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OA12 - Profiling the Multidisciplinary Management of Stage III NSCLC (ID 144)
- Event: WCLC 2019
- Type: Oral Session
- Track: Treatment of Locoregional Disease - NSCLC
- Presentations: 1
- Now Available
OA12.03 - Initial Reporting of NRG-LU001, Randomized Phase II Trial of Concurrent Chemoradiotherapy +/- Metformin HCL in Locally Advanced NSCLC (Now Available) (ID 1868)
15:45 - 17:15 | Author(s): Theodoros Tsakiridis
Preclinical and retrospective clinical data, have shown that metformin, an inexpensive diabetes drug, has the potential to improve response to chemotherapy and radiation in several solid tumors, including non-small cell lung cancer (NSCLC). These findings led to NRG-LU001, a multi-institutional, international randomized Phase II clinical trial to determine whether metformin can improve outcomes of curative chemoradiation (CRT) in locally advanced NSCLC (LA-NSCLC).Method
Unresectable stage IIIA/B NSCLC patients were randomized to either concurrent chemoradiation to 60 Gy with weekly carboplatin-paclitaxel (CP), followed by consolidation CP (Control) or the same regimen combined with metformin (2000 mg/day) (Experimental). The primary endpoint was 1-year progression free survival (PFS). PFS and overall survival (OS) were estimated using the method of Kaplan-Meier. Time to loco-regional progression (TTLRP) or distant metastasis (TTDM) were estimated using the cumulative incidence method. Adverse events (AEs) were graded using CTCAE v4.0.Result
170 patients were randomized between Aug. 2014-Dec. 2016, with planned analysis at 102 events. No significant difference in toxicity was observed between Control and Experimental arms. 1- and 2-year PFS was 60.4% (95% CI: 48.5, 70.4) and 40.1% (95% CI: 29.0, 51.0) in Control vs 51.3% (95% CI: 39.8, 61.7) and 34.5% (95% CI: 24.2, 45.1) in the Experimental arm (multivariable Cox proportional HR=1.20 (95% CI: 0.81, 1.78), p=0.36). On multivariable analysis including treatment arm, performance status, histology and stage, only higher stage (IIIA vs. IIIB) was associated with worse PFS (HR 1.79, 95% CI:1.19, 2.69, p=0.0054). OS at 2 years was 65.4% (95% CI: 53.5, 75.0) for Control vs 64.9% (95% CI: 53.1, 74.5) for the Metformin arm (HR=1.03 (95% CI: 0.64, 1.68)), while deaths due to disease were 90% vs 71%, respectively. No significant differences were found for TTLRP (HR 1.01, 95% CI: 0.57, 1.79, p=0.98) or TTDM (1.38, 95% CI: 0.76, 2.5, p=0.29). 63.4% of patients in the experimental arm received the complete course of metformin, with the most common cause of discontinuation being side effects or complications (13.4%).
In NRG-LU001, concurrent CRT and metformin presented no noticeable safety concerns. However, this combination failed to improve PFS at the hypothesized effect size. Additionally, no effect on OS or patterns of failure were identified. Blinded central review of imaging based PFS is ongoing. Somewhat unexpectedly, 37% of patients did not complete the prescribed course of metformin. Additionally, deaths due to disease were less in the experimental arm compared to control.
Acknowledgements: This project was supported by National Cancer Institute (NCI) grants: U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG SDMC), UG1CA189867 (NCORP), U24CA180803 (IROC). HS and TT are Co-Principal Investigators in this trial.
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
P1.14-33 - Canagliflozin Inhibits Lung Cancer Survival and Enhances Its Response to Radiotherapy; Effective Blockade of mTOR Pathway, HIF1a, and Mitosis (ID 2493)
09:45 - 18:00 | Author(s): Theodoros Tsakiridis
Non-small cell lung cancer (NSCLC) presents frequently at an advanced stage where standard treatment with radiotherapy (RT) and chemotherapy (CT) provides limited benefit. Driver mutations and alterations of NSCLC cell metabolism contribute to rapid growth, resistance to cytotoxic therapy and survival. In normal cells, these events are controlled by the metabolic stress sensor AMP-activated protein kinase (AMPK), a key regulator of cell metabolism that also responds to cytotoxic therapy. AMPK induces a p53-mediated cycle checkpoint and inhibits the mammalian Target of Rapamycin (mTOR) pathway.
Canagliflozin (CANA), a new diabetes agent, was developed to target the renal Na+-glucose co-transporter 2 and control glycemia through blockade of glucose re-absorption. Earlier, we found that clinically achievable doses of CANA suppress cell survival, mainly through an off-target action, to block complex I of the mitochondria oxidative phosphorylation chain, leading to activation of AMPK. In the present study, we examined the CANA’s anti-tumor efficacy in combination with RT.Method
Adenocarcinoma (A549, H1299, H1975) and squamous cell carcinoma (SK-MES-1) NSCLC cells were subjected to proliferation, clonogenic survival and metabolic assays after combined CANA (0–30mM) and RT (0–16Gy) treatments. Immunodeficient nude mice were grafted with H1299 cells and treated with Canagliflozin (100 mg/kg/day by oral gavage) and/or RT (10 Gy). Cell and tumor lysates are analyzed with immunoblotting and immunohistochemistry.Result
At low micromolar doses achieved routinely in the circulation of diabetic patients, CANA inhibited proliferation and clonogenic survival of NSCLC cells and enhance NSCLC response to RT. In control and irradiated cells, CANA inhibited de novo lipogenesis and abolished histone H3 phosphorylation, an established marker of mitosis. This was associated with the induction of cyclin-dependent kinase inhibitor p27kip1. CANA activated AMPK and mediated effective suppression of the mammalian target of rapamycin (mTOR) pathway, with inhibitory Raptor phosphorylation and blockage of p70S6k and S6 phosphorylation. Importantly, CANA also blocked early signaling events of the Epidermal Growth Factor Receptor (EGFR) pathway such Shc, Gab and PLCg1 phosphorylation and suppressed HIF1a expression. CANA suppressed H1299 tumor growth. On-going experiments analyze tumors proliferation, angiogenesis, cell death, and microenvironment markers.Conclusion
Canagliflozin (CANA), an approved and well-tolerated diabetes drug suppresses proliferation, radio-resistance and survival pathways and improves NSCLC response to RT, at doses well within its therapeutic window. This suggests a strong potential for clinical development of CANA in combination with RT for the treatment of NSCLC.
Acknowledgments: This work was supported by an RFA grant from Hamilton Health Science and funds from Canadian Institutes for Health Research (CIHR).