Programmed cell death 1 pathway inhibitors improved overall survival of small cell lung cancer patients with brain metastases

doi:10.21203/rs.3.rs-1421720/v1

Purpose

The objective of this study was to evaluate the safety and efficacy of immune checkpoint inhibitors applied in the small cell lung cancer patients with brain metastases.

Methods

We retrospectively reviewed the records of small cell lung cancer patients with brain metastases treated with chemotherapy and radiotherapy for brain metastases with or without immune checkpoint inhibitors at our institution from January 2019 to January 2021. Patients were divided into two groups. In Group A, patients received chemotherapy and radiotherapy. In Group B, patients received chemotherapy, radiotherapy and at least four cycles of immunotherapy. Overall survival and intracranial progression-free survival were assessed using Kaplan-Meier estimates and Cox regression models.

Results

A total of 295 patients were enrolled in our study. By the end of the study (March 12, 2021), the median overall survival was 28.1 months among 64 patients in Group B, and 13.2months among 231 patients in Group A respectively (hazards ratio [HR] 0.450, 95% confidence interval [CI], 0.263–0.769, P = 0.004). Both the univariate analysis and multivariate analysis suggested two factors were significantly correlated with overall survival, including immunotherapy, presence of extracranial metastases. The median intracranial progression-free survival was 7.63months in Group A, 10.47 months in Group B (HR = 0.716, 95% confidence interval [CI], 0.326–0.973, P = 0.040). The intracranial objective response rate and intracranial disease control rate was similar between them.

Conclusion

Immunotherapy plus chemotherapy and radiotherapy for brain metastases showed promising efficacy for small cell lung cancer patients with brain metastases.

programmed cell death 1 (PD-1)

programmed cell death ligand 1 (PD-L1)

small cell lung cancer

brain metastases

immune checkpoint inhibitors (ICIs)

Small cell lung cancer (SCLC) is an exceptionally aggressive subtype of lung cancer, and over 20% of SCLC patients were presented with brain metastases (BMs) at the time of initial diagnosis(Cagney, Martin, Catalano et al. 2017, Lamba, Wen and Aizer 2021). In addition, 50% SCLC patients will develop BMs sometime during the course of the disease(Takahashi, Yamanaka, Seto et al. 2017).These patients seldom have therapeutic options. Most have a poor prognosis of 5-year survival rate under 5%(Li, Xue, Yang et al. 2021). Chemotherapy has limited efficacy due to blood-brain barrier, blood-cerebrospinal fluid barrier, high interstitial fluid pressures and abnormal local perfusion(Askoxylakis, Arvanitis, Wong et al. 2017). A significant number of patients responded to radiotherapy, but the response duration and survival are not ideal. The median overall survival (OS) was 8.5 months among SCLC patients who received stereotactic radiosurgery (SRS), and only about 5 months among those who received whole-brain radiation therapy (WBRT) (Bernhardt, Adeberg, Bozorgmehr et al. 2018, Rusthoven, Yamamoto, Bernhardt et al. 2020). Neurosurgical resection helps decrease the intracranial pressure caused by BMs (1–3 BMs), and offers prolonged survival when followed by adjuvant radiotherapy.

Two randomized clinical trials, IMPOWER133(Liu, Reck, Mansfield et al. 2021)and CASPIAN(Goldman, Dvorkin, Chen et al. 2021), had shown that programmed cell death 1 ligand 1 (PD-L1) inhibitors (atezolizumab or durvalumab) combined with platinum-based doublet chemotherapy improved OS versus chemotherapy in Extensive stage small cell lung cancer (ES-SCLC) patients. Subgroup analysis of the CASPIAN clinical trial suggested that SCLC patients with BMs had OS benefit from durvalumab. Programmed cell death protein 1(PD-1) inhibitors also showed activity against BMs from non-small cell lung cancer (NSCLC) with PD-L1 ≥ 50%(Metro, Banna, Signorelli et al. 2020). However, in IMPOWER133, the OS benefit for BMs patients was not observed. Therefore, it is still not clear whether SCLC patients with BMs gain OS benefit from PD-1/PD-L1 inhibitor treatment. The objective of our study was to determine the efficacy of additional immune checkpoint inhibitors (ICIs) in the treatment of SCLC patients with BMs.

2.1 Patients selection

We retrospectively reviewed the electronic medical records of SCLC patients with BMs in our hospital between January 2019 and January 2021 with the last follow-up date March 12, 2021. Patients who matched inclusion criteria were enrolled into the study. Inclusion criteria included: (1) age > 18 years old, (2) Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2, (3) pathologically confirmed SCLC, (4) contrast-enhanced computed tomography (CT)or gadolinium-enhanced magnetic resonance imaging (MRI) confirmed BMs, 5) received at least 4 cycles of chemotherapy and radiotherapy for BMs with or without no less than 4 cycles of immunotherapy, the treatment line when ICIs were applied was not restricted, (6) completeness of full medical records. Exclusion criteria included: (1) patients received less than 4 cycles of chemotherapy or who did not complete the radiation treatment, (2) incompleteness of full medical records. According to the different treatment, patients were divided into two groups. In Group A, patients received chemotherapy and radiotherapy for BMs (CRT). In Group B, patients received CRT and immunotherapy (≥ 4 cycles).

The objective response was evaluated according to RECIST version 1.1. The death date and cause of death was followed up by telephone.

2.2 Endpoints

Primary endpoints: overall survival (OS) was defined as time from BM diagnosis to death from any cause or last follow-up. OS at 12 months.

Secondary endpoints: intracranial progression-free survival (IPFS) was defined as time from radiotherapy to the date of objective disease progression or death from any cause in the absence of progression. Noting that, in group B, the IPFS time of patients who received immunotherapy before or after radiotherapy within 1 month was calculated, but the interval of immunotherapy and radiotherapy more than 1 month was uncounted. Objective Response Rate (ORR), proportion of patients with a complete or partial response on at least one visit. Disease Control Rate (DCR), proportion of patients with a complete or partial response or stable disease on at least one visit.

Progression-free survival and objective response were assessed according to RECIST version 1.1.

Patients were evaluated by MRI or CT after each two cycles of treatment. We tried to use the same imaging examination methods to evaluate the efficacy. Considering the fact that different imaging methods may affect the interpretation of the outcomes, we tried to use the same examination method to assess the results before and after treatment.

2.3 Statistical analysis:

We use SPSS 23.0 software for statistical analysis. Categorical data were compared with Fisher’s exact or Chi-squared tests. The Kaplan-Meier method was used to estimate rates of OS, IPFS. To estimate OS differences among groups, the log-rank test was used. We used Cox regression models for Multivariate analysis. All p-values were based on the score test for a two-sided hypothesis. Two-sided tests with p < 0.05 were considered statistically significant.

3.1 Patient characteristics

Two patients in group B were excluded when data analyzed because of unfinished 4 cycles of systematic treatment. One was because of 3 grade myocarditis only after one cycle of ICIs plus chemotherapy, the other suffered from 3 grade pneumonia after two cycles of systematic treatment. Finally, a total of 295 SCLC patients with BMs were admitted to our study, with 64 patients in Group B and 231 patients in Group A. The median age of the patients at the time of diagnosis of BM was 61 years (ranging from 31–81 years). Between the two groups, baseline patient characteristics (Table 1) had no significant difference. The median size of brain metastases was 16.31mm(2-58mm). About 7 kinds of ICIs were applied in group B, including durvalumab (14), atezolizumab (14), nivolumab (6), toripalimab (6), tislelizumab (8), sintilimab (18) and camrelizumab (4). Among the 64 patients, 6 of them applied 2 kinds of drugs, including 4 received PD-1 and PD-L1 monoclonal antibody, the other 2 used two different drugs of PD-1 monoclonal antibody during treatment.

Table 1

Baseline patient characteristics.
Variable	Group A N = 231(%)	Group B N = 64 (%)	P-value
Median age, years ≤ 60 > 60	102(44.2) 129(55.8)	36(56.3) 28(43.8)	0.086
Gender Male Female	181(78.4) 50(21.6)	48(75.0) 16(25.0)	0.569
ECOG status 0–1 2	215(93.1) 16(6.9)	16(95.3) 3(4.7)	0.518
Disease stage at diagnose Limited stage extensive stage	86(38.7) 136(61.3)	25(39.1) 39(60.9)	0.963
Number of BM 1–3 > 3	108(48.0) 117(52.0)	23(35.9) 41(64.1)	0.087
diagnosis of BM and lung cancer subsequently synchronous	159(68.8) 72(31.2)	39(60.9) 25(39.1)	0.234
PCI No Yes	200(86.6) 31(13.4)	54(84.4) 10(15.6)	0.652
Smoking Yes No	139(60.2) 92(39.8)	35(54.7) 29(45.3)	0.430
ECM No Yes	111(48.1) 120(51.9)	24(37.5) 40(62.5)	0.134
Symptomatic BM No Yes	156(67.5) 75(32.5)	46(71.9) 18(28.1)	0.508
Abbreviations: *statistically significant; BM, brain metastases; ECOG, Eastern Cooperative Oncology Group; PCI, Prophylactic cranial irradiation; ECM, extracranial metastases; ICI, immune checkpoint inhibitors; PD-1, Programmed cell death protein 1; PD-L1, programmed cell death 1 ligand 1

3.2 Survival Prognosis and clinical efficacy

3.21 Analysis for OS

In univariate analysis and multivariate analysis, it suggested that two factors were related to the OS of ES-SCLC patients with controlled BMs after radiotherapy. Higher extracranial metastases rate was correlated with worse OS, while immunotherapy was an independent prognostic factor associated with improved OS.

At the time of data analyzed, at least 4 cycles of immunotherapy plus CRT were associated with a significantly improvement in OS versus the CRT group (hazard ratio [HR] 0.450, 95% confidence interval [CI], 0.263–0.769, P = 0.004). The median OS were 28.1 months for Group B, and 13.2months for Group A. The 1-year OS rate was 71.2% with B, 54.1% with Group A. (Fig. 1.)

Extracranial metastases (ECM) status was associated with worse OS. There were 135 patients with only BMs in our study, while 160 patients with both BMs and ECM. Till March 2021, more patients survived in the only BMs group than the BMs and ECM group (65.2% versus 45.0%). The median OS time of SCLC patients with only BMs was 21.5 months, compared with 11.7 months of the patients complicated with BMs and ECM (HR 0.475, 95% CI 0.313–0.723, P = 0.001). The 1-year OS rate was 69.6% versus 45.1%. (Fig. 2.)

The results of univariate and multivariate analyses of factors affecting OS were presented in Table 2.

Table 2

Univariate and multivariate analysis of overall survival.
Variable	Univariate
Variable	HR	95%CI	P	HR	95%CI	P
Age < 61/≥61	1.164	0.828–1.635	0.382	1.099	0.758–1.594	0.618
Gender Male/female	0.760	0.488–1.182	0.221	0.903	0.514–1.586	0.723
ECOG status 0–1/2	0.760	0.383–1.506	0.430	0.7734	0.346–1.556	0.420
Number of BMs ≤ 3/>3	1.108	0.783–1.568	0.563	0.989	0.665–1.470	0.957
disease stage at diagnosis limited/ extensive	1.168	0.818–1.669	0.392	0.954	0.590–1.543	0.847
diagnosis of BM and LC subsequently/ synchronous	0.830	0.574-1.200	0.322	0.745	0.474–1.173	0.204
PCI Yes/ No	0.709	0.426–1.180	0.184	0.755	0.423–1.348	0.342
Smoking status Yes/No	1.219	0.861–1.725	0.264	1.060	0.674–10669	0.800
Symptomatic BM Yes /No	1.032	0.718–1.484	0.864	1.033	0.693–1.541	0.872
ECM Yes /No	0.525	0.368–0.748	< 0.001*	0.478	0.315–0.725	0.001*
Group Group A/Group B	0.470	0.280–0.786	0.003*	0.468	0.277–0.792	0.005*
Abbreviations: *statistically significant; HR, hazard ratio; CI, confidence interval; LC, lung cancer.

3.22 Cox Regression Analysis for IPFS

Our study found that additional immunotherapy prolonged IPFS of SCLC patients with BMs. The median IPFS was 7.63months for Group A, 10.47 months for Group B (HR 0.563, 95% CI 0.326–0.973, P = 0.040). IPFS at 12 months was 33.0% versus 43.5%, IPFS at 18 months was 17.7% versus 43.5% (Fig. 3).

Patients with BMs and ECM had shorter IPFS than those with only BMs. The median IPFS was 6.97months versus 11.5months (HR 0.505, 95% CI 0.345–0.741, P < 0.001). IPFS at 12 months was 26.9% versus 45.2%, IPFS at 18 months was 9.3% versus 29.6% (Fig. 4).

3.23 analysis of IORR and IDCR

There were 12 people received immunotherapy before BMs, the median time was 4.77months (ranging from 1.6 to 14.47months) of BMs happened after treatment of immunotherapy plus chemotherapy. When assessed BMs occurred, 6 of them gave up immunotherapy afterwards.

Counting from the day of radiotherapy started, the intracranial ORR (IORR) and intracranial DCR (IDCR) rates were similar between patients in Group A and Group B. The IORR rates were 83.9% in Group A and 89.4% in Group B(P = 0.491). The IDCR rates were 93.9% versus 93.6% (P = 0.945).

The reaction of intracranial and extracranial was not exactly the same. Among 64 individuals, 34 (53.1%) of them had a better reaction of intracranial, 7 of them were the same and 23 of them had higher efficacy of extracranial.

Management of SCLC with BMs is limited, and relies essentially on radiotherapy over the decades. WBRT is the standard treatment for them. Tyler P. Robin et al. (Robin, Jones, Amini et al. 2018) suggested radiosurgery alone is associated with favorable outcomes for SCLC patients afflicted with isolated BMs.

According to the results of IMPOWER133 and CASPIAN, atezolizumab and durvalumab, two kinds of PD-L1 monoclonal antibody, both had showed anti-tumor activity for ES-SCLC patients. QZ et al.(Zhou, Zhao, Wang et al. 2020) reported a case who achieved complete remission of local lesions after receiving durvalumab monotherapy as a third-line treatment. PD-L1 inhibitors seemed to be a new choice for SCLC patients. Tumor cells downregulate the immune response and promote immune tolerance by expressing PD-L1 and binding PD-1 expressed on the T cells. Immune checkpoint inhibitor (ICI) can block the interaction(Keir, Butte, Freeman et al. 2008), stimulate the normal activity of immune cells to achieve the anti-tumor effect. In theory, both PD-1 inhibitor and PD-L1 inhibitor have anti-tumor activities. Nevertheless, there was no convincing evidence which have proved that SCLCs obtain OS or PFS benefit from PD-l inhibition(Gadgeel, Pennell, Fidler et al. 2018, Owonikoko, Park, Govindan et al. 2021, Rudin, Rudin, Navarro et al. 2020, Spigel, Vicente, Ciuleanu et al. 2021). Fortunately, a meta-analysis(Yu, Chen, Cai et al. 2021) showed that SCLC patients had OS benefit from PD-1 inhibitors plus chemotherapy compared to chemotherapy. In this study, about 24 patients in group B applied PD-L1 monoclonal antibody during treatment, 36 people received PD-1 monoclonal antibody, and the other 4 individuals accepted two kinds of drugs successively. Further analysis of our study did not figure out which kind of drug benefit more. We found that compared to SCLC patients with BMs who only received CRT, the OS and IPFS were significantly improved among patients who received CRT plus immunotherapy no less than 4 cycles. The result was similar with the study of Schapira E. et al. (Schapira, Hubbeling, Yeap et al. 2018), who found the concurrent treatment of PD-1 inhibitors and radiotherapy improved the OS (median OS 17.6months) and locoregional disease control of NSCLC patients with BMs. Besides, a phase two study of tislelizumab in combination with platinum-based for ES-SCLC also showed a promising result. It demonstrated that the median PFS of SCLC patients was 6.9 months and the median OS was 15.6 months(Wang, Zhao, Ma et al. 2020). Furthermore, a case report using pembrolizumab alone in SCLC third-line treatment achieved a complete response(Zhang, Zhu and Lv 2020).

As proved, radiotherapy could modulate the immunogenicity of tumor cells. Sadly, it rarely generated durable therapeutic responses. Repeated radiation treatments always lead to serious side effects. Prolong the therapeutic responses seems to be a good way to improve the therapeutic effect. Dovedi et al.(Dovedi, Adlard, Lipowska-Bhalla et al. 2014) observed enhanced therapeutic efficacy from combination treatment of radiotherapy and immunotherapy. And they found increased expression of PD-L1 caused by low doses of local fractionated-dose radiotherapy delivered as 10 Gy in 5 fractions, which cohered with the result of Dovedi et al.(Sharabi, Nirschl, Kochel et al. 2015). Furthermore, lots of studies showed that radiation could enhance the adaptive immune system. Anurag Gupta(Gupta, Probst, Vuong et al. 2012) indicated that irradiation could activate tumor-associated dendritic cells, which resulted in the improvement of the antigen presentation to T cells. Eric A. Reits et al.(Reits, Hodge, Herberts et al. 2006) demonstrated that irradiation could upregulate the expression of MHC class Ⅰmolecules to reinforce the detection by the immune system. Simon J. The enhanced activity of immune system caused by radiotherapy may have helped the improvement.

It’s a pity that we did not observe significantly improvement of IORR and IDCR in group B. Prerna Guleria(Guleria, Kumar, Malik et al. 2020) indicated that PD-L1 expression on SCLC was extremely low, with a ratio of only about 3%. Ryul Kim et al. (Kim, Keam, Kim et al. 2019) suggested the levels of PD-1 + TILs were significantly decreased in BMs compared with primary lung lesion. In this study, only 6 patients detected the level of PD-L1 expression, one of them was 30%, the other 5 were lower than 3%. Maybe this can explain the result. And perhaps it is the reason why the survival benefit was not obvious among SCLC patients compared with NSCLC patients.

Our data indicated that both immunotherapy and ECM were related to the OS of SCLC patients with BMs. We found that many patients passed away from uncontrolled extracranial diseases rather than BMs, which was confirmed by Riihimaki M et al. (Riihimaki, Hemminki, Fallah et al. 2014).They suggested that SCLC patients were more likely to die of liver metastases or bone metastases rather than brain metastases. In their study, the 1-year survival rate was only 19% among patients with liver metastases while it was around 41% among patients with brain metastases. Denise et al. (Bernhardt, Konig, Aufderstrasse et al. 2018) suggested that ECM status significantly impact the OS of SCLCs with BMs, controlled or stable disease of ECM had longer median OS than those progressively or not controlled. The IMPOWER133(Goldman, Dvorkin, Chen et al. 2021) suggested that SCLC patients with liver metastases had OS benefit from treatment of PD-L1 inhibitor plus chemotherapy. Thus, we hypothesized that the additional immunotherapy would contribute to the management of the extracranial diseases, in turn the prolonged OS of Group B.

Given that SCLC patients with BMs have survival benefit from chemotherapy plus immunotherapy and radiotherapy for BMs. The timing of immunotherapy applied is not clear. The result of KEYNOTE-189(Gadgeel, Rodriguez-Abreu, Speranza et al. 2020) indicated that applying pembrolizumab in first-line rather than second-line treatment brought longer PFS for NSCLC patients. However, PD-1 monoclonal antibody did not show anti-tumor efficacy neither used in first-line(Rudin, Rudin, Navarro et al. 2020) nor second-line(Spigel, Vicente, Ciuleanu et al. 2021) treatment. Moreover, some patients in Group B used ICIs across the lines, which suggests the role of continuous using of ICIs in prolonging the OS of SCLC patients.

We acknowledge the limitations of our retrospective analysis. This is a single-institution analysis. Few patients with poor ECOG status were enrolled in our study, which might result in overestimate the efficacy of immunotherapy. Patients in group B applied different kinds of immune inhibitors, which might influence the outcome. Furthermore, treatment-related brain necrosis, memory deterioration and cognitive disorder were not analyzed in this study.

Further prospective clinical studies of the treatment for extensive-stage SCLC patients should be performed.

Immunotherapy improved OS and the intracranial IPFS of SCLC patients with brain metastases. Our study supported the concept that at least 4 cycles of ICIs should be applied for SCLC patients with BMs, and cross-lines treatment of ICIs is recommended. In consideration of the limited survivability of SCLC patients, we advise the use of ICIs as early as possible.

Funding This work was supported by a grant from the National Natural Science Foundation of China to Hui Zhu [Grant number: 81972862]

Competing Interests The authors declare that they have no conflict of interest.

Author contributions

All authors contributed to the study conception and design. JYC, XQJ, YH collected and analyzed the data in the study. JYC, XQJ, YH, KXG, RYL, SQL, HZ discussed the results and contributed to the final manuscript. JYC drafted the manuscript. YZ conceived of the presented idea and finished the critical revision of the article. All authors have read and approved the final manuscript.

Data availability datasets generated and analyzed during the study are available from JYC on reasonable request.

Ethics approval This retrospective study was performed using data from anonymized patients between January 2019 and January 2021. This study was approved by The Ethical Review Board of Shandong Cancer Hospital and Institute and complied with the Helsinki declaration (No. SDTHEC20210020049).

Consent to participate the need for written informed consent was waived due to the retrospective nature of the study.

Consent for publication All authors have consented to publication of the results presented in this manuscript.

Code availability Not applicable

Acknowledgments

We thank the support by the National Natural Science Foundation of China to HZ. And we acknowledge the work done by each author.

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Programmed cell death 1 pathway inhibitors improved overall survival of small cell lung cancer patients with brain metastases

Status:

Version 1

Abstract

Purpose

Methods

Results

Conclusion

Figures

1. Introduction

2. Materials And Methods

2.1 Patients selection

2.2 Endpoints

2.3 Statistical analysis:

3. Results

3.1 Patient characteristics

3.2 Survival Prognosis and clinical efficacy

4. Discussion

5. Conclusion

Declarations

References

Status:

Version 1