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 language | English (US) |
|---|---|
| Pages (from-to) | 5841-5849 |
| Number of pages | 9 |
| Journal | Clinical Cancer Research |
| Volume | 24 |
| Issue number | 23 |
| DOIs | |
| State | Published - Dec 1 2018 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
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 journal › Article
}
TY - JOUR
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
Y1 - 2018/12/1
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.
UR - http://www.scopus.com/inward/record.url?scp=85057817109&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85057817109&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-18-0415
DO - 10.1158/1078-0432.CCR-18-0415
M3 - Article
C2 - 29891725
AN - SCOPUS:85057817109
VL - 24
SP - 5841
EP - 5849
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 23
ER -