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Article

Site-Specific Response and Resistance Patterns in Patients with Advanced Non-Small-Cell Lung Cancer Treated with First-Line Systemic Therapy

by
Lauren Julia Brown
1,2,3,4,*,
Julie Ahn
2,5,
Bo Gao
1,2,3,
Harriet Gee
3,4,5,6,
Adnan Nagrial
1,2,3,
Eric Hau
2,3,4,5 and
Inês Pires da Silva
1,2,3,7
1
Department of Medical Oncology, Westmead Hospital, Sydney, NSW 2145, Australia
2
Blacktown Cancer and Haematology Centre, Blacktown Hospital, Sydney, NSW 2148, Australia
3
Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2050, Australia
4
Westmead Institute for Medical Research, Westmead, NSW 2145, Australia
5
Sydney West Radiation Oncology Network (SWRON), Sydney, NSW 2145, Australia
6
Children’s Medical Research Institute, Westmead, NSW 2145, Australia
7
Melanoma Institute Australia, Wollstonecraft, NSW 2065, Australia
*
Author to whom correspondence should be addressed.
Cancers 2024, 16(11), 2136; https://doi.org/10.3390/cancers16112136
Submission received: 29 April 2024 / Revised: 26 May 2024 / Accepted: 27 May 2024 / Published: 4 June 2024
(This article belongs to the Special Issue Immunotherapy with Checkpoint Inhibitors for Non-small Cell Lung Cancer)
Browse Figures
Versions Notes

Abstract

:

Simple Summary

Immunotherapy or combined chemoimmunotherapy is currently first-line therapy for patients with metastatic NSCLC without a driver mutation. Despite immunotherapy contributing to improved survival outcomes, the estimated 5-year OS rate for metastatic NSCLC remains poor. The aim of our retrospective study was to assess how patients with different anatomical metastatic sites respond or develop resistance to immunotherapy, combination chemoimmunotherapy, or chemotherapy alone. We confirmed that patients with bone metastases have poorer survival outcomes compared to those without bone metastases. This highlights a group of patients that may benefit from a specific clinical trial evaluation to assess the benefit of additional novel therapeutics or upfront radiotherapy.

Abstract

Patients with advanced NSCLC have heterogenous responses to immune checkpoint inhibitors (ICIs) with or without chemotherapy. In NSCLC, the impact of the distribution of metastatic sites and the response to systemic therapy combinations remain poorly understood. In a retrospective cohort study of patients with unresectable stage III/IV NSCLC who received first-line systemic therapy, we sought to assess the association between the site of metastases with patterns of response and progression. Data regarding demographics, tumour characteristics (including site, size, and volume of metastases), treatment, and outcomes were examined at two cancer care centres. The endpoints included organ site-specific response rate, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Two-hundred and eighty-five patients were included in the analysis. In a multivariate analysis, patients with bone metastases had a reduced ORR, PFS, and OS. Primary resistance was also more likely in patients with bone metastases. Patients with bone or liver metastases had a shorter OS when receiving ICIs with or without chemotherapy, but not with chemotherapy alone, suggesting an immunological basis for therapeutic resistance. A directed assessment of the tumour microenvironment in these locations and a deeper understanding of the drivers of organ-specific resistance to immunotherapy are critical to optimise novel combination therapies and sequencing in these patients.

1. Introduction

Lung cancer remains the leading cause of cancer-related death worldwide [1]. Non-small-cell lung cancer (NSCLC) is the most common subtype of lung cancer. The advent of immunotherapy has led to a significant improvement in outcomes for patients with metastatic NSCLC. Immune checkpoint inhibitors (ICIs) targeting programmed cell death receptor 1 (PD-1) and its ligand (PD-L1) including pembrolizumab, atezolizumab, and nivolumab are now the standard of care for the first-line management of patients with metastatic NSCLC with or without chemotherapy. In the first-line, ICIs alone or in combination with chemotherapy have also been shown to improve progression-free survival (PFS) and overall survival (OS) in patients with metastatic NSCLC without a driver mutation [2,3,4,5]. Additionally, combination immunotherapy with ipilimumab and nivolumab has been shown to be superior to chemotherapy alone for the management of metastatic NSCLC [6]. The efficacy of anti-PD-(L)1 inhibitors has also now been established in early stage, resectable [7,8,9,10,11,12], and non-resectable stage III NSCLC [13]. Despite immunotherapy contributing to improved survival outcomes, the estimated 5-year OS rate for metastatic NSCLC remains very poor—between 10 and 20% [1].
The patterns of metastatic spread in NSCLC are well described, based on registry data [14], retrospective analyses [15,16], and autopsy studies [17]. The most common extrathoracic metastatic sites for patients with NSCLC are the liver, brain, bone, and adrenal glands [14,15,16,17]. However, there is significant heterogeneity between studies with regards to the reported frequencies of metastatic involvement, depending on the histologic subtype. This is of significance as retrospective analyses have suggested that metastases to different organs may have differential responses. For example, liver metastases are less responsive to immunotherapy, whilst lymph node metastases have a higher response rate to ICIs in both metastatic NSCLC [18,19] and melanoma [20,21,22].
Exactly how the response to systemic therapy, including ICI and chemotherapy combinations in the first-line, is influenced by the distribution of metastatic involvement remains poorly understood. The incremental benefit of chemotherapy in particular metastatic sites remains unknown. We sought to assess the association between the site of metastases with patterns of response, progression, and survival in a cohort of patients with advanced non-small-cell lung cancer receiving first-line immunotherapy, chemoimmunotherapy, or chemotherapy.

2. Materials and Methods

2.1. Patients and Treatment

We retrospectively identified two-hundred and eighty-five consecutive patients who were treated at two tertiary cancer centres in NSW, Australia between January 2014 and September 2021 (allowing for all patients to have at least 24 months of follow-up). Patients were included if they received first-line systemic therapy for the management of advanced NSCLC (defined as metastatic, stage IV NSCLC, or stage IIIB/C NSCLC untreatable with definitive chemoradiation). Patients were treated with either first-line (1) immunotherapy: anti-PD-1 antibody alone (nivolumab, pembrolizumab or atezolizumab), or combination anti-CTLA-4 (ipilimumab) and anti-PD-1 (nivolumab); (2) chemoimmunotherapy: histology-driven platinum doublet chemotherapy in combination with an anti-PD-1 antibody (nivolumab or pembrolizumab); or (3) chemotherapy alone. As per international guidelines, patients who received immunotherapy alone had a PD-L1 expression of ≥50%. Patients received chemotherapy in addition to immunotherapy if they had a PD-L1 expression of <50% or if it was deemed appropriate by the treating clinician. Patients were treated with chemotherapy alone prior to 2018 when anti-PD-1 antibodies became available via government reimbursement in Australia or in cases where patients had pre-existing conditions contraindicating immunotherapy.
Approval from the Institutional Ethics Review Board (Western Sydney Local Health District Human Research Ethics Committee; 2020/ETH02064) was obtained. In accordance with the approved protocol, the requirement for obtaining individual patient consent was waived.
The data collected included patient demographics, tumour histology, location, volume and size of metastatic disease, treatment details including response rates at different metastatic sites, progression details, and survival outcomes. The volume of disease was defined as low, <5 metastases; moderate, 5–20 metastatic lesions; and high, >20 metastases. Extracranial lesions measuring ≥ 5 mm and cranial lesions measuring ≥ 2 mm were included in the analysis of volume of disease. The number of metastatic deposits measuring ≥ 5 cm was recorded.

2.2. Disease Assessment

Computed tomography (CT) of the chest, abdomen, and pelvis (3-mm slices) was obtained at baseline (before starting treatment), then every 12–16 weeks or more frequently, according to institutional practice. All patients had imaging of the brain prior to commencement of systemic therapy, either with CT or magnetic resonance imaging (MRI). In patients with known brain metastases, they were followed up with brain MRI every 12–16 weeks.
In each patient, metastatic lesions were measured on CT or MRI before and during treatment if they were ≥5 mm in the long axis, brain metastases ≥ 2 mm in the long axis, and lymph node [LN] metastases ≥ 15 mm in the short axis. Site-specific response in individual organs was recorded for all patients. This was classified as a complete response (CR) (disappearance or reduction to <10 mm in the short axis for an LN metastasis), a partial response (PR) (≥30% reduction), stable disease (SD) (neither a CR, PR, nor progressive disease [PD]), or PD (≥20% growth) in the affected organ. For bone metastases, this was assessed as either SD or PD given most bone lesions without a soft tissue component do not achieve a PR or CR. For patients with brain metastases, or other lesions, that had treatment with prior local therapy (radiotherapy, SRS or surgery) were assessed as achieving SD or PD. If other assessable cranial lesions had not been treated with local therapy, then the intracranial site-specific response could be assessed as per the other sites. For patients receiving immunotherapy (either alone or in combination with chemotherapy), the baseline volume of disease was recorded for each patient by organ site and assessment of the percentage change in disease volume was recorded for all lesions at each time point.
Early progression (primary resistance) was defined as progression within 6 months of commencement of systemic treatment, whereas late progression (acquired resistance) was defined as PD after an initial response (PR or CR) or SD for at least 6 months.

2.3. Statistical Assessment

Descriptive analysis was used for baseline characteristics. Continuous variables were summarised using medians and interquartile ranges (IQRs). Categorical variables were summarised using proportions. A Chi-squared test was employed to compare categorical variables between two independent groups. A nonparametric test (Mann–Whitney U test) was used to assess continuous variables between two independent groups. Objective response rate (ORR) was defined as the proportion of patients who had a partial response (PR) or complete response (CR) to treatment. OS and PFS were calculated from the date of commencement of treatment to the date of an event (either death [OS] or progression [PFS]). Patients without a clinical event were censored at the last follow-up date. Univariate and multivariate analyses of ORR were conducted using logistic regression modelling. Univariate and multivariate time-to-event analyses (OS and PFS) were conducted using the Cox regression analysis. Predictors of response, OS, and PFS, used in the models, included tumour and patient characteristics, size, volume and location of metastases, and treatment type. All statistical analyses were performed using R (version 4.2.3, R Foundation for Statistical Computing, Vienna, Austria) and some graphics were created using GraphPad Prism (version 10.0.2).

3. Results

3.1. Patient Characteristics

Two-hundred and eighty-five patients with advanced NSCLC were included. Patients received first-line treatment with either single-agent immunotherapy, chemotherapy or combination of chemoimmunotherapy. The median age was 68 years (IQR 60, 74), 174 (61%) were male, 74 (26%) were current smokers and 170 (60%) had a past history of smoking. Two-hundred and forty-four (86%) had an ECOG status of 0–1. The histological subtypes of NSCLC included 181 (64%) with adenocarcinoma, 67 (24%) with squamous cell carcinoma, 29 (10%) with undifferentiated large-cell carcinoma and 8 (3%) with not otherwise specified (NOS) carcinoma. Of the patients who had PD-L1 testing on their tumour, 58 (58 of 211, 27%) were PD-L1 negative, 52 (52 of 211, 25%) were PD-L1 1–49%, and 101 (101 of 211, 48%) were PD-L1 ≥ 50%. Seventy-four (26%) patients did not have routine PDL1 testing, given that this was not present in routine clinical practice before 2017 (Table 1). Twenty-two (7.7%) patients had stage IIIC NSCLC, unable to be treated with surgery or definitive chemoradiation, and 263 (93%) had stage IV disease.
One-hundred and six (37%) patients received chemoimmunotherapy, 96 (34%) received immunotherapy (7 of which received combination ipilimumab and nivolumab) and 83 (29%) received chemotherapy alone. Radiotherapy prior to first-line systemic therapy was received by 98 patients (39%).
Sites of metastatic disease before starting systemic therapy included 151 (53%) with lung metastases (separate to the primary lung lesion), 236 (83%) with lymph node metastases; either thoracic or extra-thoracic, 95 (33%) with pleural disease, 85 (30%) with bone, 60 (21%) with brain, 53 (19%) with adrenal and 47 (16%) with liver metastases.

3.2. Objective Response Rate

With a median follow-up time of 45 months (IQR 23; 71 months), the ORR was 41%. Of the 266 patients with a recorded response, 7 (2.6%) had CR recorded as their best response, 101 (38%) had PR, 83 (31%) had SD, 66 (25%) had PD and 9 (3.4%) had mixed response (Figure 1a).
In total, 37 (13%) patients in the cohort had a response for ≥24 months including 22 treated with immunotherapy alone, 9 treated with chemoimmunotherapy, and 6 with chemotherapy.
The ORR was 44% (47 of 106) for patients who received chemoimmunotherapy, 30% (32 of 96) for those who received immunotherapy, and 27% (29 of 83) in patients treated with chemotherapy (p = 0.4) (Figure 1b). Multivariate analysis including all covariates and treatment type confirmed the presence of bone metastases was associated with a reduced likelihood of achieving a response (OR 0.35; 95% CI 0.16–0.73; p < 0.01). Pleural disease (OR 1.93; 95% CI 1.02–3.74; p = 0.05) and history of smoking (OR 6.67; 95% CI 2.09–23.3; p < 0.01) were associated with an increased likelihood of response (Table 2, Supplementary Table S1).

3.3. Site-Specific Response Rate

The patterns of response were also evaluated at each site of disease, measured as the best response at each site or anatomical location (Figure 1c). Lung lesions (43.9%), adrenal (44.2%), and lymph node metastases (43.5%) had the highest proportion of lesions achieving a complete or partial response compared with the other sites of disease. In contrast, bone (41.7%), liver (35.6%), and brain metastases (28.3%) had a higher proportion of progressive disease as their best response compared with the other sites of disease.
The median disease volume at baseline at each site was largest in the lung (58 mm) and smallest in the brain (27 mm) (Figure 2a). In the cohorts of patients who received ICIs (immunotherapy and chemoimmunotherapy cohorts), the best change in tumour volume from baseline varied according to the site of disease; the greatest regression was observed in the lymph nodes (median −40%; range −100% to 260%), brain (median −40%; range −100% to 103%), adrenal glands (−37%; range −100% to 117%), lung (median −27%; range −100% to 260%), and pleura (median −33%; range −100% to 40%). Liver metastases had the lowest tumour volume regression (median −10%; range −100% to 720%) (Figure 2b). Patients with a higher burden of disease at baseline were more likely to have an objective response (median volume 127 mm vs. 97 mm; p < 0.001) (Figure 2c).
Of the 60 patients with brain metastases, 40 underwent local intracranial therapy prior to systemic therapy. Additionally, 17 (17 of 60, 28%) patients had surgical resection followed by cavity stereotactic radiosurgery (SRS), 12 (12 of 60, 20%) received SRS alone, 10 (10 of 60, 17%) received whole brain radiotherapy (WBRT), and one (1.7%) received surgery alone. Of the patients who had local therapy alone, 4 of 20 had an intracranial response (20%), with 10 patients having stable disease (50%). Of the 17 (17 of 60, 28.3%) patients who had progressive disease as their best response, 6 received local therapy alone, 6 underwent resection and cavity SRS, 3 received SRS alone, 1 received WBRT, and 1 received surgery alone.

3.4. Progression-Free Survival

The median PFS was 5 months (95% CI 5–7 months) (Figure 3a). The median PFS was 4 months on chemotherapy (95% CI 4–5 months), 6 months on immunotherapy (95% CI 4–10 months), and 8 months on chemoimmunotherapy (95% CI 6–12 months; p < 0.001) (Supplementary Figure S1).
Patients with bone metastases had a median PFS of 4 months (95% CI 2–5 months). By contrast, PFS was 6 months (95% CI 5–9 months) in those without bone metastases (HR 1.63 (95% CI 1.23–2.17); p < 0.001) (Figure 4a). Patients with liver metastases had a median PFS of 4 months (95% CI 2–7 months) versus 6 months (95% CI 5–8 months) in those without liver metastases (HR 1.56 (95% CI 1.10–2.21); p = 0.01) (Figure 4b).
Multivariate analysis confirmed the presence of bone metastases (HR 1.70; p < 0.01) and presence of a metastatic lesion ≥ 5 cm at any anatomical site (HR 1.74; p < 0.01) were associated with shorter PFS. Patients treated with immunotherapy with (HR 0.34) or without chemotherapy (HR 0.52) was associated with a longer PFS (p < 0.01). PD-L1 positive disease (PDL1 ≥ 1% HR 0.74, PDL1 ≥ 50% HR 0.63; p < 0.01) and history of smoking (Ex-smoker HR 0.51, current smoker HR 0.61; p = 0.02) were associated with improved PFS (Table 2, Supplementary Table S2). No difference was noted in PFS for patients who received upfront radiotherapy.

3.5. Overall Survival

The median OS for all patients was 17 months (95% CI 14–21 months) (Figure 3b). The median OS was 19 months (95% CI 16–28 months) for patients on chemotherapy, 15 months (95% CI 11–22 months) for patients on immunotherapy, and 16 months (95% CI 12–23 months) on chemoimmunotherapy (p = 0.72) (Supplementary Figure S2).
Patients with bone metastases had a median OS of 10 months (95% CI 8–13 months) versus 21 months (95% CI 17–27 months) in those without bone metastases (HR 1.95 (95% CI 1.45–2.62); p < 0.0001) (Figure 4c). Patients with liver metastases had a median OS of 10 months (95% CI 8–21 months) versus 18 months (95% CI 15–22 months) in those without liver metastases (HR 1.64 (95% CI 1.15–2.34); p < 0.01) (Figure 4d). There was no statistically significant difference in OS or PFS for other sites of metastatic disease.
The multivariate analysis confirmed that the presence of bone metastases (HR 2.01; p < 0.001), a high volume of disease (HR 1.66; p = 0.03), and squamous histology (HR 2.05; p < 0.01) were associated with shorter OS. (Table 2, Supplementary Table S3). No difference was noted in OS for patients who received upfront radiotherapy.
Patients with bone metastases (Supplementary Table S4) or liver metastases (Supplementary Table S5) had a shorter OS when receiving chemoimmunotherapy or immunotherapy compared to patients without bone and liver metastases. There was no difference in the OS of patients with bone metastases vs. no bone metastases or liver metastases vs. no liver metastases receiving chemotherapy.

3.6. Primary and Acquired Resistance

Progression occurred in 227 patients. Of these, 147 (65%) developed early (primary) resistance and eighty (35%) developed acquired resistance. Early (primary) resistance was more common in patients who received chemotherapy (69%) and acquired resistance was more common in patients who received chemoimmunotherapy (40%).
Patients with bone disease were more likely to experience early progression compared to those without bone lesions (76.1% vs. 59.6%, p = 0.02), whereas patients with pleural disease were more likely to experience late progression or acquired resistance compared to those without pleural disease (41.3% vs. 30.6%; p = 0.03). There was no difference in the timing of progression for those with liver, brain, or adrenal disease.

4. Discussion

For patients with metastatic NSCLC, response patterns to ICIs are variable and so too are the survival outcomes. Small studies have demonstrated that the distribution of metastatic sites predicts the response to immunotherapy in NSCLC [18,19,21,23]. We present the first data examining the influence of metastatic site on important clinical outcomes in patients receiving first-line chemoimmunotherapy vs. immunotherapy vs. chemotherapy alone, as well as the influence of radiotherapy. Our results highlight the important influence of the metastatic distribution on therapeutic response, in particular immunotherapy response. In our study, we have demonstrated the following: (1) Patients with bone metastases had a reduced ORR, PFS, and OS; (2) patients with bone or liver metastases have a shorter OS when receiving ICIs with or without chemotherapy; (3) patients with bone metastases were more likely to experience primary resistance.
Despite 20–48% of patients with metastatic NSCLC having bone metastases at diagnosis [24,25,26], there are limited clinical trials that specifically report on the outcomes of this subpopulation. This may be partly due to the focus on liver or brain metastases [27,28], which are reported more commonly in clinical trials, owing to known poorer prognostic implications [6,29,30,31,32,33,34,35]. Our results confirm previous findings from the Checkmate 9LA study of first-line nivolumab, ipilimumab, and chemotherapy compared with chemotherapy, which demonstrated poorer OS in patients receiving the chemoimmunotherapy combination for patients with bone metastases [34]. Those with bone metastases had a median OS of 11.9 months (HR 0.74; 95% CI 0.53–1.01) compared with those without bone metastases of 20.5 months (HR 0.65; 95% CI 0.51–0.82). The Checkmate 227 study of first-line nivolumab plus ipilimumab versus chemotherapy also reported similar results [6]. Patients with bone metastases receiving dual immunotherapy had a median OS of 13.4 months (HR 0.75; 95% CI 0.55–1.03) vs. 18.8 months (HR 0.81; 95% CI 0.67–0.99) in those without bone metastases. A large retrospective analysis of patients with NSCLC who received immunotherapy also demonstrated reduced immunotherapy efficacy and OS in patients with bone metastases [36].
The reduced ORR, OS, and PFS in patients with bone metastases suggests there is a systemic impact from the presence of bone metastases. There are several factors contributing to the potential immune resistance and decreased efficacy of immunotherapy in patients with bone metastases. Known as the “bone marrow niche”, this specialised microenvironment safeguards disseminated tumour cells from immune surveillance [37]. The complex interplay among immune cells, myeloid cells, and stromal cells within the bone yields both anti-tumour and tumour-promoting effects. While certain immune cells can trigger anti-tumour responses, others, such as myeloid-derived suppressor cells [38], regulatory T cells [39], and tumour-associated macrophages [40], contribute to immune suppression and facilitate tumour growth. This intricate dynamic creates an immunosuppressive environment, potentially leading to immunotherapy resistance within the bone. Prior retrospective studies investigating bone modifying agents such as bisphosphates or denosumab in addition to immunotherapy are yet to demonstrate any difference in survival outcomes for these patients [41,42,43]. A single-arm study of second-line nivolumab combined with denosumab demonstrated the efficacy of this combination [44]. However, randomised trials of chemotherapy ± denosumab have not shown any additional survival benefit [45,46]. Given that the basis of resistance in the bone appears to be immune related, further prospective evaluation specifically evaluating the benefit of first-line ICIs ± bone modification agents or denosumab in patients with NSCLC and bone metastases would be beneficial.
We also observed that patients with liver metastases exhibited a lower PFS and OS in comparison to patients without liver metastases. However, this difference did not reach statistical significance in the multivariate analysis. The presence of liver metastases is a poor prognostic factor for patients with lung cancer [27]. Prior studies of melanoma have demonstrated reduced ORR, PFS, or OS to either anti-PD-1 monotherapy [20,21] or combination immunotherapy [22] in patients with liver metastases. This pattern of response and survival outcomes in patients with liver metastases has also been demonstrated in NSCLC [21,47] and other cancers including hepatocellular carcinoma [48], microsatellite stable colorectal cancer [49], and triple-negative breast cancer [50,51] treated with anti-PD1 monotherapy. A previous study conducted on melanoma patients showed a distinct change in the systemic cytokine profile among patients with liver metastases compared to those without liver metastases [52]. In this study, reduced responses were also observed in the extra-hepatic metastases, suggesting that the existence of liver metastases might induce a systemic immunosuppressive effect leading to poorer survival outcomes. Furthermore, a recent assessment of the liver tumour microenvironment in NSCLC has demonstrated lower proportions of CD8 T cells within the liver compared with paired primary lung samples [53]. This study also demonstrated antigen processing pathways, natural killer cell cytotoxicity, and T-cell receptor signalling pathways were reduced in liver tumour samples compared to the primary lung tumour, providing a basis for immunotherapy resistance in patients with NSCLC and liver metastases. A deeper understanding of immunosuppressive mechanisms in liver metastases are required to overcome resistance.
Our study did not reveal improved outcomes for patients with bone or liver metastases who received chemoimmunotherapy when compared to those who received immunotherapy alone. This is yet to be evaluated in prospective trials. Notably, a real-world analysis involving PDL1-high NSCLC patients treated with either chemoimmunotherapy or immunotherapy alone exhibited no differences in outcomes for individuals with liver metastases [54].
While our study cohort did not include patients treated with both chemoimmunotherapy and VEGF inhibitors, post-hoc analyses from the IMpower-150 trial involving NSCLC patients with liver metastases have indicated that those who received a combination of carboplatin, paclitaxel, atezolizumab, and bevacizumab experienced improved outcomes compared to those who received only bevacizumab and chemotherapy [32]. A recent meta-analysis highlighted that the addition of VEGF inhibition has demonstrated the potential to enhance the response to immunotherapy in liver metastases, both in NSCLC and other cancers [55]. This introduces a potential treatment avenue for patients with liver metastases that requires further prospective evaluation.
Patients with a higher burden of disease at baseline were more likely to have an objective response (p < 0.001). This is contrary to what has previously been demonstrated in melanoma, where smaller metastases were more likely to achieve a CR than larger metastases [22]. Whilst patients with a higher burden of disease were more likely to have achieved an objective response, our study demonstrated that those with ≥20 metastases were associated with a lower OS (HR 1.66, p = 0.03). This confirms the findings of a prior study demonstrating that higher tumour volume was associated with poorer OS outcomes in metastatic NSCLC treated with anti-PD1 therapy [56].
Patients with bone metastases have a higher rate of primary resistance than those who did not. Improving our understanding of which patient phenotypes have primary immunotherapy resistance should direct clinical trial development targeting these resistant populations. The use of stereotactic body radiotherapy (SABR) prior to pembrolizumab in patients with metastatic NSCLC has demonstrated improved PFS and OS in the PD-L1-negative subgroup [57]. This suggests the role of upfront radiotherapy may be of benefit in patients with primary resistance to immunotherapy. Although our study did not confirm this, this may be due to the retrospective nature of the study, dose and location of radiotherapy or sequencing of radiotherapy. The SABR-COMET trial assessed the use of SABR for patients with oligometastatic disease, to all metastatic sites in combination with standard-of-care systemic therapy, with the aim of cytoreduction. This demonstrated an improvement in OS for patients with oligometastatic disease [58,59], with 35% of patients receiving SABR to bone metastases and 13% to liver metastases. Hypofractionated radiotherapy in a pooled analysis of two phase II trials has also demonstrated the ability to re-invigorate immunotherapy responses in patients with resistance to ICIs with NSCLC, leading to ongoing disease control [60].
Several novel therapies may also help to overcome resistance mechanisms in resistant organ sites. Preclinical NSCLC studies have demonstrated that the synergistic use of anti-PD-1 therapy in addition to antibody–drug conjugates improves response in immunotherapy-resistant models [61]. Numerous trials are currently underway assessing antibody drug conjugates in combination with immunotherapy including EVOKE-02 (NCT05186974), TROPION-Lung02 (NCT04526691) and -04 (NCT04612751), an AXL-ADC with PD-1 inhibitor (NCT04681131). However, further data are awaited regarding the efficacy of these combinations in specific organ sites and resistant patient populations. Given the success of radionuclide therapies for the management of castration-resistant prostate cancer with extensive bone metastases [62,63,64], further efforts exploring this option in managing bone metastases in other solid organ tumours are required.

Limitations

There are several limitations of our study. Firstly, its retrospective design introduces the potential for selection bias, such as inadvertently excluding patients lost to follow-up. Secondly, the study is confined to two cancer centres and involves a small sample size. Consequently, the groups were heterogeneous, particularly the chemotherapy group, which was smaller and had fewer patients with bone metastases. This variability may have influenced the identification of predictive factors associated with outcomes and survival. Finally, not all patients in this study had baseline PET imaging or WBBS imaging to assess the presence of bone metastases, an issue that is broad across prospective clinical trials, with the use of bone scans usually only mandated if the patient is symptomatic. Thus, there is a risk that small metastases at some sites may not have been detected and included in the volume of metastases assessment. As bone metastases are not always accurately assessed using CT imaging [65,66], it is also possible that patients who had asymptomatic bone metastases were not included in the bone metastases cohort, thereby reducing the accuracy of the conclusions made. Additionally, patients with bone metastases were only assessed as SD or PD due to the difficulty with measurement of bone disease, which may have limited the accuracy of the site-specific response assessment in the bone.

5. Conclusions

This detailed analysis of response patterns to systemic therapy in NSCLC suggests that treatment outcomes vary depending on the metastatic site of disease. This is the first study to analyse site-specific response patterns in NSCLC receiving chemoimmunotherapy. Poor outcomes were especially significant in patients with bone and liver metastases undergoing chemoimmunotherapy and immunotherapy, suggesting that there may be underlying immunosuppressive factors within these organs contributing to resistance and reduced survival. Further investigation is needed to deepen our understanding of the specific tumour microenvironment in these locations and the drivers of organ-specific resistance to immunotherapy. This is critical to determine the optimal treatment type and sequencing for patients with bone and liver metastases with NSCLC and to improve treatment response and outcomes.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cancers16112136/s1, Figure S1: PFS by treatment type; Figure S2: OS by treatment type, Table S1: Univariate and Multivariate analysis for ORR; Table S2: Univariate and Multivariate analysis for PFS; Table S3: Univariate and Multivariate analysis for OS; Table S4: OS and PFS for bone metastases by treatment type; Table S5: OS and PFS for liver metastases by treatment type.

Author Contributions

Conceptualization, L.J.B., E.H., A.N. and I.P.d.S.; methodology, L.J.B., E.H. and I.P.d.S.; formal analysis, L.J.B. and J.A.; investigation, L.J.B. and J.A.; data curation, L.J.B. and J.A.; writing—original draft preparation, L.J.B., E.H. and I.P.d.S.; writing—review and editing, all authors; visualization, L.J.B.; supervision, E.H., A.N. and I.P.d.S.; project administration, L.J.B.; funding acquisition, A.N. and L.J.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Western Sydney Local Health District 2023 Research and Education Network Grant, grant number REN-2023-010. LJB is funded by the Jerry Koutt’s ICPMR Postgraduate Scholarship and the University of Sydney Postgraduate Award.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board (Western Sydney Local Health District Human Research Ethics Committee (2020/ETH02064, approved 25 November 2020).

Informed Consent Statement

Patient consent was waived due to the retrospective and low risk nature of the study in accordance with the relevant guidelines in the National Statement on Ethical Conduct in Human Research 2007 (updated 2018).

Data Availability Statement

The data for this study is unavailable due to privacy or ethical restrictions.

Conflicts of Interest

The authors disclose the following conflicts of interest. LJB: Nil. JA: Nil. BG: Nil. HG: Honoria from Astra Zeneca. EH: Honoria and research funding from Astra Zeneca. Honoria from Novartis. AN: Advisory board member for MSD, BMS, Roche, Astra Zeneca, Pfizer Merck Serono. IPS: Consultant Advisor for MSD; Speaker. Honararia from Roche, Novartis, Bristol Myers Squibb. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

References

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef] [PubMed]
  2. Paz-Ares, L.; Luft, A.; Vicente, D.; Tafreshi, A.; Gümüş, M.; Mazières, J.; Hermes, B.; Çay Şenler, F.; Csőszi, T.; Fülöp, A.; et al. Pembrolizumab plus Chemotherapy for Squamous Non–Small-Cell Lung Cancer. N. Engl. J. Med. 2018, 379, 2040–2051. [Google Scholar] [CrossRef]
  3. Reck, M.; Rodríguez-Abreu, D.; Robinson, A.G.; Hui, R.; Csőszi, T.; Fülöp, A.; Gottfried, M.; Peled, N.; Tafreshi, A.; Cuffe, S.; et al. Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer. N. Engl. J. Med. 2016, 375, 1823–1833. [Google Scholar] [CrossRef] [PubMed]
  4. Gandhi, L.; Rodríguez-Abreu, D.; Gadgeel, S.; Esteban, E.; Felip, E.; De Angelis, F.; Domine, M.; Clingan, P.; Hochmair, M.J.; Powell, S.F.; et al. Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer. N. Engl. J. Med. 2018, 378, 2078–2092. [Google Scholar] [CrossRef] [PubMed]
  5. Mok, T.S.K.; Wu, Y.-L.; Kudaba, I.; Kowalski, D.M.; Cho, B.C.; Turna, H.Z.; Castro, G., Jr.; Srimuninnimit, V.; Laktionov, K.K.; Bondarenko, I.; et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): A randomised, open-label, controlled, phase 3 trial. Lancet 2019, 393, 1819–1830. [Google Scholar] [CrossRef] [PubMed]
  6. Hellmann, M.D.; Paz-Ares, L.; Bernabe Caro, R.; Zurawski, B.; Kim, S.-W.; Carcereny Costa, E.; Park, K.; Alexandru, A.; Lupinacci, L.; de la Mora Jimenez, E.; et al. Nivolumab plus Ipilimumab in Advanced Non–Small-Cell Lung Cancer. N. Engl. J. Med. 2019, 381, 2020–2031. [Google Scholar] [CrossRef] [PubMed]
  7. Forde, P.M.; Spicer, J.; Lu, S.; Provencio, M.; Mitsudomi, T.; Awad, M.M.; Felip, E.; Broderick, S.R.; Brahmer, J.R.; Swanson, S.J.; et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. New Engl. J. Med. 2022, 386, 1973–1985. [Google Scholar] [CrossRef]
  8. Felip, E.; Altorki, N.; Zhou, C.; Csőszi, T.; Vynnychenko, I.; Goloborodko, O.; Luft, A.; Akopov, A.; Martinez-Marti, A.; Kenmotsu, H.; et al. IMpower010 Investigators. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB–IIIA non-small-cell lung cancer (IMpower010): A randomised, multicentre, open-label, phase 3 trial. Lancet 2021, 398, 1344–1357. [Google Scholar] [CrossRef] [PubMed]
  9. Lu, S.; Wu, L.; Zhang, W.; Zhang, P.; Wang, W.; Fang, W.; Xing, W.; Chen, Q.; Mei, J.; Yang, L.; et al. Perioperative toripalimab + platinum-doublet chemotherapy vs chemotherapy in resectable stage II/III non-small cell lung cancer (NSCLC): Interim event-free survival (EFS) analysis of the phase III Neotorch study. J. Clin. Oncol. 2023, 41, 425126. [Google Scholar] [CrossRef]
  10. Cascone, T.; Leung, C.H.; Weissferdt, A.; Pataer, A.; Carter, B.W.; Godoy, M.C.B.; Feldman, H.; William, W.N.; Xi, Y.; Basu, S.; et al. Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non-small cell lung cancer: The phase 2 platform NEOSTAR trial. Nat. Med. 2023, 29, 593–604. [Google Scholar] [CrossRef] [PubMed]
  11. Provencio, M.; Serna-Blasco, R.; Nadal, E.; Insa, A.; García-Campelo, M.R.; Rubio, J.C.; Dómine, M.; Majem, M.; Rodríguez-Abreu, D.; Martínez-Martí, A.; et al. Overall Survival and Biomarker Analysis of Neoadjuvant Nivolumab Plus Chemotherapy in Operable Stage IIIA Non–Small-Cell Lung Cancer (NADIM phase II trial). J. Clin. Oncol. 2022, 40, 2924–2933. [Google Scholar] [CrossRef] [PubMed]
  12. O’brien, M.; Paz-Ares, L.; Marreaud, S.; Dafni, U.; Oselin, K.; Havel, L.; Esteban, E.; Isla, D.; Martinez-Marti, A.; Faehling, M.; et al. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB–IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): An interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol. 2022, 23, 1274–1286. [Google Scholar] [CrossRef] [PubMed]
  13. Antonia, S.J.; Villegas, A.; Daniel, D.; Vicente, D.; Murakami, S.; Hui, R.; Yokoi, T.; Chiappori, A.; Lee, K.H.; De Wit, M.; et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2017, 377, 1919–1929. [Google Scholar] [CrossRef] [PubMed]
  14. Wang, X.; Wang, Z.; Pan, J.; Lu, Z.-Y.; Xu, D.; Zhang, H.-J.; Wang, S.-H.; Huang, D.-Y.; Chen, X.-F. Patterns of Extrathoracic Metastases in Different Histological Types of Lung Cancer. Front. Oncol. 2020, 10, 715. [Google Scholar] [CrossRef] [PubMed]
  15. Park, H.K.; Han, J.; Kwon, G.Y.; Yeo, M.-K.; Bae, G.E. Patterns of Extrathoracic Metastasis in Lung Cancer Patients. Curr. Oncol. 2022, 29, 8794–8801. [Google Scholar] [CrossRef] [PubMed]
  16. Tamura, T.; Kurishima, K.; Nakazawa, K.; Kagohashi, K.; Ishikawa, H.; Satoh, H.; Hizawa, N. Specific organ metastases and survival in metastatic non-small-cell lung cancer. Mol. Clin. Oncol. 2014, 3, 217–221. [Google Scholar] [CrossRef] [PubMed]
  17. Milovanovic, I.S.; Stjepanovic, M.; Mitrovic, D. Distribution patterns of the metastases of the lung carcinoma in relation to histological type of the primary tumor: An autopsy study. Ann. Thorac. Med. 2017, 12, 191–198. [Google Scholar] [CrossRef] [PubMed]
  18. Schmid, S.; Diem, S.; Li, Q.; Krapf, M.; Flatz, L.; Leschka, S.; Desbiolles, L.; Klingbiel, D.; Jochum, W.; Fruh, M. Organ-specific response to nivolumab in patients with non-small cell lung cancer (NSCLC). Cancer Immunol. Immunother. 2018, 67, 1825–1832. [Google Scholar] [CrossRef] [PubMed]
  19. Nishino, M.; Ramaiya, N.H.; Chambers, E.S.; Adeni, A.E.; Hatabu, H.; Jänne, P.A.; Hodi, F.S.; Awad, M.M. Immune-related response assessment during PD-1 inhibitor therapy in advanced non-small-cell lung cancer patients. J. Immunother. Cancer 2016, 4, 84. [Google Scholar] [CrossRef] [PubMed]
  20. Lee, J.H.J.; Lyle, M.; Menzies, A.M.; Chan, M.M.K.; Lo, S.; Clements, A.; Carlino, M.S.; Kefford, R.F.; Long, G.V. Metastasis-specific patterns of response and progression with anti-PD-1 treatment in metastatic melanoma. Pigment. Cell Melanoma Res. 2017, 31, 404–410. [Google Scholar] [CrossRef]
  21. Tumeh, P.C.; Hellmann, M.D.; Hamid, O.; Tsai, K.K.; Loo, K.L.; Gubens, M.A.; Rosenblum, M.; Harview, C.L.; Taube, J.M.; Handley, N.; et al. Liver Metastasis and Treatment Outcome with Anti-PD-1 Monoclonal Antibody in Patients with Melanoma and NSCLC. Cancer Immunol. Res. 2017, 5, 417–424. [Google Scholar] [CrossRef] [PubMed]
  22. da Silva, I.P.; Lo, S.; Quek, C.; Gonzalez, M.; Carlino, M.S.; Long, G.V.; Menzies, A.M. Site-specific response patterns, pseudoprogression, and acquired resistance in patients with melanoma treated with ipilimumab combined with anti–PD-1 therapy. Cancer 2019, 126, 86–97. [Google Scholar] [CrossRef] [PubMed]
  23. Brown, L.J.; da Silva, I.P.; Moujaber, T.; Gao, B.; Hui, R.; Gurney, H.; Carlino, M.; Nagrial, A. Five-year survival and clinical correlates among patients with advanced non-small cell lung cancer, melanoma and renal cell carcinoma treated with immune check-point inhibitors in Australian tertiary oncology centres. Cancer Med. 2023, 12, 6788–6801. [Google Scholar] [CrossRef] [PubMed]
  24. Kuchuk, M.; Addison, C.L.; Clemons, M.; Kuchuk, I.; Wheatley-Price, P. Incidence and consequences of bone metastases in lung cancer patients. J. Bone Oncol. 2013, 2, 22–29. [Google Scholar] [CrossRef] [PubMed]
  25. Santini, D.; Barni, S.; Intagliata, S.; Falcone, A.; Ferraù, F.; Galetta, D.; Moscetti, L.; La Verde, N.; Ibrahim, T.; Petrelli, F.; et al. Natural History of Non-Small-Cell Lung Cancer with Bone Metastases. Sci. Rep. 2015, 5, 18670. [Google Scholar] [CrossRef] [PubMed]
  26. Katakami, N.; Kunikane, H.; Takeda, K.; Takayama, K.; Sawa, T.; Saito, H.; Harada, M.; Yokota, S.; Ando, K.; Saito, Y.; et al. Prospective Study on the Incidence of Bone Metastasis (BM) and Skeletal-Related Events (SREs) in Patients (pts) with Stage IIIB and IV Lung Cancer—CSP-HOR 13. J. Thorac. Oncol. 2014, 9, 231–238. [Google Scholar] [CrossRef] [PubMed]
  27. Ren, Y.; Dai, C.; Zheng, H.; Zhou, F.; She, Y.; Jiang, G.; Fei, K.; Yang, P.; Xie, D.; Chen, C. Prognostic effect of liver metastasis in lung cancer patients with distant metastasis. Oncotarget 2016, 7, 53245–53253. [Google Scholar] [CrossRef] [PubMed]
  28. Sperduto, P.W.; Yang, T.J.; Beal, K.; Pan, H.; Brown, P.D.; Bangdiwala, A.; Shanley, R.; Yeh, N.; Gaspar, L.E.; Braunstein, S.; et al. Estimating Survival in Patients With Lung Cancer and Brain Metastases An Update of the Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA). JAMA Oncol. 2017, 3, 827–831. [Google Scholar] [CrossRef]
  29. Powell, S.F.; Rodríguez-Abreu, D.; Langer, C.J.; Tafreshi, A.; Paz-Ares, L.; Kopp, H.-G.; Rodríguez-Cid, J.; Kowalski, D.M.; Cheng, Y.; Kurata, T.; et al. Outcomes With Pembrolizumab Plus Platinum-Based Chemotherapy for Patients With NSCLC and Stable Brain Metastases: Pooled Analysis of KEYNOTE-021, -189, and -407. J. Thorac. Oncol. 2021, 16, 1883–1892. [Google Scholar] [CrossRef] [PubMed]
  30. Reck, M.; Rodríguez–Abreu, D.; Robinson, A.G.; Hui, R.; Csőszi, T.; Fülöp, A.; Gottfried, M.; Peled, N.; Tafreshi, A.; Cuffe, S.; et al. Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non–Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. J. Clin. Oncol. 2019, 37, 537–546. [Google Scholar] [CrossRef] [PubMed]
  31. Sezer, A.; Kilickap, S.; Gümüş, M.; Bondarenko, I.; Özgüroğlu, M.; Gogishvili, M.; Turk, H.M.; Cicin, I.; Bentsion, D.; Gladkov, O.; et al. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: A multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet 2021, 397, 592–604. [Google Scholar] [CrossRef] [PubMed]
  32. Nogami, N.; Barlesi, F.; Socinski, M.A.; Reck, M.; Thomas, C.A.; Cappuzzo, F.; Mok, T.S.; Finley, G.; Aerts, J.G.; Orlandi, F.; et al. IMpower150 Final Exploratory Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in Key NSCLC Patient Subgroups With EGFR Mutations or Metastases in the Liver or Brain. J. Thorac. Oncol. 2021, 17, 309–323. [Google Scholar] [CrossRef] [PubMed]
  33. Jotte, R.; Cappuzzo, F.; Vynnychenko, I.; Stroyakovskiy, D.; Rodríguez-Abreu, D.; Hussein, M.; Soo, R.; Conter, H.J.; Kozuki, T.; Huang, K.-C.; et al. Atezolizumab in Combination With Carboplatin and Nab-Paclitaxel in Advanced Squamous NSCLC (IMpower131): Results From a Randomized Phase III Trial. J. Thorac. Oncol. 2020, 15, 1351–1360. [Google Scholar] [CrossRef] [PubMed]
  34. Paz-Ares, L.; Ciuleanu, T.-E.; Cobo, M.; Schenker, M.; Zurawski, B.; Menezes, J.; Richardet, E.; Bennouna, J.; Felip, E.; Juan-Vidal, O.; et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): An international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021, 22, 198–211. [Google Scholar] [CrossRef] [PubMed]
  35. Reck, M.; Ciuleanu, T.-E.; Lee, J.-S.; Schenker, M.; Zurawski, B.; Kim, S.-W.; Mahave, M.; Alexandru, A.; Peters, S.; Pluzanski, A.; et al. Systemic and Intracranial Outcomes With First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC and Baseline Brain Metastases from CheckMate 227 Part 1. J. Thorac. Oncol. 2023, 18, 1055–1069. [Google Scholar] [CrossRef] [PubMed]
  36. Landi, L.; D’Inca, F.; Gelibter, A.; Chiari, R.; Grossi, F.; Delmonte, A.; Passaro, A.; Signorelli, D.; Gelsomino, F.; Galetta, D.; et al. Bone metastases and immunotherapy in patients with advanced non-small-cell lung cancer. J. Immunother. Cancer 2019, 7, 316. [Google Scholar] [CrossRef] [PubMed]
  37. Reinstein, Z.Z.; Pamarthy, S.; Sagar, V.; Costa, R.; Abdulkadir, S.A.; Giles, F.J.; Carneiro, B.A. Overcoming immunosuppression in bone metastases. Crit. Rev. Oncol. 2017, 117, 114–127. [Google Scholar] [CrossRef] [PubMed]
  38. Gabrilovich, D.I.; Ostrand-Rosenberg, S.; Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 2012, 12, 253–268. [Google Scholar] [CrossRef] [PubMed]
  39. Kunzmann, V.; Kimmel, B.; Herrmann, T.; Einsele, H.; Wilhelm, M. Inhibition of phosphoantigen-mediated γδ T-cell proliferation by CD4+ CD25+ FoxP3+ regulatory T cells. Immunology 2009, 126, 256–267. [Google Scholar] [CrossRef] [PubMed]
  40. Vasiliadou, I.; Holen, I. The role of macrophages in bone metastasis. J. Bone Oncol. 2013, 2, 158–166. [Google Scholar] [CrossRef]
  41. Cao, Y.; Afzal, M.Z.; Shirai, K. Does denosumab offer survival benefits? Our experience with denosumab in metastatic non-small cell lung cancer patients treated with immune-checkpoint inhibitors. J. Clin. Oncol. 2021, 39, e21039. [Google Scholar] [CrossRef]
  42. Li, H.-S.; Lei, S.-Y.; Li, J.-L.; Xing, P.-Y.; Hao, X.-Z.; Xu, F.; Xu, H.-Y.; Wang, Y. Efficacy and safety of concomitant immunotherapy and denosumab in patients with advanced non-small cell lung cancer carrying bone metastases: A retrospective chart review. Front. Immunol. 2022, 13, 908436. [Google Scholar] [CrossRef] [PubMed]
  43. Qin, A.; Zhao, S.; Miah, A.; Wei, L.; Patel, S.; Johns, A.; Grogan, M.; Bertino, E.M.; He, K.; Shields, P.G.; 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. Cancer Netw. 2021, 19, 915–921. [Google Scholar] [CrossRef]
  44. Decroisette, C.; Monnet, I.; Ricordel, C.; Demaegdt, A.; Falchero, L.; Bylicki, O.; Geier, M.; Justeaux, G.; Bernardi, M.; Andre, M.; et al. 1035P A phase II trial of nivolumab and denosumab association as second-line treatment for stage IV non-small-cell lung cancer (NSCLC) with bone metastases: DENIVOS study (GFPC 06-2017). Ann. Oncol. 2022, 33, S1028–S1029. [Google Scholar] [CrossRef]
  45. Peters, S.; Danson, S.; Hasan, B.; Dafni, U.; Reinmuth, N.; Majem, M.; Tournoy, K.G.; Mark, M.T.; Pless, M.; Cobo, M.; et al. A Randomized Open-Label Phase III Trial Evaluating the Addition of Denosumab to Standard First-Line Treatment in Advanced NSCLC: The European Thoracic Oncology Platform (ETOP) and European Organisation for Research and Treatment of Cancer (EORTC) SPLENDOUR Trial. J. Thorac. Oncol. 2020, 15, 1647–1656. [Google Scholar] [CrossRef] [PubMed]
  46. Peters, S.; Danson, S.; Ejedepang, D.; Dafni, U.; Hasan, B.; Radcliffe, H.-S.; Bustin, F.; Crequit, J.; Coate, L.; Guillot, M.; et al. Combined, patient-level, analysis of two randomised trials evaluating the addition of denosumab to standard first-line chemotherapy in advanced NSCLC – The ETOP/EORTC SPLENDOUR and AMGEN-249 trials. Lung Cancer 2021, 161, 76–85. [Google Scholar] [CrossRef] [PubMed]
  47. Adachi, Y.; Tamiya, A.; Taniguchi, Y.; Enomoto, T.; Azuma, K.; Kouno, S.; Inagaki, Y.; Saijo, N.; Okishio, K.; Atagi, S. Predictive factors for progression-free survival in non-small cell lung cancer patients receiving nivolumab based on performance status. Cancer Med. 2019, 9, 1383–1391. [Google Scholar] [CrossRef] [PubMed]
  48. Lu, L.-C.; Hsu, C.; Shao, Y.-Y.; Chao, Y.; Yen, C.-J.; Shih, I.-L.; Hung, Y.-P.; Chang, C.-J.; Shen, Y.-C.; Guo, J.-C.; et al. Differential Organ-Specific Tumor Response to Immune Checkpoint Inhibitors in Hepatocellular Carcinoma. Liver Cancer 2019, 8, 480–490. [Google Scholar] [CrossRef]
  49. Wang, C.; Sandhu, J.; Ouyang, C.; Ye, J.; Lee, P.P.; Fakih, M. Clinical Response to Immunotherapy Targeting Programmed Cell Death Receptor 1/Programmed Cell Death Ligand 1 in Patients With Treatment-Resistant Microsatellite Stable Colorectal Cancer With and Without Liver Metastases. JAMA Netw. Open 2021, 4, e2118416. [Google Scholar] [CrossRef] [PubMed]
  50. Adams, S.; Schmid, P.; Rugo, H.S.; Winer, E.P.; Loirat, D.; Awada, A.; Cescon, D.W.; Iwata, H.; Campone, M.; Nanda, R.; et al. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: Cohort A of the phase II KEYNOTE-086 study. Ann. Oncol. 2019, 30, 397–404. [Google Scholar] [CrossRef] [PubMed]
  51. Emens, L.A.; Cruz, C.; Eder, J.P.; Braiteh, F.; Chung, C.; Tolaney, S.M.; Kuter, I.; Nanda, R.; Cassier, P.A.; Delord, J.-P.; et al. Long-term Clinical Outcomes and Biomarker Analyses of Atezolizumab Therapy for Patients with Metastatic Triple-Negative Breast Cancer: A Phase 1 Study. JAMA Oncol. 2019, 5, 74–82. [Google Scholar] [CrossRef] [PubMed]
  52. Silva, I.; Tasker, A.; Quek, C.; Rawson, R.; Lim, S.Y.; Wang, K.; Conway, J.; Velickovic, R.; Ahmed, T.; Lo, S.; et al. Abstract 975: Liver metastases (mets) induce systemic immunosuppression and immunotherapy resistance in metastatic melanoma. Cancer Res. 2019, 79, 975. [Google Scholar] [CrossRef]
  53. Deng, J.-Y.; Gou, Q.; Yang, L.; Chen, Z.-H.; Yang, M.-Y.; Yang, X.-R.; Yan, H.-H.; Wei, X.-W.; Liu, J.-Q.; Su, J.; et al. Immune suppressive microenvironment in liver metastases contributes to organ-specific response of immunotherapy in advanced non-small cell lung cancer. J. Immunother. Cancer 2023, 11, e007218. [Google Scholar] [CrossRef] [PubMed]
  54. Pérol, M.; Felip, E.; Dafni, U.; Polito, L.; Pal, N.; Tsourti, Z.; Ton, T.; Merritt, D.; Morris, S.; Stahel, R.; et al. Effectiveness of PD-(L)1 inhibitors alone or in combination with platinum-doublet chemotherapy in first-line (1L) non-squamous non-small-cell lung cancer (Nsq-NSCLC) with PD-L1-high expression using real-world data. Ann. Oncol. 2022, 33, 511–521. [Google Scholar] [CrossRef] [PubMed]
  55. Conway, J.W.; Braden, J.; Lo, S.N.; Scolyer, R.A.; Carlino, M.S.; Menzies, A.M.; Long, G.V.; da Silva, I.P. VEGF Inhibitors Improve Survival Outcomes in Patients with Liver Metastases across Cancer Types—A Meta-Analysis. Cancers 2023, 15, 5012. [Google Scholar] [CrossRef] [PubMed]
  56. Chardin, D.; Paquet, M.; Schiappa, R.; Darcourt, J.; Bailleux, C.; Poudenx, M.; Sciazza, A.; Ilie, M.; Benzaquen, J.; Martin, N.; et al. Baseline metabolic tumor volume as a strong predictive and prognostic biomarker in patients with non-small cell lung cancer treated with PD1 inhibitors: A prospective study. J. Immunother. Cancer 2020, 8, e000645. [Google Scholar] [CrossRef] [PubMed]
  57. Theelen, W.S.M.E.; Peulen, H.M.U.; Lalezari, F.; Van Der Noort, V.; De Vries, J.F.; Aerts, J.G.J.V.; Dumoulin, D.W.; Bahce, I.; Niemeijer, A.-L.N.; De Langen, A.J.; et al. Effect of Pembrolizumab After Stereotactic Body Radiotherapy vs Pembrolizumab Alone on Tumor Response in Patients With Advanced Non–Small Cell Lung Cancer: Results of the PEMBRO-RT Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019, 5, 1276–1282. [Google Scholar] [CrossRef] [PubMed]
  58. Palma, D.A.; Olson, R.; Harrow, S.; Gaede, S.; Louie, A.V.; Haasbeek, C.; Mulroy, L.; Lock, M.; Rodrigues, P.G.B.; Yaremko, B.P.; et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): A randomised, phase 2, open-label trial. Lancet 2019, 393, 2051–2058. [Google Scholar] [CrossRef]
  59. Palma, D.A.; Olson, R.; Harrow, S.; Gaede, S.; Louie, A.V.; Haasbeek, C.; Mulroy, L.; Lock, M.; Rodrigues, G.B.; Yaremko, B.P.; et al. Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. J. Clin. Oncol. 2020, 38, 2830–2838. [Google Scholar] [CrossRef] [PubMed]
  60. Popp, I.; Vaes, R.D.; Wieten, L.; Adebahr, S.; Hendriks, L.; Haghighi, E.B.; Degens, J.; Schäfer, H.; Greil, C.; Peeters, S.; et al. Radiotherapy to reinvigorate immunotherapy activity after acquired resistance in metastatic non-small-cell lung cancer: A pooled analysis of two institutions prospective phase II single arm trials. Radiother. Oncol. 2023, 190, 110048. [Google Scholar] [CrossRef] [PubMed]
  61. Boshuizen, J.; Pencheva, N.; Krijgsman, O.; Altimari, D.D.; Castro, P.G.; de Bruijn, B.; Ligtenberg, M.A.; Heuvel, E.G.-V.D.; Vredevoogd, D.W.; Song, J.-Y.; et al. Cooperative Targeting of Immunotherapy-Resistant Melanoma and Lung Cancer by an AXL-Targeting Antibody–Drug Conjugate and Immune Checkpoint Blockade. Cancer Res. 2021, 81, 1775–1787. [Google Scholar] [CrossRef] [PubMed]
  62. Parker, C.; Nilsson, S.; Heinrich, D.; Helle, S.I.; O’Sullivan, J.M.; Fosså, S.D.; Chodacki, A.; Wiechno, P.; Logue, J.; Seke, M.; et al. Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer. N. Engl. J. Med. 2013, 369, 213–223. [Google Scholar] [CrossRef] [PubMed]
  63. Higano, C.S.; George, D.J.; Shore, N.D.; Sartor, O.; Miller, K.; Conti, P.S.; Sternberg, C.N.; Saad, F.; Sade, J.P.; Bellmunt, J.; et al. Clinical outcomes and treatment patterns in REASSURE: Planned interim analysis of a real-world observational study of radium-223 in metastatic castration-resistant prostate cancer. EClinicalMedicine 2023, 60, 101993. [Google Scholar] [CrossRef]
  64. Sartor, O.; de Bono, J.; Chi, K.N.; Fizazi, K.; Herrmann, K.; Rahbar, K.; Tagawa, S.T.; Nordquist, L.T.; Vaishampayan, N.; El-Haddad, G.; et al. Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N. Engl. J. Med. 2021, 385, 1091–1103. [Google Scholar] [CrossRef] [PubMed]
  65. Choi, J.; Raghavan, M. Diagnostic Imaging and Image-Guided Therapy of Skeletal Metastases. Cancer Control. 2012, 19, 102–112. [Google Scholar] [CrossRef] [PubMed]
  66. O’Sullivan, G.J.; Carty, F.L.; Cronin, C.G. Imaging of bone metastasis: An update. World J. Radiol. 2015, 7, 202–211. [Google Scholar] [CrossRef] [PubMed]
Cancers 16 02136 g001
Figure 1. (a) Objective response rate in entire cohort; (b) Objective response rate by systemic therapy; (c) Site-specific response rate. Legend: CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; ICI: Immune checkpoint inhibitor; Ch: Chemotherapy.
Figure 1. (a) Objective response rate in entire cohort; (b) Objective response rate by systemic therapy; (c) Site-specific response rate. Legend: CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; ICI: Immune checkpoint inhibitor; Ch: Chemotherapy.
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Cancers 16 02136 g002
Figure 2. (a) Baseline median tumour volume in entire cohort; (b) Percentage change in tumour volume by site in immunotherapy and chemoimmunotherapy cohort; (c) Baseline tumour volume and objective response rate in immunotherapy and chemoimmunotherapy cohort; legend: **: p < 0.01; ***: p < 0.001.
Figure 2. (a) Baseline median tumour volume in entire cohort; (b) Percentage change in tumour volume by site in immunotherapy and chemoimmunotherapy cohort; (c) Baseline tumour volume and objective response rate in immunotherapy and chemoimmunotherapy cohort; legend: **: p < 0.01; ***: p < 0.001.
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Cancers 16 02136 g003aCancers 16 02136 g003b
Figure 3. (a) Progression-free survival of entire cohort; (b) Overall survival of entire cohort. Legend: PFS: progression-free survival; OS: overall survival; CI: confidence interval.
Figure 3. (a) Progression-free survival of entire cohort; (b) Overall survival of entire cohort. Legend: PFS: progression-free survival; OS: overall survival; CI: confidence interval.
Cancers 16 02136 g003aCancers 16 02136 g003b
Cancers 16 02136 g004aCancers 16 02136 g004bCancers 16 02136 g004cCancers 16 02136 g004d
Figure 4. (a) Progression-free survival by bone metastases; (b) Progression-free survival by liver metastases; (c) Overall survival by bone metastases; (d) Overall survival by liver metastases. Legend: PFS: progression-free survival; OS: overall survival; CI: confidence interval; HR: hazard ratio.
Figure 4. (a) Progression-free survival by bone metastases; (b) Progression-free survival by liver metastases; (c) Overall survival by bone metastases; (d) Overall survival by liver metastases. Legend: PFS: progression-free survival; OS: overall survival; CI: confidence interval; HR: hazard ratio.
Cancers 16 02136 g004aCancers 16 02136 g004bCancers 16 02136 g004cCancers 16 02136 g004d
Table 1. Baseline Characteristics.
Table 1. Baseline Characteristics.
CharacteristicAll
n = 285 (%)		Immunotherapy
n = 96 (%)		Chemoimmunotherapy
n = 106 (%)		Chemotherapy
n = 83 (%)
Age *68 (60, 74)70 (62, 75)66 (58, 72)67 (60, 73)
Sex
Female111 (39)36 (38)40 (38)35 (42)
Male174 (61)60 (63)66 (62)48 (58)
ECOG PS
0105 (37)27 (28)41 (39)37 (45)
1139 (49)52 (54)56 (53)31 (37)
≥241 (14)17 (18)9 (8)15 (18)
Tumour Type
Adenocarcinoma181 (64)54 (56)68 (64)59 (71)
SCC67 (24)28 (29)22 (21)17 (20)
ULCC29 (10)12 (13)12 (11)5 (6)
NOS8 (3)2 (2)4 (4)2 (2)
PD-L1 Expression
Tested211 (74)81 (84)102 (96)28 (34)
<1%58 (27)2 (2.4)40 (39)16 (57)
≥1%52 (25)9 (11)33 (32)10 (36)
≥50%101 (48)70 (83)29 (28)2 (7.1)
Not tested74 (26)15 (16)4 (3.8)55 (66)
Upfront RT
Radiotherapy98 (34)37 (39)46 (43)15 (18)
No radiotherapy187 (66)59 (61)60 (57)68 (82)
Lung Metastases
Not present134 (47)47 (49)55 (52)32 (39)
Present151 (53)49 (51)51 (48)51 (61)
LN Metastases
Not present49 (17)16 (17)21 (20)12 (14)
Present236 (83)80 (83)85 (80)71 (86)
Brain Metastases
Not present225 (79)76 (79)81 (76)68 (82)
Present60 (21)20 (21)25 (24)15 (18)
Liver Metastases
Not present238 (84)86 (90)84 (79)68 (82)
Present47 (16)10 (10)22 (21)15 (18)
Bone Metastases
Not present200 (70)71 (74)62 (58)67 (81)
Present85 (30)25 (26)44 (42)16 (19)
Adrenal Metastases
Not present232 (81)76 (79)83 (78)73 (88)
Present53 (19)20 (21)23 (22)10 (12)
Pleural Metastases
Not present190 (67)64 (67)73 (69)53 (64)
Present95 (33)32 (33)33 (31)30 (36)
* Interquartile range. Legend: n: number; ECOG PS: Eastern Cooperative Oncology Group Performance Status; SCC: squamous cell carcinoma; ULCC: undifferentiated large-cell carcinoma; NOS: not otherwise specified; PD-L1: programmed cell death ligand 1 receptor; RT: radiotherapy.
Table 2. Significant Associations with Response and Survival in the Multivariate Analysis.
Table 2. Significant Associations with Response and Survival in the Multivariate Analysis.
ORRPFSOS
CharacteristicOR (95% CI)p-ValueHR (95% CI)p-ValueHR (95% CI)p-Value
Pleural Metastases 0.05
  Not present1.00
  Present1.93 (1.02, 3.74)
Bone Metastases <0.01 <0.01 <0.001
  Not present1.00 1.00 1.00
  Present0.35 (0.16, 0.73) 1.70 (1.17, 2.47) 2.01 (1.37, 2.97)
Smoking Status <0.01 0.02
  Never Smoked1.00 1.00
  Ex-Smoker3.06 (1.11, 9.19) 0.51 (0.32, 0.82)
  Current Smoker6.67 (2.09, 23.3) 0.61 (0.35, 1.06)
Treatment Type <0.001
  Chemotherapy 1.00
  Immunotherapy 0.52 (0.31, 0.86)
  Chemoimmunotherapy 0.34 (0.21, 0.56)
Metastatic lesion ≥ 5 cm <0.01
  Not present 1.00
  Present 1.74 (1.21, 2.50)
PD-L1 Status 0.01
  <1% 1.00
  ≥1% 0.74 (0.44, 1.24)
  ≥50% 0.63 (0.41, 0.97)
Tumour Type <0.01
  Adenocarcinoma 1.00
  SCC 2.05 (1.39, 3.04)
  ULCC 0.88 (0.47, 1.63)
  NOS 0.36 (0.05, 2.74)
Volume of metastases 0.03
  <20 metastases 1.00
  ≥20 metastases 1.66 (1.05, 2.62)
Legend: ORR: objective response rate; PFS: progression-free survival; OS: overall survival; OR: odds ratio; HR: hazard ratio; CI: confidence interval; PD-L1: Programmed Cell Death Ligand 1; SCC: squamous cell carcinoma; ULCC: undifferentiated large-cell carcinoma; NOS: not otherwise specified.
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MDPI and ACS Style

Brown, L.J.; Ahn, J.; Gao, B.; Gee, H.; Nagrial, A.; Hau, E.; Silva, I.P.d. Site-Specific Response and Resistance Patterns in Patients with Advanced Non-Small-Cell Lung Cancer Treated with First-Line Systemic Therapy. Cancers 2024, 16, 2136. https://doi.org/10.3390/cancers16112136

AMA Style

Brown LJ, Ahn J, Gao B, Gee H, Nagrial A, Hau E, Silva IPd. Site-Specific Response and Resistance Patterns in Patients with Advanced Non-Small-Cell Lung Cancer Treated with First-Line Systemic Therapy. Cancers. 2024; 16(11):2136. https://doi.org/10.3390/cancers16112136

Chicago/Turabian Style

Brown, Lauren Julia, Julie Ahn, Bo Gao, Harriet Gee, Adnan Nagrial, Eric Hau, and Inês Pires da Silva. 2024. "Site-Specific Response and Resistance Patterns in Patients with Advanced Non-Small-Cell Lung Cancer Treated with First-Line Systemic Therapy" Cancers 16, no. 11: 2136. https://doi.org/10.3390/cancers16112136

APA Style

Brown, L. J., Ahn, J., Gao, B., Gee, H., Nagrial, A., Hau, E., & Silva, I. P. d. (2024). Site-Specific Response and Resistance Patterns in Patients with Advanced Non-Small-Cell Lung Cancer Treated with First-Line Systemic Therapy. Cancers, 16(11), 2136. https://doi.org/10.3390/cancers16112136

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