Bone Metastases May Be Associated With Poorer Survival on ICI Therapy in mNSCLC


The high prevalence of bone metastases in non–small cell lung cancer led 2 institutions to investigate how these metastases impact survival in patients treated with immune checkpoint inhibitors.

Dr Angel Qin Michigan Medicine

Angel Qin, MD

Baseline bone metastases may indicate worse prognosis for patients with metastatic non–small cell lung cancer (mNSCLC) who are treated with immune checkpoint inhibitors (ICIs), according to retrospective data from patients treated at University of Michigan and The Ohio State University.

The study also found that using bone-modifying agents (BMAs) did no reduce skeletal-related events in these patients, nor did it impact survival.

“Bone metastases appear to be less likely to respond to checkpoint inhibition and convey a negative prognostic significance,” Angel Qin, MD, clinical associate professor at the University of Michigan Health, told Targeted Oncology™, in an interview. “This is a special population in which additional research is warranted especially in the era of frontline immunotherapy and chemo-immunotherapy when there are multiple different regimens to choose from. We need to understand what the mechanisms of resistance are to checkpoint inhibition and how we can overcome them.”

Significant morbidity has been identified in patients with mNSCLC and bone metastases, which often calls for the need to administer intense pain medication. Bone metastases have a high prevalence and thus far, this is the largest study to address the clinical question of how bone metastases impact mortality in patients with mNSCLC.

“At the University of Michigan, about 30% of patients are noted to have bone metastases at the time of diagnosis of stage IV NSCLC and about 10% of these patients experience a skeletal-related event, which includes need for palliative radiation, surgical intervention, and development of a pathologic fracture,” Qin stated during the interview. “We are very lucky to be part of a large multidisciplinary team including Radiation Oncology, Orthopedic Surgery, Neurosurgery, Physical Medicine and Rehabilitation, and Palliative Care and can easily access these specialists to optimize care for our patients. For example, patients with spinal metastases are followed in a dedicated clinic staffed by Neurosurgery and Radiation Oncology.”

According to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for Non–Small Cell Lung Cancer, the FDA-approved BMAs pamidronate, zoledronic acid, and denosumab should be used for the management of bone metastases in all solid tumors. Even with these recommendations, research has not investigated the fact that patients with mNSCLC metastasized to the bone have a lower response rate on ICIs. Moreover, experts believe that bone may represent an immunosuppressive tumor microenvironment that negatively impacts efficacy.

Adding to the limited research around the subject, the retrospective study evaluated how bone metastases and skeletal-related events correlate with overall survival (OS) in patients with mNSCLC treated with ICIs, as well as how BMA treatment of these patients impacts survival and skeletal-related events.

The cohort treated with an ICI was assessed at either institution between 2014 to 2017. Investigators conducted routine imaging to look for the presence of bone metastases prior to administering ICI therapy. The skeletal-related events included pathologic bone fracture, palliative osseous radiation, or surgical intervention. Utilizing the Kaplan-Meier method, OS was calculated from the time of initiation of ICI therapy to the date of death from any cause or was censored at loss to follow-up.

In total 330 patients with mNSCLC who received an ICI were identified. The cohort had a median age of 62.4 years and was predominantly make (47%). Eighty-eight percent of patients in the cohort were current or former smokers, and 66% had adenocarcinoma histology. The majority of patients (48%) were in their second line of therapy at the time they were treated with an ICI. The most common ICI used in these patients was nivolumab (Opdivo) in 64%. The other ICI used in the center were pembrolizumab (Keytruda) in 17%, atezolizumab (Tecentriq) in 6%, and another ICI in 13%. Thirty-eight percent of the cohort had bone metastases at baseline.

Overall, the cohort had a median OS of 10 months (95% CI, 8.4-12.0), and the investigators noted that there were no differences in OS across the subgroups assessed.

Regarding skeletal-related events, the median time to an event was 2.8 months. Further, histology, mutational status, sex, and age were not predictive of the development of skeletal-related events.

A closer look at OS and its correlation with bone metastases released that patients with baseline bone metastases had shorter survival compared with those who did not 5.9 months (95% CI, 4.2-7.8) versus 13.4 months (95% CI, 10.8-17.0), respectively (P < .001). When patients were controlled for ECOG performance status, histology line of therapy and metastatic burden, patients with bone metastases still fared worse than those without (HR, 1.57; 95% CI, 1.19-2.08; P = .001).

The survival analysis also uncovered that the development of skeletal-related events correlated with shorted OS, irrespective of whether bone metastases were present at baseline. The median OS among those with skeletal-related events was 7.5 months (95% CI, 4.6-10.0) compared with 10.6 months (95% CI, 8.4-12.8) in patients without skeletal-related events (P = .041). Further, the use of BMA as recommended by the NCCN, did not impact OS (P = .778), nor did the type of BMA used (P = .622).

Based on the findings of this retrospective study, Qin stated “bone metastases should be followed carefully, and we should design prospective studies to evaluate best treatment options. Oncologists should consider early referral to specialists if the location of the metastases conveys significant risk, and consider early bone-directed therapy to prevent the skeletal-related event.”


Qin A, Zhao S, Miah A, et al. Bone metastases, skeletal-related events, and survival in patients with metastatic non–small cell lung cancer treated with immune checkpoint inhibitors. J Natl Compr Canc Netw. 2021;19(8):915-921 doi: 10.6004/jnccn.2020.7668

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