Pembrolizumab exposure–response assessments challenged by association of cancer cachexia and catabolic clearance

David C. Turner, Anna G. Kondic, Keaven M. Anderson, Andrew G. Robinson, Edward B. Garon, Jonathan Riess, Lokesh Jain, Kapil Mayawala, Jiannan Kang, Scot W. Ebbinghaus, Vikram Sinha, Dinesh P. de Alwis, Julie A. Stone

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Abstract

Purpose: To investigate the relationship of pembrolizumab pharmacokinetics (PK) and overall survival (OS) in patients with advanced melanoma and non–small cell lung cancer (NSCLC). Patients and Methods: PK dependencies in OS were evaluated across three pembrolizumab studies of either 200 mg or 2 to 10 mg/kg every 3 weeks (Q3W). Kaplan–Meier plots of OS, stratified by dose, exposure, and baseline clearance (CL 0 ), were assessed per indication and study. A Cox proportional hazards model was implemented to explore imbalances of typical prognostic factors in high/low NSCLC CL 0 subgroups. Results: A total of 1,453 subjects were included: 340 with pembrolizumab-treated melanoma, 804 with pembrolizumab-treated NSCLC, and 309 with docetaxel-treated NSCLC. OS was dose independent from 2 to 10 mg/kg for pembrolizumab-treated melanoma [HR ¼ 0.98; 95% confidence interval (CI), 0.94–1.02] and NSCLC (HR ¼ 0.98; 95% CI, 0.95–1.01); however, a strong CL 0 –OS association was identified for both cancer types (unadjusted melanoma HR ¼ 2.56; 95% CI, 1.72–3.80 and NSCLC HR ¼ 2.64; 95% CI, 1.94–3.57). Decreased OS in subjects with higher pembrolizumab CL 0 paralleled disease severity markers associated with end-stage cancer anorexia-cachexia syndrome. Correction for baseline prognostic factors did not fully attenuate the CL 0 –OS association (multivariate-adjusted CL 0 HR ¼ 1.64; 95% CI, 1.06–2.52 for melanoma and HR ¼ 1.88; 95% CI, 1.22–2.89 for NSCLC). Conclusions: These data support the lack of dose or exposure dependency in pembrolizumab OS for melanoma and NSCLC between 2 and 10 mg/kg. An association of pembrolizumab CL 0 with OS potentially reflects catabolic activity as a marker of disease severity versus a direct PK-related impact of pembrolizumab on efficacy. Similar data from other trials suggest such patterns of exposure–response confounding may be a broader phenomenon generalizable to antineoplastic mAbs.

Original languageEnglish (US)
Pages (from-to)5841-5849
Number of pages9
JournalClinical Cancer Research
Volume24
Issue number23
DOIs
StatePublished - Dec 1 2018

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Cachexia
Non-Small Cell Lung Carcinoma
Melanoma
Survival
Confidence Intervals
Neoplasms
Pharmacokinetics
docetaxel
pembrolizumab
Anorexia
Proportional Hazards Models
Antineoplastic Agents

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Pembrolizumab exposure–response assessments challenged by association of cancer cachexia and catabolic clearance. / Turner, David C.; Kondic, Anna G.; Anderson, Keaven M.; Robinson, Andrew G.; Garon, Edward B.; Riess, Jonathan; Jain, Lokesh; Mayawala, Kapil; Kang, Jiannan; Ebbinghaus, Scot W.; Sinha, Vikram; de Alwis, Dinesh P.; Stone, Julie A.

In: Clinical Cancer Research, Vol. 24, No. 23, 01.12.2018, p. 5841-5849.

Research output: Contribution to journalArticle

Turner, DC, Kondic, AG, Anderson, KM, Robinson, AG, Garon, EB, Riess, J, Jain, L, Mayawala, K, Kang, J, Ebbinghaus, SW, Sinha, V, de Alwis, DP & Stone, JA 2018, 'Pembrolizumab exposure–response assessments challenged by association of cancer cachexia and catabolic clearance', Clinical Cancer Research, vol. 24, no. 23, pp. 5841-5849. https://doi.org/10.1158/1078-0432.CCR-18-0415
Turner, David C. ; Kondic, Anna G. ; Anderson, Keaven M. ; Robinson, Andrew G. ; Garon, Edward B. ; Riess, Jonathan ; Jain, Lokesh ; Mayawala, Kapil ; Kang, Jiannan ; Ebbinghaus, Scot W. ; Sinha, Vikram ; de Alwis, Dinesh P. ; Stone, Julie A. / Pembrolizumab exposure–response assessments challenged by association of cancer cachexia and catabolic clearance. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 23. pp. 5841-5849.
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abstract = "Purpose: To investigate the relationship of pembrolizumab pharmacokinetics (PK) and overall survival (OS) in patients with advanced melanoma and non–small cell lung cancer (NSCLC). Patients and Methods: PK dependencies in OS were evaluated across three pembrolizumab studies of either 200 mg or 2 to 10 mg/kg every 3 weeks (Q3W). Kaplan–Meier plots of OS, stratified by dose, exposure, and baseline clearance (CL 0 ), were assessed per indication and study. A Cox proportional hazards model was implemented to explore imbalances of typical prognostic factors in high/low NSCLC CL 0 subgroups. Results: A total of 1,453 subjects were included: 340 with pembrolizumab-treated melanoma, 804 with pembrolizumab-treated NSCLC, and 309 with docetaxel-treated NSCLC. OS was dose independent from 2 to 10 mg/kg for pembrolizumab-treated melanoma [HR ¼ 0.98; 95{\%} confidence interval (CI), 0.94–1.02] and NSCLC (HR ¼ 0.98; 95{\%} CI, 0.95–1.01); however, a strong CL 0 –OS association was identified for both cancer types (unadjusted melanoma HR ¼ 2.56; 95{\%} CI, 1.72–3.80 and NSCLC HR ¼ 2.64; 95{\%} CI, 1.94–3.57). Decreased OS in subjects with higher pembrolizumab CL 0 paralleled disease severity markers associated with end-stage cancer anorexia-cachexia syndrome. Correction for baseline prognostic factors did not fully attenuate the CL 0 –OS association (multivariate-adjusted CL 0 HR ¼ 1.64; 95{\%} CI, 1.06–2.52 for melanoma and HR ¼ 1.88; 95{\%} CI, 1.22–2.89 for NSCLC). Conclusions: These data support the lack of dose or exposure dependency in pembrolizumab OS for melanoma and NSCLC between 2 and 10 mg/kg. An association of pembrolizumab CL 0 with OS potentially reflects catabolic activity as a marker of disease severity versus a direct PK-related impact of pembrolizumab on efficacy. Similar data from other trials suggest such patterns of exposure–response confounding may be a broader phenomenon generalizable to antineoplastic mAbs.",
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T1 - Pembrolizumab exposure–response assessments challenged by association of cancer cachexia and catabolic clearance

AU - Turner, David C.

AU - Kondic, Anna G.

AU - Anderson, Keaven M.

AU - Robinson, Andrew G.

AU - Garon, Edward B.

AU - Riess, Jonathan

AU - Jain, Lokesh

AU - Mayawala, Kapil

AU - Kang, Jiannan

AU - Ebbinghaus, Scot W.

AU - Sinha, Vikram

AU - de Alwis, Dinesh P.

AU - Stone, Julie A.

PY - 2018/12/1

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N2 - Purpose: To investigate the relationship of pembrolizumab pharmacokinetics (PK) and overall survival (OS) in patients with advanced melanoma and non–small cell lung cancer (NSCLC). Patients and Methods: PK dependencies in OS were evaluated across three pembrolizumab studies of either 200 mg or 2 to 10 mg/kg every 3 weeks (Q3W). Kaplan–Meier plots of OS, stratified by dose, exposure, and baseline clearance (CL 0 ), were assessed per indication and study. A Cox proportional hazards model was implemented to explore imbalances of typical prognostic factors in high/low NSCLC CL 0 subgroups. Results: A total of 1,453 subjects were included: 340 with pembrolizumab-treated melanoma, 804 with pembrolizumab-treated NSCLC, and 309 with docetaxel-treated NSCLC. OS was dose independent from 2 to 10 mg/kg for pembrolizumab-treated melanoma [HR ¼ 0.98; 95% confidence interval (CI), 0.94–1.02] and NSCLC (HR ¼ 0.98; 95% CI, 0.95–1.01); however, a strong CL 0 –OS association was identified for both cancer types (unadjusted melanoma HR ¼ 2.56; 95% CI, 1.72–3.80 and NSCLC HR ¼ 2.64; 95% CI, 1.94–3.57). Decreased OS in subjects with higher pembrolizumab CL 0 paralleled disease severity markers associated with end-stage cancer anorexia-cachexia syndrome. Correction for baseline prognostic factors did not fully attenuate the CL 0 –OS association (multivariate-adjusted CL 0 HR ¼ 1.64; 95% CI, 1.06–2.52 for melanoma and HR ¼ 1.88; 95% CI, 1.22–2.89 for NSCLC). Conclusions: These data support the lack of dose or exposure dependency in pembrolizumab OS for melanoma and NSCLC between 2 and 10 mg/kg. An association of pembrolizumab CL 0 with OS potentially reflects catabolic activity as a marker of disease severity versus a direct PK-related impact of pembrolizumab on efficacy. Similar data from other trials suggest such patterns of exposure–response confounding may be a broader phenomenon generalizable to antineoplastic mAbs.

AB - Purpose: To investigate the relationship of pembrolizumab pharmacokinetics (PK) and overall survival (OS) in patients with advanced melanoma and non–small cell lung cancer (NSCLC). Patients and Methods: PK dependencies in OS were evaluated across three pembrolizumab studies of either 200 mg or 2 to 10 mg/kg every 3 weeks (Q3W). Kaplan–Meier plots of OS, stratified by dose, exposure, and baseline clearance (CL 0 ), were assessed per indication and study. A Cox proportional hazards model was implemented to explore imbalances of typical prognostic factors in high/low NSCLC CL 0 subgroups. Results: A total of 1,453 subjects were included: 340 with pembrolizumab-treated melanoma, 804 with pembrolizumab-treated NSCLC, and 309 with docetaxel-treated NSCLC. OS was dose independent from 2 to 10 mg/kg for pembrolizumab-treated melanoma [HR ¼ 0.98; 95% confidence interval (CI), 0.94–1.02] and NSCLC (HR ¼ 0.98; 95% CI, 0.95–1.01); however, a strong CL 0 –OS association was identified for both cancer types (unadjusted melanoma HR ¼ 2.56; 95% CI, 1.72–3.80 and NSCLC HR ¼ 2.64; 95% CI, 1.94–3.57). Decreased OS in subjects with higher pembrolizumab CL 0 paralleled disease severity markers associated with end-stage cancer anorexia-cachexia syndrome. Correction for baseline prognostic factors did not fully attenuate the CL 0 –OS association (multivariate-adjusted CL 0 HR ¼ 1.64; 95% CI, 1.06–2.52 for melanoma and HR ¼ 1.88; 95% CI, 1.22–2.89 for NSCLC). Conclusions: These data support the lack of dose or exposure dependency in pembrolizumab OS for melanoma and NSCLC between 2 and 10 mg/kg. An association of pembrolizumab CL 0 with OS potentially reflects catabolic activity as a marker of disease severity versus a direct PK-related impact of pembrolizumab on efficacy. Similar data from other trials suggest such patterns of exposure–response confounding may be a broader phenomenon generalizable to antineoplastic mAbs.

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