Bisphosphonates enhance EGFR-TKIs efficacy in advanced NSCLC patients with EGFR activating mutation: A retrospective study

Abstract

BackgroundBisphosphonates have exhibited anti-tumor activity in non-small cell lung cancer (NSCLC). We aimed to evaluate whether the combination of bisphosphonates with tyrosine kinase inhibitors of EGFR (EGFR-TKIs) could obtain a synergistic effect on advanced NSCLC patients with EGFR mutations.MethodsBetween January 2008 and October 2013, 114 advanced EGFR mutations NSCLC patients who received EGFR-TKIs as first-line therapy were recruited from two cancer centers. Patients were separated into EGFR-TKIs alone or EGFR-TKIs plus bisphosphonates (combination) group. Median progression free survival (mPFS), median overall survival (mOS) distributions and survival curves were analyzed.ResultsAmong the 114 patients, 62 had bone metastases (19 patients treated with EGFR-TKIs, 43 patients treated with EGFR-TKIs + bisphosphonates). Median PFS and OS were significantly improved in combination group compared with EGFR-TKIs group (mPFS: 15.0 vs 7.3 months, P = 0.0017; mOS: 25.2 vs 10.4 months, P = 0.0015) in patients with bone metastases. Among the 71 patients (19 patients with bone metastases) treated with EGFR-TKIs alone, patients with bone metastases had poor survival prognosis (mPFS:7.3 vs 12.1 months, P = 0.0434; mOS:10.4 vs 22.0 months, P = 0.0036). The survival of patients with bone metastases who received EGFR-TKIs plus bisphosphonates therapy was non-inferior to patients without bone metastases treated with EGFR-TKIs alone (mPFS: 15.0 vs 12.1 months, p = 0.1871; mOS: 25.2 vs 22.0 months, p = 0.9798).ConclusionsConcomitant use of bisphosphonates and EGFR-TKIs improves therapeutic efficacy and brings survival benefits to NSCLC patients with EGFR mutation and bone metastases.

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

“…Several preclinical studies found that bisphosphonates could enhance the effects of EGFR-TKIs on EGFR mutant NSCLC both in vitro and in vivo 18 20 . In clinical setting, a small cohort study with limited cases also showed that EGFR-TKIs plus bisphosphonates could significantly prolong PFS and OS in patients with EGFR mutant NSCLC and BM than those received EGFR-TKIs alone as the first-line therapy (PFS: 15.0 vs 7.3 months, P = 0.03; OS: 25.2 vs 10.4 months, P = 0.0015) 19 . In line with these studies, the present study also found that EGFR-TKIs plus bisphosphonates could prolong PFS than EGFR-TKIs alone (mPFS: 11.6 vs 9.2 months, P = 0.006).…”

“…In the past few years, dramatic improvement has been achieved for patients who get acquired resistance of EGFR-TKI due to the implementation of novel therapeutic strategies such as local therapies, anti-angiogenesis and third-generation EGFR-TKI. The patients enrolled into this study were chronological later than the patients in the previous study 19 . Thus, the treatment beyond the disease progression of EGFR-TKI might contribute the discrepancy.…”

“…Systemic chemotherapy is still the main therapeutic choice for advanced NSCLC without driver mutations. Several preclinical studies indicated that bisphosphonates could induce tumor cells apoptosis, inhibit tumor cell invasion and metastasis, affect immune microenvironment and therefore have antitumor effects in a variety of tumors, including NSCLC 18 19 21 22 . While in clinical setting, a recent randomized phase II study failed to show the ability of zoledronic acid to augment the cytotoxic effects of the combination of docetaxel/carboplatin and to delay disease progression in patients with inoperable stage IIIB or IV NSCLC 23 .…”

“…Furthermore, preclinical data also showed that bisphosphonates could enhance the inhibitory effects of EGFR-TKIs on NSCLC with EGFR mutation both in vitro and in vivo 18 . In clinical setting, a retrospective study with a small cohort of 62 cases found that bisphosphonates plus EGFR-TKIs had statistically significantly longer progression-free survival (PFS) and OS than EGFR-TKIs alone (median PFS: 15.0 vs 7.3 months, P = 0.03; OS: 25.2 vs 10.4 months, P = 0.0015) 19 . However, this study could just present a clue of bisphosphonates on EGFR TKI due to the limited cases and larger cohorts study is needed to further validate the role of bisphosphonates 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.…”