarkers, clinical baseline, and related predictors is usually unknown and must be deduced empirically from experimental data. Such relationships enable the development of tailored therapeutics and implementation of a precision medicine strategy in clinical trials to help stratify patients in terms of disease progression, clinical response, treatment differentiation, and so on. These relationships often require complex modeling to develop the prognostic and predictive signatures. For the purpose of easier interpretation and implementation in clinical practice, defining a multivariate biomarker signature in terms of thresholds (cutoffs/cut points) on individual biomarkers is preferable. In this paper, we propose some methods for developing such signatures in the context of continuous, binary and time-to-event endpoints. Results from simulations and case study illustration are also provided. Copyright © 2017 John Wiley & Sons, Ltd.

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“…Most importantly, a very recent publication identified the chemical compound linifanib as a potent inducer of UCP1 expression in primary inguinal adipocytes in vitro and in vivo (Zhao et al, 2019a). Of note, linifanib (ABT-869), an orally bioavailable, small-molecule receptor tyrosine kinase inhibitor, has been reported to exhibit potent antiangiogenic and antitumor effects in preclinical studies and is currently undergoing phase III trials (McKeegan et al, 2015;Horinouchi, 2016). Thus, additional research on the effect of a specific UCP1 activator in the context of obesity seems to be enormously promising, and existing linifanib preclinical studies could facilitate its application in obese subjects.…”

Section: Solute Carrier 25: the Mitochondrial Carrier Familymentioning

confidence: 99%

Solute Carrier Transporters as Potential Targets for the Treatment of Metabolic Disease

et al. 2019

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Plasma biomarker signature associated with improved survival in advanced non-small cell lung cancer patients on linifanib

Cited by 14 publications

References 30 publications

Adalimumab medium-term dosing strategy in moderate-to-severe hidradenitis suppurativa: integrated results from the phase III randomized placebo-controlled PIONEER trials

Adalimumab medium-term dosing strategy in moderate-to-severe hidradenitis suppurativa: integrated results from the phase III randomized placebo-controlled PIONEER trials

Patient subgroup identification for clinical drug development

Solute Carrier Transporters as Potential Targets for the Treatment of Metabolic Disease

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