Combination therapy with immune checkpoint inhibitors and denosumab improves clinical outcomes in non-small cell lung cancer with bone metastases.

The concomitant use of denosumab and immune checkpoint inhibitor (ICI) treatment may have synergistic effects and enhance antitumor activity; however, this has not been fully evaluated. This study aimed to evaluate the clinical outcomes of non-small cell lung cancer (NSCLC) patients with bone metastases receiving combination therapy and to identify the best combination regimen. Eighty-six NSCLC patients with bone metastases who received ICI treatment were enrolled in this study. The patients were divided into two groups; a denosumab combination group (D + ICI group; n = 47) and a non-combination group (non-D + ICI group; n = 39). The response rate (RR) for bone metastases, disease control rate (DCR), overall survival (OS), real world progression-free survival (rwPFS), and the incidence of immune-related adverse events (irAEs) were evaluated. Additionally, the time when denosumab treatment should commence and concomitant treatment duration were evaluated. The D + ICI group showed significantly better RR (40.4 % vs. 20.5 %, p = 0.01), DCR (67.3 % vs. 38.7 %, p = 0.02), OS (14.2 vs. 8.6 months, p = 0.02), and rwPFS (7.4 vs. 3.6 months, p < 0.01) than the non-D + ICI group; however, incidence of irAEs showed no difference (29.7 % vs. 12.8 %, p = 0.07). Although clinical outcomes did not differ regardless of whether denosumab was initiated before or after ICI treatment, the group that received concomitant denosumab for more than four months had significantly better RR (46.2 % vs. 17.4 %, p = 0.03), OS (20.3 vs. 3.8 months, p < 0.01), and rwPFS (10.9 vs. 2.8 months, p < 0.01) than the group that received concomitant denosumab for less than four months. However, the landmark analysis showed no significant differences in OS (20.4 vs. 12.7 months, p = 0.11) and rwPFS (22.8 vs. 11.2 months, p = 0.21), and the results of denosumab duration were influenced by long-term survivors. Denosumab showed favorable synergistic effects with ICI treatment and may significantly improve the response to bone metastasis and prognosis without increasing the incidence of irAEs.

Asano Y ，Yamamoto N ，Demura S ，Hayashi K ，Takeuchi A ，Kato S ，Miwa S ，Igarashi K ，Higuchi T ，Taniguchi Y ，Okuda M ，Matsumoto I ，Yano S ，Tsuchiya H ... -  《-》

Immune Checkpoint Inhibitors With or Without Bone-Targeted Therapy in NSCLC Patients With Bone Metastases and Prognostic Significance of Neutrophil-to-Lymphocyte Ratio.

Bone metastases (BMs) are a negative prognostic factor in patients with non-small cell lung cancer (NSCLC). Although immune-checkpoint inhibitors (ICIs) have dramatically changed the therapeutic landscape of NSCLC, little information is available on BMs from NSCLC treated with ICIs alone or in association with bone-targeted therapy (BTT) such as zoledronate or denosumab. From 2014 to 2020, 111 of the 142 patients with BMs secondary to NSCLC extrapolated from the prospective multicenter Italian BM Database were eligible for analysis. Information on blood count, comorbidities, and toxicity was retrospectively collected. The neutrophil-to-lymphocyte ratio (NLR) pre- and post-treatment was calculated. Survival was analyzed using the Kaplan-Meier method, with statistical significance of survival differences assessed using the log-rank test. Median age was 66 (range, 42-84) years. Performance status (PS) Eastern Cooperative Oncology Group (ECOG) was 0-1 in 79/111 patients. The majority of patients (89.2%) had adenocarcinoma histology. At a median follow-up of 47.4 months, median progression-free (mPFS) and overall survival (mOS) was 4.9 (95%CI, 2.8-10.0) and 11.9 (95%CI, 8.2-14.4) months, respectively. Forty-six (43.4%) patients with BM NSCLC underwent first- or further-line therapy with ICIs: 28 (60.8%) received nivolumab, 9 (19.6%) pembrolizumab, and 9 (19.6%) atezolizumab. Of the 46 patients treated with ICIs, 30 (65.2%) underwent BTT: 24 (80.0%) with zoledronate and 6 (20.0%) with denosumab. The ICI-alone group had an mOS of 15.8 months [95%CI, 8.2-not evaluable (NE)] vs. 21.8 months (95%CI, 14.5-not evaluable) for the ICI plus BTT group and 7.5 (95%CI, 6.1-10.9) months for the group receiving other treatments (p < 0.001). NLR ≤5 had a positive impact on OS. BTT appears to have a synergistic effect when used in combination with ICIs, improving patient survival.

Bongiovanni A ，Foca F ，Menis J ，Stucci SL ，Artioli F ，Guadalupi V ，Forcignanò MR ，Fantini M ，Recine F ，Mercatali L ，Spadazzi C ，Burgio MA ，Fausti V ，Miserocchi A ，Ibrahim T ... -  《Frontiers in Immunology》

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

Bone metastasis (BoM) is common in patients with advanced non-small cell lung cancer (NSCLC) and considered as one of the negative prognostic factors. However, the impact of BoM on clinical outcomes of patients with advanced NSCLC treated with immune checkpoint inhibitors (ICIs) remains unclear. A total of 103 patients treated with ICI monotherapy and 101 patients treated with ICIs combined with chemotherapy or antiangiogenesis therapy were retrospectively analyzed. The differences in progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) between BoM+ and BoM- were investigated. Of those 101 patients who received combination therapy, no significant difference between BoM- and BoM+ in terms of both median PFS and median OS (median PFS, 10.1 vs. 12.1 months, P = 0.6; median OS, NR vs. 24.6 months, P = 0.713) was determined. In contrast, of the 103 patients who received ICI monotherapy, BoM+ patients had an inferior PFS (4.2 vs. 6.7 months, P = 0.0484) and OS (12.5 vs. 23.9 months, P = 0.0036) compared with BoM- patients. The univariate and multivariate analysis in the ICI monotherapy group also identified BoM as an independent factor attenuating the efficacy of ICI monotherapy. Of all BoM+ patients who received ICI monotherapy, neither palliative radiotherapy nor bisphosphonate drugs improved OS (palliative radiotherapy: 12.5 vs. 16.7 months, P = 0.487; bisphosphonate drugs: 12.5 vs. 9.7 months, P = 0.568). BoM attenuated the efficacy of ICI monotherapy in patients with advanced NSCLC. Of BoM+ patients who received ICI monotherapy, neither palliative radiotherapy nor bisphosphonate drugs improved OS. Other therapeutic strategies are needed for patients with BoM.

Li X ，Wang L ，Chen S ，Zhou F ，Zhao J ，Zhao W ，Su C ... -  《-》

Clinical outcomes for immune checkpoint inhibitors plus chemotherapy in non-small-cell lung cancer patients with uncommon driver gene alterations.

Qin H ，Yan H ，Chen Y ，Xu Q ，Huang Z ，Jiang W ，Wang Z ，Deng L ，Zhang X ，Zhang L ，Yang N ，Zeng L ，Zhang Y ... -  《BMC CANCER》

Impact of denosumab use on the survival of untreated non-squamous non-small cell lung cancer patients with bone metastases.

Udagawa H ，Niho S ，Kirita K ，Umemura S ，Matsumoto S ，Yoh K ，Goto K ... -  《-》