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Sangtian Liu
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P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 2
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P76.07 - Metformin Enhances the Efficacy of EGFR-TKIs in Advanced Non-Small Cell Lung Cancer Patients With Type 2 Diabetes Mellitus (ID 897)
00:00 - 00:00 | Author(s): Sangtian Liu
- Abstract
Introduction
Lung cancer remains the leading cause of cancer-related mortality around the world. Despite epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) therapy have shown remarkable clinical efficacy in non-small cell lung cancer (NSCLC) patients, resistance is almost inevitable and is still a major obstacle. Studies have suggested that the prolonged use of metformin, a common oral anti-diabetes agent, also an IGF-1R inhibitor, is associated with survival benefits among NSCLC Type 2 diabetes mellitus (T2DM) patients. However, the clinical efficacy of metformin and EGFR-TKIs in combination, especially third-generation TKIs, on NSCLC patients with T790M mutation has not been well validated. Therefore, we retrospectively reviewed the effect of metformin use on the clinical efficacy of EGFR-TKIs in NSCLC patients with T2DM, and we also carried out in vitro experiment to demonstrate the effects of metformin in EGFR-TKI resistant cell lines in aspect of proliferation and apoptosis.
Methods
We retrospectively reviewed clinicopathological characteristics and response of NSCLC patients with type 2 diabetes mellitus (T2DM) who received EGFR-TKIs treatment. Therapeutic outcome including objective response rate (ORR), median progression-free survival (PFS) and overall survival (OS) of first-line EGFR-TKIs and second-line osimertinib were compare between patients received metformin and other anti-diabetes drugs. In addition, the effect of metformin on gefitinib-resistant cell line PC9R and osimertinib-resistant cell line PC9R/OR was examined in vitro using Cell Counting Kit-8, and apoptosis analysis, the IC 50, apoptosis rate and combination index (CI) was calculated.
Results
In fist-line EGFR-TKIs treatment, ORR in metformin use group was significantly higher (85.7% vs. 47.4%, p=0.001). The PFS1 and OS1 in metformin use group were significantly longer (21.6 months vs. 9.2 months, p =0.000; 48.4 months vs. 36.6 months, p =0.049). Further analysis revealed that metformin obviously prolonged the median PFS2 of osimertinib treatment among patients who progressed to prior line EGFR-TKIs with T790M. In vitro analysis, metformin showed synergistic interaction both with gefitinib in PC9R (CI=0.77) and with osimertinib in PC9R/OR (CI=0.77) in proliferation inhibition analysis. Metformin can also augment apoptosis effect of these TKI-resistant cells to EGFR-TKIs in vitro (p<0.05).
Conclusion
The results of our study suggest metformin use could be beneficial to NSCLC patients with T2DM treated with either first-line EGFR-TKIs or second-line osimertinib treatment.
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P76.11 - Patients With Short PFS to EGFR-TKIs Predicted Better Response to Subsequent Anti-PD-1/PD-L1 Based Immunotherapy in EGFR Mutated NSCLC (ID 1032)
00:00 - 00:00 | Presenting Author(s): Sangtian Liu
- Abstract
Introduction
Several studies and meta-analysis have confirmed that non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) sensitive mutation can’t benefit from anti-PD1/PD-L1 monotherapy. Our previous study confirmed that anti-PD1/PD-L1 with chemotherapy have survival benefit in EGFR-TKI resistant patients. While which subgroup of EGFR mutated patients could benefit from anti-PD1/PD-L1 based treatment is not clear.
Methods
Advanced NSCLC patients harboring EGFR sensitive mutations (19DEL/L858R) after resistant to EGFR-TKIs and received anti-PD1/PD-L1 based treatment any lines were retrospectively analyzed from January 2016 to June 2019. Clinical characteristics, progress-free-survival (PFS), objective response rate (ORR) and treatment-related side effects were recorded for all patients.
Results
Fifty-eight patients with EGFR sensitive mutation treated with PD-1/PD-L1 based treatment were enrolled. The median age was 58.8 years old. Male accounted for 56.9%. 84.5% were never smoker, 48.3% were 19DEL and 51.7% were L858R. 93.1% were stage IV. Among them, 43.1% of patients received ICIs in second line. Most of them (52/58, 89.7%) received combination treatment including 48 of them combined with chemotherapy and 4 of them combined with antiangiogenic therapy. The median PFS of previous EGFR-TKIs treatment (TKI-PFS) and anti-PD-1/PD-L1 based immunotherapy (IO-PFS) was 10.4 months and 5.5 months respectively. Correlation analysis showed that the TKI-PFS had an obvious negative relevance with the corresponding IO-PFS. Then we divided patients into long and short group with TKI-PFS cutoff at 10 months. Uni- and multivariate analysis demonstrated that TKI-PFS less than 10 months was independently associated with better clinical outcomes from subsequent immunotherapy. Kaplan-Meier analysis showed that patients with TKI-PFS < 10 months had a significantly longer IO-PFS than those ≥ 10 months, with median IO-PFS of 15.1 versus 3.8 months respectively (HR, 0.27, p=0.003). The ORR of immunotherapy was 31.8% in short TKI-PFS group and 10% in long TKI-PFS group (p=0.04). Subgroup analysis of IO-PFS showed a high consistency with the overall study, as no matter with age < 65 years old, male, no smoker, ECOG PS0-1, EGFR 19DEL or L858R, treated with gefitinib or erlotinib, received immunotherapy in second line or third line and beyond, the results significantly favored patients with TKI-PFS < 10 months.
Conclusion
The PFS of EGFR-TKIs is an independent predictive marker for subsequent IO combination treatment in EGFR mutated patients after resistant to EGFR-TKI. EGFR mutated NSCLC patients with short PFS to EGFR-TKIs conferred better response to following anti-PD-1/PD-L1 based immunotherapy. The underlying mechanism need to be further explored.
