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Abstract

Background:

Immune checkpoint inhibitors (ICIs) represent a keystone of cancer treatment, including non-small-cell lung cancer (NSCLC). Unfortunately, the efficacy of ICIs remains poor in patients with bone metastases from NSCLC. Recently, several case reports have suggested the clinical benefit of radiotherapy in advanced NSCLC patients. However, whether this positive effect is applicable during ICI treatment of NSCLC involving bones remains to be established.

Methods:

We retrospectively reviewed the records of patients with bone metastases who received ICIs as monotherapy (anti-PD1 or anti-programmed death-ligand 1) as well as in combination with platinum-based-chemotherapy (carboplatin or cisplatin). We next analyzed the presence or the absence of radiotherapy targeting bone metastases (RT) among these patients during immunotherapy.

Results:

A total of 40 patients were included in this study; among them, 10 (25%) received palliative RT for symptomatic bone metastases during cancer immunotherapy treatment with ICIs (RT group); the remaining 30 (75%) patients did not receive bone irradiation (Non-RT group). We observed that the RT group had a significantly longer overall survival (OS) than the Non-RT group, with a median survival of 16 months in the RT group versus 3 months in the Non-RT group (log-rank test p < 0.048; hazard ratio (HR) for OS = 0.44; 95% confidence interval (CI): 0.18–1.00). Similar results were observed with respect to progression-free survival (PFS; log-rank test p < 0.016; HR for PFS = 0.34; 95% CI: 0.15–1.00).

Conclusion:

Our results suggest that radiotherapy to bone metastases may improve ICIs efficacy in patients with bone metastatic NSCLC.

Keywords

abscopal effect bone metastasis bystander effect immune checkpoint inhibitors immunotherapy non-small-cell lung cancer radiotherapy

Introduction

Lung cancer is the second most common cancer in both men and women and is the leading cause of cancer-related death worldwide. Fortunately, the overall survival (OS) rate of patients with metastatic non-small-cell lung cancer (NSCLC) has improved in recent years and such improvement is probably due to the advent of immune checkpoint inhibitors (ICIs).¹ Several biomarkers (e.g., programmed death-ligand 1 (PD-L1), tumor mutation burden) and clinical characteristics (e.g., gut microbiota, performance status, neutrophil to lymphocyte ratio) have helped us to identify which patients could benefit the most from ICIs treatment.² Nevertheless, there is still a significant percentage of patients with little chance to be cured.

In fact, the life expectancy is particularly disappointing among NSCLC patients with bone metastases,³ despite the aforementioned advent of ICIs.⁴ Palliative bone radiation therapy (RT) may help to mitigate the magnitude of the bone pain.⁵ Pre-specified subgroup analysis focusing “ad hoc” on bone metastatic patients is lacking in immunotherapy clinical trials,^6–9 as well as in two meta-analyses.^10,11 Thus, the appropriate clinical management of NSCLC patients with bone metastases remains an open issue.

In this retrospective analysis, we explored the potential role of concomitant treatment with palliative bone RT and ICIs in a mono-institutional cohort of 40 patients with bone metastases from NSCLC. We also examined, in both a univariate way and multivariate way, other clinicopathological characteristics associated with the prognosis of this peculiar subset of metastatic NSCLC patients.

Materials and methods

Patients were retrospectively identified from our institutional database of cancer diagnoses. Specifically, patients were required to have both a diagnosis of bone metastases arising from NSCLC primary tumor and to be on ICI treatment. The outpatients received ICI treatment at our Day Hospital between June 2016 and February 2021, irrespective of the treatment line or the type of ICI (i.e., antiPD1 or antiPD-L1 therapy). The diagnosis and staging of NSCLC were according, respectively, to the World Health Organization criteria and the IASCL/TNM 8th edition staging lung cancer system.^12,13 Cases of uncertain bone involvement were excluded. All consecutive patients who met the criteria of NSCLC and ICI administration were included. ICI drugs included anti-PD1 nivolumab or pembrolizumab, as well as antiPD-L1 atezolizumab. Clinical and laboratory details at diagnosis of NSCLC as well as at the time of starting ICI treatment were abstracted from medical records. All therapeutic interventions were recorded and assessed after the ICI administration and treatment categories included supportive care only, chemotherapy, and radiotherapy for bone metastases. Noteworthy, only patients undergone concomitant administration of both bone radiotherapy and ICIs systemic treatment were included in the radiotherapy subgroup analysis. Imaging responses were evaluated using modified Response Evaluation Criteria in Solid Tumors (RECIST version 1.1).¹⁴ All patients signed a consent form prior to undergoing ICI treatment to allow data publication.

Data were summarized according to frequency and percentage for categorical variables and by medians and ranges for continuous variables. Progression-free survival (PFS) was measured as the time from the beginning of ICI to progression or death. OS was measured as the time from the beginning of ICI to progression or death. Patients alive without progression at the time of analysis were censored at their last follow-up assessment. All statistical analyses were performed using SPSS (version 27 software; IBM Corporation, Armonk, NY, USA). Data were calculated as frequencies for categorical variables and median (standard deviation) for continuous variables. Categorical variables were compared using the Chi-square test or Fisher’s exact test, and continuous variables were compared using the independent unpaired t-test. PFS and OS were assessed by Kaplan–Meier survival curves and statistical differences were calculated using the log-rank test. Hazard ratios (HRs) estimated from the Cox analysis were reported with 95% confidence intervals (CIs). All p-values were two-sided and p-values of less than 0.05 were considered statistically significant.

Results

A total of consecutive 40 patients who met the criteria of NSCLC and ICI administration (nivolumab, pembrolizumab, or atezolizumab) were included in this retrospective analysis; 10 (25%) received palliative RT for symptomatic bone metastases during cancer immunotherapy treatment with ICIs (RT group); the remaining 30 (75%) patients did not receive bone irradiation (Non-RT group). The patient characteristics are displayed in Table 1. The median age was 70, 70, and 67 years old, in the whole cohort of patients, the RT group, the Non-RT group and the, respectively. Around 75% of patients were men, and the baseline ECOG performance status was ⩽2 in all patients. Almost 72% of the patients (n = 28) had non-squamous NSCLC stage IV. Most of the patients were former or current smokers (n = 30, 75%), had PD-L1 tumor expression (n = 24, 80%), and had no driver mutation (n = 37, 92%). The characteristics of the two groups were not different from each other, as shown in Table 1. There was a tendency to a greater squamous histology in the RT group than in the Non-RT group as well as a female gender and a biomarker driver disease, although non-significant differences have been observed as shown in Table 1.

Table 1.

Patient characteristics (n = 40).

Variables	RT group (n = 10)	Non-RT group (n = 30)	p-Value
Age (years)
Median (range)	67 (57–80)	70 (35–81)	0.58^a
⩾70	4 (40%)	15 (50%)
<70	6 (60%)	15 (50%)
Gender
Female	4 (40%)	5 (16%)	0.13^a
Male	6 (70%)	25 (84%)
Performance status
0–1	8 (80%)	19 (60%)	0.45^b
⩾2	2 (20%)	11 (40%)
Histology
SCC	3 (30%)	6 (20%)	0.65^b
Non-SCC	7 (70%)	24 (80%)
M1 liver involvement
Yes	7 (70%)	22 (74%)	1.00^b
No	3 (30%)	8 (26%)
M1 brain involvement
Yes	3 (30%)	6 (20%)	0.65^b
No	7 (70%)	24 (80%)
Smoking status
Current or former smoker	8 (80%)	27 (90%)	0.58^b
Never smoker	2 (20%)	3 (10%)
Driver mutation status
Positive	2 (20%)	1 (3%)	0.15^b
Negative	8 (80%)	29 (97%)
PD-L1 expression
0%	4 (40%)	12 (40%)	1.00^a
1%–49%	2 (20%)	6 (20%)
>50%	4 (40%)	12 (40%)
Chemotherapy
Yes	8 (80%)	29 (97%)	0.15^b
No	2 (20%)	1 (3%)

Driver mutation analysis includes EGFR/Her1, ALK, and ROS1. PD-L1 staining was performed using Dako 22C3 monoclonal human antibody. Systemic chemotherapy: cisplatin, carboplatin, docetaxel, gemcitabine, paclitaxel, pemetrexed, and vinorelbine.

Chi-square χ² test.

Fisher’s exact test.

ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor; PD-L1, programmed death-ligand 1; RT, palliative bone radiation therapy; SCC, squamous cell carcinoma.

We performed a univariate analysis of various clinicopathological factors and we found by the stepwise multivariate analysis that the irradiation of bone metastases has a non-significant impact on ICI efficacy in terms of both OS and PFS (for details see Figure S1). The RT group had a significantly longer OS than the Non-RT group, with a median survival of 16 months in the RT group versus 3 months in the Non-RT group (log-rank test p < 0.048; HR for OS = 0.44 (95% CI: 0.18–1.00)), as shown in Figure 1. Similarly, the RT group had a significantly longer PFS than the Non-RT group, with a median survival of 5.5 months in the RT group versus 2 months in the Non-RT group log-rank test p < 0.016. HR for PFS = 0.34 (95% CI: 0.15–1.00), as shown in Figure 2.

Figure 1.

OS among all patients undergone to ICIs stratified by palliative RT treatment for bone metastases. RT group median OS = 16 months (95% CI: 1–43); Non-RT group median OS = 3 months (95% CI: 1.0–5.3) log-rank test p < 0.048. HR for OS = 0.44 (95% CI: 0.18–1.00).

Figure 2.

PFS among all patients undergone to ICIs stratified by palliative RT treatment for bone metastases. RT group median PFS = 5.5 months (95% CI: 1.00–25.25); Non-RT group median PFS = 2 months (95% CI: 0.00–2.43) log-rank test p < 0.016. HR for PFS = 0.34 (95% CI: 0.15–1.00).

Focusing on patients with the oncogene-addicted disease (N = 3; two patients with anaplastic lymphoma kinase—ALK—translocation of whom one in the RT group and one in the Non-RT group, and one Epidermal Growth Factor—EGFR—exon 21 mutation L858R positive in the RT group), no survival differences appeared and all these patients underwent first-line targeted therapy. The patient with EGFR in the RT group remained alive after 33 months, whereas both ALK-positive patients died within 1 year of ICI treatment.

Discussion

Nowadays, immunotherapy is widely used in patients with lung cancer in both advanced and early disease settings.

We examined the impact of palliative radiotherapy for bone metastases on ICI efficacy in a cohort of 40 patients with stage IV NSCLC and we observed a positive impact of bone RT on PFS and OS. The patient characteristics were well balanced between the two groups, except for the squamous histology that was over-represented in the RT group, presumably because of the doctor’s propensity to suggest RT treatment modality in the presence of the radiosensitive squamous histology rather than adenocarcinoma metastatic cancer cells.

We observed a significant increase in the median OS, nearly 13 months longer, in patient who underwent bone radiotherapy (RT) during ICI treatment, regardless of the specific used (data not shown) as well as other clinicopathological predictors. Likewise, the PFS was significantly longer in the RT group.

Our results are consistent with a similar large retrospective analysis performed in the Asian patient population undergoing pembrolizumab therapy and palliative bone RT.¹⁵ On the other hand, only a few (N = 13) patients who received bone metastatic radiotherapy were included in two perspective-negative phase II trials aimed at investigating the benefit of adding radiotherapy to ICI treatment.^16,17 In our opinion, the negative outcomes from these two perspective trials may not be applied to NSCLC patients undergoing concomitant bone irradiation and ICI treatment because of the paucity of bone metastatic patients.

In fact the positive impact of RT on survival that we observed during immunotherapy aligns with other previous reports.^18,19

It has been hypothesized that the abscopal effect of radiotherapy might be explained by pro-immunogenic effects induced by ionizing radiation. This suggests that ICI systemic therapy can be administered concurrently or shortly after RT, as demonstrated in our study.²⁰ Consequently, thinking about using radiotherapy for bone metastases at the same time as ICI treatment might be a good choice. However, because of the retrospective nature of our analysis, further studies are necessary to validate this hypothesis. Specifically, prospective trials with a larger cohort of patients with bone metastases are needed to strengthen these observations. Another important limitation of our retrospective analysis is the under-representation of oncogene-addicted disease, perhaps because at that time we used a small gene panel (i.e., EGFR, ROS1, ALK, PD-L1) by polymerase chain reaction probes and/or immunohistochemistry instead of next-generation sequencing tools.

Conclusion

Our results support the notion that palliative RT for bone metastases arising from NSCLC may improve the efficacy of ICI treatment and that the abscopal effect may be more efficiently exploited during immunotherapy, rather than other systemic treatment modalities. In summary, we suggest that RT to bone metastases might be administered concomitantly to ICI treatment not only to mitigate the pain but also to enhance immunotherapy efficacy.

Supplemental Material

sj-docx-1-tam-10.1177_17588359251332451 – Supplemental material for The role of bone radiotherapy during immune checkpoint inhibitors treatment of non-small-cell lung cancer: a single-institution experience

Supplemental material, sj-docx-1-tam-10.1177_17588359251332451 for The role of bone radiotherapy during immune checkpoint inhibitors treatment of non-small-cell lung cancer: a single-institution experience by Ivan Facilissimo, Guido Natoli, Fabio Gaspari, Tiziana Comandone, Diego Bongiovanni, Paola Gollini, Claudia Provenza and Alessandro Comandone in Therapeutic Advances in Medical Oncology

Footnotes

Acknowledgements

The authors thank all patients, their families, and particularly their caregivers for the confidence placed in us.

Author’s note

Poster presentation: ESMO 2021 annual meeting.

Declarations

ORCID iD

Guido Natoli

Supplemental material

Supplemental material for this article is available online.

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