1. NRG-LU001 Initial reporting of a randomized phase II trial of concurrent chemo-radiotherapy (CRT) +/- metformin in locally advanced Non-Small Cell Lung Cancer (NSCLC).
Theodoros Tsakiridis, Chen Hu, Heath Skinner, Rafael Santana-Davila, Bo Lu, Jeremy J Erasmus, Anthony J Doemer, Gregory M M Videtic, James Coster, Alex Xuexhong Yang, Richard Y Lee, Maria Werner-Wasik, Philip E Schaner, Steven E McCormack, Benjamin T Esparaz, Ronald C McGarry, Jose Bazan, Timothy Struve and Jeffrey D Bradley

2. Disclosures TT : Research Grant funding: Sanofi,
Honoraria: Sanofi, AbbVie, Astra Zeneca, Bayer
These are my disclosures

3. Rationale
Preclinical evidence suggested that metformin, which induces metabolic stress through blockade of mitochondria respiration, leads to:
activation of tumor suppressing pathways
blockade of mTORC1 and cell cycle
Inhibition of lung cancer proliferation
enhancement of NSCLC response
to chemotherapy and radiotherapy
Storozhuk et al (2013) British J Cancer, Troncone et l (2017) Oncotarget

4. NRG LU001: Protocol Schema
MET: metformin

5. NRG LU001 Metformin delivery

6. Statistical Considerations
Primary Objective
To determine whether metformin HCL added to chemo-radiotherapy can improve progression-free survival (PFS) in patients with locally advanced NSCLC.
Statistical Considerations
Study was designed to detect a 15% improvement in 12 month PFS (from 50 to 65%) or equivalently, a HR=0.622

7. Population ACCRUAL Opened August 2014 Closed December 2016
Primary Analysis: February 25, 2019
Population

8. Metformin Tolerability

9. Metformin Compliance

10. Progression-Free Survival
All Patients (ITT)
Metformin Per Protocol
60.4%
Locally Reported Outcomes

11. Locally Reported Outcomes
Overall Survival
All Patients (ITT)
Metformin Per Protocol
65.4%
Locally Reported Outcomes

12. Local-Regional Failure Distant Failure
All Patients (ITT)
All Patients (ITT)
Locally Reported Outcomes

13. Cause of Death

14. NRG-LU001 Conclusions
Metformin is well-tolerated by the majority of non-diabetic patients with NSCLC treated with standard chemo-radiotherapy
Reasons for reduced compliance with metformin treatment require further analysis
Addition of metformin during cytotoxic therapy did not improve center-reported PFS, OS, LRF or DM in this group of patients
Disease specific mortality was numerically lower in the metformin treated arm
Survival events are further evaluated with central radiology review and additional sensitivity analyses

15. NRG-LU001 Conclusions
Survival outcomes of standard of care chemo-radiotherapy were improved in NRG-LU001 compared to those observed in recently reported phase III trials
The results of this study demonstrate the efficiency and value of continued investigation of NSCLC in multi-institutional settings like NRG Oncology

16. Acknowledgements Author’s Affiliations
T. Tsakiridis1, C.Hu2, H. Skinner3, R. Santana-Davila4, B. Lu5, J.J Erasmus6, A.J. Doemer7, G.M.M.Videtic8, J.Coster9, A.X.Yang10, R.Y. Lee11, M.WernerWasik5, P.E. Schaner12, S.E. McCormack13, B.T. Esparaz14, R.C. McGarry15, J.Bazan16, T. Struve17 and J.D. Bradley18
1. Juravinski Cancer Centre at Hamilton Health Sciences; 2. NRG Oncology Statistics and Data Management Center; 3. UPMC Hillman Cancer Center; 4. Seattle Cancer Care Alliance; 5. Thomas Jefferson University Hospital; 6. M D Anderson Cancer Center; 7. Henry Ford Hospital; 8. Cleveland Clinic; 9. University of Kansas; 10. Saint Francis Cancer Center ; 11. The Cancer Center of Hawaii-Liliha; 12. Dartmouth-Hitchcock Medical Center; 13. Metro-Minnesota Community Oncology Research Consortium; 14. Heartland NCORP; 15. University of Kentucky/Markey Cancer Center; 16. Ohio State University Comprehensive Cancer Center; 17. University of Cincinnati/Barrett Cancer Center; 18. Siteman Cancer Center at Washington University
T. Tsakiridis and H. Skinner are Co-Principal Investigators in this trial
Grant/Sponsor Acknowledgements: National Cancer Institute (NCI) grants:
- U10CA (NRG Oncology Operations) U10CA (NRG SDMC)
- UG1CA (NCORP), U24CA (IROC)