Bisphosphonates enhance antitumor effect of EGFR-TKIs in patients with advanced EGFR mutant NSCLC and bone metastases

Abstract

Whether bisphosphonates could enhance the effect of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC) patients with EGFR mutation and bone metastases (BM) remains unknown. EGFR mutation status were collected from 1560 patients with NSCLC and BM. 356 NSCLC patients with EGFR mutation and BM were identified. Among them, 91 patients received EGFR-TKIs alone and 105 patients received EGFR-TKIs plus bisphosphonates as first-line therapy. Comparing to TKIs alone, EGFR-TKIs plus bisphosphonates had a statistically significant longer progression-free survival (PFS: 11.6 vs. 9.3 months; HR = 0.68, P = 0.009), while a similar overall survival (OS: 20.5 vs. 19.5 months; HR = 0.95, P = 0.743) in patients with EGFR-mutant NSCLC and BM. The incidence of skeletal-related events in combined group was numerically lower than that in EGFR-TKIs alone group (29.7% vs. 39.4%, P = 0.147). In multivariate analysis, EGFR mutation was found to be a significant independent prognostic factor for OS in NSCLC patients with BM (HR = 0.710, P = 0.021). In conclusion, EGFR mutation was the significant independent prognostic factor for OS and the addition of bisphosphonates to EGFR-TKIs could enhance the antitumor effect of EGFR-TKIs in patients with EGFR-mutant NSCLC and BM.

Adverse impact of bone metastases on clinical outcomes of patients with advanced non‐small cell lung cancer treated with immune checkpoint inhibitors

“…Nevertheless, a series of prospective clinical studies are ongoing to investigate the synergistic effect of immunotherapy-radiotherapy strategies in patients with advanced NSCLC. 36 We have demonstrated that concomitant use of bisphosphonates and EGFR-TKIs brings survival benefits to NSCLC patients with EGFR mutations and bone metastases, 37,38 but there are few clinical data on proving the synergistic effect of immunotherapy and bisphosphonates in NSCLC. Interestingly, a recent study revealed that increased T h 17 cells and lack of T h 1 cells in bone marrow confers resistance to ICI treatment in prostate cancer and anti-TGF-β antibodies rather than anti-RANKL antibodies potentiates ICI efficacy by restoring T h 1 lineage polarization, 28 suggesting a potential role of TGF-β inhibitors in patients with BoM.…”

Retrospective study on the efficacy of bisphosphonates in tyrosine kinase inhibitor‑treated patients with non‑small cell lung cancer exhibiting bone metastasis

“…A retrospective study of 62 patients with NSCLC exhibiting BM demonstrated that, in comparison with the EGFR TKI alone regimen group, the EGFR TKI plus Bps group exhibited significantly prolonged PFS and OS time (mPFS: 15.0 vs. 7.3 months; P=00017 and mOS: 25.2 vs. 10.4 months; P=0.0015) (12). However, another retrospective study involving 356 patients with NSCLC exhibiting BM demonstrated that the EGFR-TKI plus Bps group had a statistically significantly longer PFS time (PFS: 11.6 vs. 9.3 months; HR, 0.68; P=0.009) but similar OS time (OS: 20.5 vs. 19.5 months; HR, 0.95; P=0.743) in patients with EGFR-mutant NSCLC and BM (13). As in the two aforementioned retrospective studies, the present study also demonstrated that in the genetic mutation group, Bps could enhance the antitumor effect of TKIs (including EGFR TKIs and ALK TKIs) to prolong PFS time in patients with NSCLC exhibiting BM, and numerically better BM-OS time was also observed.…”

“…In 2015, a retrospective study of 62 patients with NSCLC exhibiting BM demonstrated that significantly prolonged progression-free survival (PFS) time and OS time were achieved in patients treated with a combination of EGFR TKI and Bps in comparison with patients treated with EGFR TKI monotherapy [median (m)PFS: 15.0 vs. 7.3 months; P=0.03 and OS, 25.2 vs. 10.4 months; P=0.0015] (12). Another retrospective study that included 356 patients with NSCLC exhibiting BM reported that in comparison with EGFR TKI monotherapy, EGFR TKI in combination with Bps demonstrated longer PFS time [11.6 vs. 9.3 months; hazard ratio (HR), 0.68; P=0.009] (13). However, in comparison with the previously discussed retrospective study, contradictory results of OS time were observed in that no significant difference was observed in OS between the study group and the control group (20.5 vs. 19.5 months; HR, 0.95; P=0.743) (13).…”

“…Another retrospective study that included 356 patients with NSCLC exhibiting BM reported that in comparison with EGFR TKI monotherapy, EGFR TKI in combination with Bps demonstrated longer PFS time [11.6 vs. 9.3 months; hazard ratio (HR), 0.68; P=0.009] (13). However, in comparison with the previously discussed retrospective study, contradictory results of OS time were observed in that no significant difference was observed in OS between the study group and the control group (20.5 vs. 19.5 months; HR, 0.95; P=0.743) (13).…”

Zoledronic acid re‑sensitises gefitinib‑resistant lung cancer cells by inhibiting the JAK/STAT3 signalling pathway and reversing epithelial‑mesenchymal transition

“…Clinical research has shown that bisphosphonates may exert antitumour effects and delay the progression of NSCLC ( 13 ). Our study, and another retrospective clinical study, demonstrated that ZA prolonged the overall survival (OS) of bone metastatic NSCLC patients receiving TKI as first-line therapy ( 13 , 14 ).…”