Reporting of Incidence and Outcome of Bone Metastases in Clinical Trials Enrolling Patients with Epidermal Growth Factor Receptor Mutated Lung Adenocarcinoma—A Systematic Review

Abstract

Bone metastases, occurring in 30–60% of patients with non-small cell lung cancer (NSCLC), are associated with decreased survival, cancer-induced bone pain, and skeletal-related events (SREs). Those with an activating epidermal growth factor mutation (EGFR+) seem to be more prone to develop bone metastases. To gain more insight into bone metastases-related outcomes in EGFR+ NSCLC, we performed a systematic review on Pubmed (2006–2021). Main inclusion criteria: prospective, phase II/III trials evaluating EGFR-tyrosine kinase inhibitors, ≥10 EGFR+ patients included, data on bone metastases and/or bone-related outcomes available. Out of 663 articles, 21 (3176 EGFR+ patients) met the eligibility criteria; 4 phase III (one double blind), 17 phase II trials (three randomized) were included. In seven trials dedicated bone imaging was performed at baseline. Mean incidence of bone metastases at diagnosis was 42%; 3–33% had progression in the bone upon progression. Except for one trial, it was not specified whether the use of bone target agents was permitted, and in none of the trials, occurrence of SREs was reported. Despite the high incidence of bone metastases in EGFR+ adenocarcinoma, there is a lack of screening for, and reporting on bone metastases in clinical trials, as well as permitted bone-targeted agents and SREs.

Incidence of Bone Metastases and Skeletal-Related Events in Patients With EGFR-Mutated NSCLC Treated With Osimertinib

“…Baseline and cumulative incidence of bone metastases and SREs is high in patients with EGFR+ metastatic NSCLC treated with first- and second-generation EGFR TKIs, and therefore, better treatment options are necessary. 11 We found that most patients (45%) already had bone metastases at first diagnosis of metastatic NSCLC, and this percentage increased to 51% at initiation of osimertinib if patients were treated with osimertinib in second line and beyond. At diagnosis of metastatic EGFR+ NSCLC, 15% of patients with bone metastases were diagnosed with having an SRE, and the cumulative incidence increased to 39%.…”

“…In other series (including a systematic review) evaluating EGFR TKI trials (N = 1196) and several retrospective series evaluating patients (N = 126–1081) treated with EGFR TKI, the percentage of patients with bone metastases at diagnosis of metastatic NSCLC was similar to our study ( Supplementary Table 1 ). 11 , 23 Nevertheless, data about bone progression and development of SREs during EGFR TKI treatment are scarce. 11 The percentage of patients who develop bone progression during osimertinib in our series is comparable with that of a smaller series (N = 126) evaluating outcomes on first-line osimertinib (10% versus 12%) and with trials evaluating first- and second-generation EGFR TKIs (11% versus 3%–26%) ( Supplementary Table 1 ).…”

“… 10 The incidence of SREs in this patient population is high (24%–58%). 1 , 11 In a retrospective series (N = 189), incidence and time to first SRE were similar between patients with EGFR +, KRAS +, and EGFR/KRAS wild-type NSCLC when treated with first-/second-generation EGFR TKI or chemotherapy, respectively. 1 Nevertheless, patients with EGFR + NSCLC had a significantly longer post-metastatic bone disease survival compared with the other patients (median 15 mo [ EGFR +], 9.0 mo [ KRAS +], and 3.2 mo [ EGFR/KRAS wild type]), ( EGFR+ - KRAS+ , p = 0.049, EGFR+ - EGFR+ /KRAS+ wildtype, p = 0.004).…”

“…Reporting of prevalence of bone metastases, SREs and bone-specific outcomes in patients with EGFR+ NSCLC in clinical trials evaluating EGFR TKIs, including osimertinib, is lacking. 11 Therefore, we performed this multicenter cohort study to evaluate bone metastases-related outcomes in patients treated with osimertinib.…”

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

“…Randomized clinical trials have shown that front-line treatment with first-, second-, and third-generation EGFR -tyrosine kinase inhibitors (TKIs) greatly improved the survival outcomes of advanced EGFR -mutated NSCLC patients [ 5 ]. However, investigations about the prognosis of EGFR -mutated NSCLC patients with bone metastasis are limited [ 7 ].…”