Does denosumab offer survival benefits? —Our experience with denosumab in metastatic non-small cell lung cancer patients treated with immune-checkpoint inhibitors

Abstract

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small-cell lung cancer (NSCLC). Denosumab is a humanized monoclonal antibody to RANK ligand used to prevent skeletal-related events of bone metastases in solid tumors. We are reporting the clinical outcomes in our NSCLC patients who received RANKL inhibitor in combination with ICIs. Methods: This observational study used retrospective data from a tertiary cancer center from 2015-2020.Stage IV non-small cell lung cancer patients who received denosumab within 30 days of ICIs (pembrolizumab, nivolumab, atezolizumab, ipilimumab) were included. Kaplan-Meier curves were obtained for survival analysis. Results: We identified 69 patients and all had skeletal metastases, and 37.7% had brain metastases. Median OS was 6.3 months and median PFS was 2.8 months, with overall response rate (ORR) of 18.8% and disease control rate (DCR) of 40.6%. Median OS in patients with concomitant denosumab and ICIs more than 3 months was 11.5 months, comparing to 3.6 months in patients with <3 months of concomitant therapy (P=0.0005). OS and PFS did not differ with respect to brain metastases or number of skeletal metastases.However, the duration of ICIs and denosumab overlap was associated with improved OS and PFS. Among the 18.8% of patients who achieved complete response (CR) and partial response (PR), six-month survival rate was 100% and one-year survival rate was 69.2%. Most of the patients tolerated denosumab well, and hypocalcemia was the most commonly reported side effect. Conclusions: Patients receiving combination therapy did not perform poorly comparing to published studies despite of poor prognostic features such as brain metastases and numerous skeletal metastases. Although we did notice potential benefit of the longer duration of concomitant use of ICI and denosumab, future prospective clinical trials are needed to evaluate the synergistic effect of RANKL inhibitors/ICI and if duration of RANKL inhibitors matters.

Combination of Bone-Modifying Agents with Immunotarget Therapy for Hepatocellular Carcinoma with Bone Metastases

“…Theoretically, combining ICIs and RANKL inhibitors may convert the immunosuppressive bone microenvironment to a “hot” one, thus enhancing clinical responses in patients with advanced-stage cancers. The synergistic effect of BMA s+ ICIs has been reported by preclinical studies in other solid tumors (PC, NSCLC, and melanoma) with BoM [ 11 , 12 , 48 ], which demonstrated survival benefits and delay of primary tumor progression. In our study, the efficacy of BMAs with immunotargeted therapy and two types of BMAs in patients with HCC and BoM have been comprehensively evaluated.…”

“…There is evidence that regardless of the BoM burden of NSCLC patients, the longer time ICIs and denosumab were used concurrently, the more benefit could be achieved [ 12 , 48 , 49 ]. In clinical practice, patients with BoM may not receive sequential BMAs, especially patients with advanced stages and poor physical condition.…”

Does denosumab offer survival benefits? Our experience with denosumab in metastatic non-small cell lung cancer patients treated with immune-checkpoint inhibitors.

“…Overall, 11 (15.9%) of the patients received prior chemotherapy and 47 (68.1%) of the patients received radiation therapy. Median number of metastatic sites was 4 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]. All patients have skeletal metastases and majority of the patients had <3 skeletal metastases (62.3% vs. 37.7%).…”

“…According to a posthoc analysis of phase III clinical trial in metastatic lung cancer patients, median overall survival was 8.9 months for patients receiving denosumab compared with 7.7 months for patients receiving zoledronic acid (10). Udagawa et al reported that in chemotherapy naïve non-squamous nonsmall cell lung cancer patients with 80% having bone metastasis and unknown brain metastasis status, the median OS in the denosumab group, zoledronic acid group and no treatment group were 21.4 months, 12.7 months and 10.5 months, respectively (15). Liede and others reported that in NSCLC patients with 76% having Stage IV disease at diagnosis but unknown brain metastasis status, the ORR was 33.1% in patients treated concurrently with denosumab and anti-PD1 mAb (16).…”

Overall Survival Improvement in Patients with Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer and Bone Metastasis Treated with Denosumab

“…A small number of clinical studies have reported that denosumab is beneficial for the improvement of OS in NSCLC patients with bone metastasis [ 3 , 21 , 26 , 27 ]. The potential factors contributing to the survival benefit of denosumab remain unclear.…”