1335P - The relationship between nivolumab pharmacokinetics and cancer cachexia biomarkers in patients with metastatic non-small cell lung cancer (NSCLC)

Background

In patients with NSCLC, a strong inverse relationship between nivolumab clearance and response has been observed, with cachexia as a proposed confounding factor. To further explore underlying mechanisms, we assessed the relationship between nivolumab pharmacokinetics (PK), body composition and serum cachexia biomarkers.

Methods

Patients with advanced NSCLC treated with nivolumab monotherapy according to standard of care were included. The model structure was obtained from a published PK-model. Clearance and covariate relationships (cachexia parameters and patients characteristics) were stepwise assessed in this cohort. At baseline, C-reactive protein (CRP), interleukin (IL)6, growth differentiation factor (GDF) 15 and -8, adiponectin and leptin were measured. Skeletal muscle mass (SMM), subcutaneous and visceral adipose tissue (SAT and VAT) were measured at the first lumbar vertebra on computed tomography images at baseline, week 6, and week 12 and adjusted for height squared (SMMi, VATi, SATi). Early body weight loss was defined as >2% weight loss during the first 42 (±10) days.

Results

Out of 154 patients, 149 provided samples for nivolumab PK analysis, and 117 for serum cachexia biomarkers. Nivolumab clearance showed a significant positive association with GDF15 (p< 0.001) and CRP (p<0.001). Men showed higher clearance compared to women (p< 0.001). Weight loss and changes in SMMi were not significantly associated with clearance. The median concentration of GDF15 was 2406 pg/ml (IQR 1655-3900). Similar GDF15 concentrations were found in patients with early weight loss. Patients with elevated GDF15 levels ( >2000 pg/ml) had significantly worse overall survival (HR = 1.70, 95%CI 1.13-2.54).

Conclusions

Baseline GDF15 was significantly associated with nivolumab clearance and with poor survival in patients with advanced NSCLC. As GDF15 is known to inhibit immune infiltration in tumors and to induce cachexia, this might be the strongest confounder between nivolumab clearance and survival. Future research is required to explore how GDF15 production is stimulated and to unravel its exact biological mechanism of action.

Clinical trial identification

NL-OMON27631, Date of registration: 06-02-2018.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

J. Degens: Financial Interests, Institutional, Advisory Board: Johnson & Johnson; Financial Interests, Institutional, Speaker, Consultant, Advisor: BMS. D.W. Dumoulin: Financial Interests, Personal, Advisory Board: Amgen, Bristol Myers Squibb; Financial Interests, Institutional, Other, preceptorship: MSD; Financial Interests, Institutional, Funding: Bristol Myers Squibb. W.V.D. Worp: Financial Interests, Personal and Institutional, Funding: Danone Nutricia Research. L.E. Hendriks: Financial Interests, Institutional, Advisory Board: Amgen, Boehringer Ingelheim, Lilly, Novartis, Pfizer, Takeda, Merck, Janssen, MSD, AnHeart; Financial Interests, Institutional, Invited Speaker, for educational webinar: AstraZeneca, Lilly; Financial Interests, Institutional, Invited Speaker, educational webinar/interview: Bayer; Financial Interests, Institutional, Invited Speaker, Educationals: MSD; Financial Interests, Personal, Invited Speaker, for webinars: Medtalks; Financial Interests, Personal, Invited Speaker, payment for post ASCO round table discussion: VJOncology; Financial Interests, Personal, Invited Speaker, payment for post ASCO/ESMO/WCLC presentations, educational committee member: benecke; Financial Interests, Institutional, Invited Speaker, payment for post ESMO/ASCO discussion: high5oncology; Financial Interests, Institutional, Other, podcast on brain metastases: Takeda; Financial Interests, Institutional, Other, educational webinar: Janssen; Financial Interests, Institutional, Invited Speaker, satellite symposium at conference: GSK, Sanofi; Financial Interests, Personal, Invited Speaker, presentation guideline: Medimix; Financial Interests, Institutional, Invited Speaker, podcast and educational: Pfizer; Financial Interests, Personal, Other, member of the committee that revised these guidelines: Dutch guidelines NSCLC, brain metastases and leptomeningeal metastases; Financial Interests, Institutional, Research Grant, for IIS: Roche, Boehringer Ingelheim, AstraZeneca, Takeda, Novartis; Financial Interests, Institutional, Research Grant, donation for health care improvement project: Merck; Financial Interests, Institutional, Research Grant, funding for healthcare improvement project: Pfizer; Financial Interests, Institutional, Research Grant, for IIS, under negotiation: gilead; Financial Interests, Institutional, Local PI: AstraZeneca, GSK, Novartis, Merck Serono, Roche, Takeda, Blueprint Medicines, Mirati, AbbVie, MSD, Gilead; Non-Financial Interests, Other, Chair metastatic NSCLC for lung cancer group: EORTC; Non-Financial Interests, Other, secretary NVALT studies foundation: NVALT; Non-Financial Interests, Other, vice chair scientific committee: Dutch Thoracic Group. C.H. Van Der Leest: Financial Interests, Institutional, Advisory Board: MSD, BMS. J.G. Aerts: Financial Interests, Institutional, Advisory Board: AstraZeneca, Pamgene; Financial Interests, Personal, Advisory Board: MSD, Eli Lilly, CureVac; Financial Interests, Personal, Invited Speaker: AstraZeneca, Eli Lilly; Financial Interests, Personal, Other, Inventor/medical advisor: Amphera; Financial Interests, Personal, Stocks/Shares, value is undetermined: Amphera; Financial Interests, Institutional, Royalties, and personal if granted: Amphera; Financial Interests, Institutional, Local PI: Eli Lilly, Novartis, verastem, MSD; Financial Interests, Institutional, Coordinating PI: BMS, AstraZeneca; Financial Interests, Institutional, Funding: Nutricia/Danone; Non-Financial Interests, Member of Board of Directors: Int Ass for the study of Lung Cancer (AISLC, Int Mesothelioma Interest Group. R.H. Mathijssen: Financial Interests, Institutional, Invited Speaker: Bayer, Novartis; Financial Interests, Institutional, Advisory Board: Servier, NaDeNo Nanoscience; Financial Interests, Institutional, Research Grant, Investigator-initiated research: Astellas, Bayer, Cristal Therapeutics, Pfizer, Roche, Sanofi, Servier, Boehringer-Ingelheim, Novartis, Nordic Pharma; Financial Interests, Institutional, Coordinating PI: Pamgene; Financial Interests, Institutional, Funding: Echo Pharmaceuticals, Deuter Oncology. A.C. Dingemans: Financial Interests, Institutional, Advisory Board: Roche, Amgen, Bayer, AstraZeneca, Boehringer Ingelheim, Jansen, Mirati; Financial Interests, Institutional, Invited Speaker: Lilly, Jansen; Financial Interests, Institutional, Other, IDMC: Roche; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Local PI: Lilly, Amgen, Daiichi Sankyo, JNJ, Mirati; Financial Interests, Institutional, Coordinating PI: Roche; Financial Interests, Institutional, Steering Committee Member: Roche; Non-Financial Interests, Other, Chair EORTC lung cancer group: EORTC; Non-Financial Interests, Member: IASCL, ASCO, AACR. S. Bins: Financial Interests, Institutional, Research Grant: Nordic Pharma. All other authors have declared no conflicts of interest.