Real-world efficacy and safety of anlotinib as third- or further-line treatment in refractory small cell lung cancer

Abstract

Purpose

As a novel antiangiogenic multi-target tyrosine kinase inhibitor recently approved in China, anlotinib has exhibited promising anticancer efficacy and acceptable safety profile in the salvage treatment of small cell lung cancer (SCLC) in clinical trials. Here we retrospectively investigated the efficacy and safety of anlotinib as third- or further-line treatment in patients with refractory SCLC.

Patients and methods

A total of 40 patients with refractory SCLC treated with anlotinib monotherapy were included in this study. The clinicopathological data, treatment information, survival data and safety data were retrospectively collected. Survival curves were constructed using the Kaplan–Meier method. Univariate analysis was performed by log-rank testing.

Results

Altogether, 40 patients of extensive-stage SCLC or progressive limited-stage SCLC received anlotinib monotherapy as third- or further-line treatment from July 2018 to June 2020. Four patients achieved partial response (PR), 14 patients achieved stable disease (SD), no complete response (CR) was recorded, and 22 patients experienced progressive disease (PD). The disease control rate (DCR) was 45.0%. The median progression-free survival (PFS) was 3.0 months (95% CI 2.241–3.759), and the median overall survival (OS) was 7.8 months (95% CI 3.190–12.410). The common adverse effects (AEs) included hypertension, fatigue, anorexia, cough, rash and nausea. Grade 3 treatment-related AEs occurred in 3 (7.5%) patients. One patient interrupted anlotinib treatment due to repeated grade 1 epistaxis. Univariate analysis revealed that patients without liver metastases, previously treated with radiotherapy or with Eastern Cooperative Oncology Group (ECOG) scores of 0 or 1 had longer OS with anlotinib treatment. Cox regression analysis demonstrated that patients without liver metastases and patients with ECOG score ≤ 1 had longer PFS, while patients without liver metastases had longer OS.

Conclusion

Anlotinib is beneficial to refractory SCLC as third- or further-line treatment, especially in patients without liver metastasis and with better physical status. Related adverse effects are tolerable and manageable.

Introduction

Lung cancer is the main leading cause of cancer-related death all over the world including in China (Torre et al. 2016). Small cell lung cancer (SCLC) accounts for about 15% of all lung carcinomas and tends to always occur in heavy smokers (Saltos 2020). SCLC is an aggressive malignancy characterized by rapid tumor growth, early distant metastasis, and quick resistance to anti-cancer treatments (Taniguchi 2020). Upon the first diagnosis, more than half of SCLC patients are diagnosed with extensive-stage SCLC (ES-SCLC) which is defined by the presence of metastases outside the hemithorax of the primary tumor. Although ES-SCLC is sensitive to initial first-line platinum and etoposide combination chemotherapy with a high objective response rate (ORR) of more than 50%, the progression-free survival (PFS) is rather limited and the prognosis is extremely dismal with a median overall survival (OS) ranging from 8 to 12 months and a 2-year OS rate of only about 5% (Russo et al. 2017). As for second-line treatments, topotecan remains the standard regimen worldwide even with a quite poor response rate and short response duration (Antonia et al. 2016). SCLC treatment has no major breakthroughs in more than two decades until the recent approval of immune checkpoint inhibitors (ICIs) including programmed cell death-ligand 1 (PD-L1) antibodies and programmed cell death protein-1 (PD-1) antibodies in first-line and later-line treatment, respectively (Iams 2020). However, most patients especially those with refractory SCLC still demonstrate either primary resistance or rapid acquired resistance to ICIs. Thus, there is an urgent need to develop novel therapeutic regimens and expand the scope of current therapeutic strategies for SCLC.

According to the conception proposed by Dr. Judah Folkman, angiogenesis plays a significant role in the development and progression of cancers and this theory has been verified by many studies in multiple cancer types (Ramjiawan 2017). Nowadays, anti-angiogenesis therapy targeting one of the major hallmarks of tumor has become an indispensable anti-tumor strategy. However, the clinical efficacy of anti-angiogenic agents remains controversial in the management of SCLC (Stratigos et al. 2016). Multiple angiogenesis inhibitors have been studied in SCLC in different clinical trials. Unfortunately, none of them has been proved to significantly improve the overall survival of SCLC patients. For example, bevacizumab in combination with chemotherapy could only improve the PFS of SCLC patients but not OS (Shi et al. 2019). The OS benefit of other anti-angiogenic drugs, such as sunitinib, apatinib and nintedanib, was also demonstrated to be very limited in SCLC with only transient median PFS benefit and low overall response rate (Abdelraouf et al. 2016; Wu et al. 2019; Han et al. 2016). However, the therapeutic value of anti-angiogenic agents in SCLC once again came under the spotlight due to the recent promising clinical study results of a novel tyrosine kinase inhibitor (TKI) anlotinib.

As a novel TKI primarily targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR), anlotinib has been proved to have therapeutic effects in multiple solid tumors including medullary thyroid cancer, non-small cell lung cancer and soft tissue sarcomas (Shen et al. 2018). In a recent multi-center, randomized and double-blind phase II trial ALTER 1202, anlotinib significantly improved both the PFS and OS of SCLC patients compared with placebo as third- or further-line treatment (Cheng et al. 2018). Given its outstanding efficacy and safety profile, anlotinib was approved in refractory SCLC as third- or further-line treatment by the National Medical Products Administration of China in late 2019. However, it must be realized that ALTER 1202 is only a phase II clinical trial with a relatively small sample size; thus, future phase III trials with large sample sizes are needed to further prove the therapeutic role of anlotinib in refractory SCLC. In addition, real-world data are also needed to comprehensively evaluate the efficacy and safety of anlotinib in the treatment of refractory SCLC.

In the current study, we retrospectively investigated the efficacy and safety of anlotinib as third- or further-line treatment in patients with refractory SCLC in a real-world setting in Shandong Province Tumor Hospital from China. The adverse events (AEs) associated with anlotinib treatment were also analyzed in this study.

Materials and methods

Patients

We retrospectively collected the information of refractory SCLC patients who received anlotinib monotherapy as third-line or later-line treatment in Shandong Cancer Hospital from July 2018 to June 2020. ES-SCLC and progressive limited-stage SCLC patients who have failed at least two lines of standard chemotherapy with or without previous radiotherapy were included for analysis. Patients who have received immunotherapy before the usage of anlotinib monotherapy and patients receiving anlotinib-based combination therapy were excluded. Other exclusion criteria included uncontrolled pleural effusion, uncontrolled hemoptysis, severe brain metastases complication, or mixed SCLC histology. The disease has to be measurable with at least one unidimensional measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

Treatment methods

All patients received oral anlotinib at 8, 10 or 12 mg once per day for 2 weeks on and 1 week off in a 3-week cycle until intolerable toxicity, disease progression, or death. The dose of anlotinib was allowed to be modified or shortly interrupted to manage treatment-related AEs.

Efficacy and toxicities

The therapeutic efficacy was evaluated every two or three cycles of anlotinib according to the RECIST 1.1 criteria using computed tomography scans and/or nuclear magnetic resonance imaging. PFS was defined as the beginning of usage of anlotinib to the time point of disease progression or death (caused by any reason). OS was defined as from the beginning of the use of anlotinib to the time point of death (caused by any reason). ORR was calculated via adding complete response (CR) rate and partial response (PR) rate. The disease control rate (DCR) was calculated via adding complete response (CR) rate, partial response (PR) rate, and stable disease (SD) rate. Toxicities caused by anlotinib were assessed based on Common Terminology Criteria for Adverse Events version 5.0 (CTCAE 5.0). The data cutoff date was Aug 31, 2020.

Statistical analysis

SPSS 22.0 (SPSS Inc., Chicago, IL, USA) was used in this retrospective study for statistical analysis. Survival analyses were performed using the Kaplan–Meier method. Univariate analyses of PFS and OS were conducted by Log-rank test. Cox regression analysis was constructed for PFS and OS for multivariable analysis. Statistical significance was defined as p < 0.05. Synthesizing the statistical difference and clinical significance, variables with p < 0.05 in univariate analyses were included in a multivariate model as possible confounders or effect modifiers. The safety was evaluated by the rate of AEs of different grades according to CTCAE 5.0.

Results

Patients

A total of 40 patients with refractory SCLC were included for analysis in the present study and their baseline characteristics were shown in Table 1. Among them, 80% patients (n = 32) were male, 40% patients (n = 16) were with age ≥ 65 years, 55% patients (n = 22) had a smoking history, 72.5% patients (n = 29) had an Eastern Cooperative Oncology Group (ECOG) PS > 1, and 60% patients (n = 24) were initially diagnosed with ES-SCLC. At baseline, 27.5% patients (n = 11) were diagnosed with brain metastases and 22.5% patients (n = 9) were diagnosed with liver metastases. Time from the ending of first-line chemotherapy to disease progression or relapse, history of radiotherapy, previous radiotherapy site, history of previous VEGFR-TKI treatment were also shown in Table 1. All patients received at least two cycles of anlotinib monotherapy treatment. Among them, 75% patients (n = 30) started anlotinib at the dose of 12 mg, 17.5% patients (n = 7) at 10 mg and 7.5% patients (n = 3) at 8 mg. One patient stopped anlotinib treatment due to unmanageable epistaxis at the third cycle.

Table 1.

Baseline demographic and clinical characteristics of 40 refractory SCLC patients

Characteristic	Patients N (%)
Gender
Male	32 (80.0)
Female	8 (20.0)
Age(years)
< 65	24 (60.0)
≥ 65	16 (40.0)
Smoking status
Smoker	22 (55.0)
Never smoker	18 (45.0)
ECOG PS
≤ 1	11 (27.5)
> 1	29 (72.5)
Stage
Limited	16 (40.0)
Extensive	24 (60.0)
Number of distant metastases
< 2	31 (77.5)
≥ 2	9 (22.5)
Brain metastases
Yes	11 (27.5)
No	29 (72.5)
Liver metastases
Yes	9 (22.5)
No	31 (77.5)
Number of previous chemotherapy lines
= 2	31 (77.5)
> 2	9 (22.5)
Time from end of first-line chemotherapy to relapse
≤ 3 months	19 (47.5)
> 3 months	21 (52.5)
History of radiotherapy
Yes	31 (77.5)
No	9 (22.5)
Previous radiotherapy site
No previous radiotherapy	9 (22.5)
Previous thoracic radiotherapy	8 (20.0)
Previous radiotherapy of metastases	6 (15.0)
Previous radiotherapy of thorax + metastases	17 (42.5)
History of VEGFR-TKI treatment
Yes	3 (7.5)
No	37 (92.5)

ECOG PS Eastern Cooperative Oncology Group performance status, VEGFR vascular endothelial growth factor receptor, TKI tyrosine kinase inhibitor

Clinical efficacy

The median PFS (mPFS) was 3.0 months (95% CI 2.241–3.759; Fig. 1A) and the median OS (mOS) was 7.8 months (95% CI 3.190–12.410; Fig. 1B). Four (10.0%) patients reached PR according to RECIST 1.1, no patient reached CR, and 14 (35.0%) patients maintained SD as best response (Table 2), while 22 patients (55.0%) experienced PD. The ORR reached 10% (4/40), and the DCR was 45% (18/40; Table 2). By the time of data cutoff date, 4 patients (10%) have not experienced PD yet. One patient with brain metastasis but not liver metastasis reached the longest PFS of 12.9 months. The median PFS and OS in patients without liver metastasis were significantly longer than that of the patients with liver metastasis (mPFS 3.9 vs 1.9 months, p < 0.001; mOS 11.1 vs 4.1 months, p = 0.001). Univariate analysis of PFS showed that distant metastasis number < 2, absence of liver metastasis, ECOG ≤ 1 were independent predictors of survival (p < 0.05) (Table 3). Univariate analysis of OS showed that no liver metastases, ECOG ≤ 1, previous radiotherapy were independent predictors associated with favorable survival (p < 0.05) (Table 4). Variables with p < 0.05 (ECOG PS, number of distant metastases, liver metastases, history of radiotherapy) in univariate analyses were included in a multivariate model. Multivariate analysis of PFS showed that absence of liver metastasis and ECOG ≤ 1 were independent predictors of survival (Table 5, Fig. 2). Multivariate analysis of OS showed that the absence of liver metastasis was an independent predictor associated with favorable survival (Table 5, Fig. 2).

Fig. 1.

Kaplan–Meier survival curves of progression-free survival (PFS) (A) and overall survival (OS) (B) for the 40 refractory SCLC patients

Table 2.

Objective response rate of anlotinib in all patients

Response	Patients N (%)
Overall response
Complete response	0 (0)
Partial response	4 (10.0)
Stable disease	14 (35.0)
Progressive disease	22 (55.0)
Objective response	4 (10.0)
Disease control	18 (45.0)

Table 3.

Univariate analysis of progression-free survival (PFS)

Characteristic	PFS(months)	95%CI	P value
Gender
Male	3.0	2.33–3.72	0.334
Female	2.1	0.74–3.51
Age(years)
< 65	3.0	2.31–3.75	0.891
≥ 65	2.9	2.16–3.57
Smoking status
Smoker	3.0	2.01–3.98	0.679
Never smoker	2.9	1.82–4.03
ECOG PS
≤ 1	5.6	2.71–8.48	0.005
> 1	2.6	1.79–3.34
Stage
Limited	3.9	1.25–6.54	0.054
Extensive	2.8	2.04–3.55
Number of distant metastases
< 2	3.4	2.22–4.63	0.007
≥ 2	2.1	1.83–2.42
Brain metastases
Yes	3.0	0.40–5.69	0.433
No	3.0	2.06–2.93
Liver metastases
Yes	1.9	1.63–2.22	< 0.001
No	3.9	2.61–5.18
Number of previous chemotherapy lines
= 2	3.0	2.06–3.93	0.715
> 2	3.0	2.73–3.32
Time from end of first-line chemotherapy to relapse
≤ 3 months	3.0	2.33–3.73	0.776
> 3 months	2.9	1.34–4.52
History of radiotherapy
Yes	3.9	2.15–5.31	0.092
No	2.6	1.78–3.35
Previous radiotherapy site
No previous radiotherapy	2.6	1.78–3.35	0.203
Previous thoracic radiotherapy	2.8	2.65–3.01
Previous radiotherapy of metastases	4.6	0.24–8.90
Previous radiotherapy of thorax + metastases	4.8	2.18–7.36
History of VEGFR-TKI treatment
Yes	2.9	2.35–3.50	0.447
No	3.0	2.31–3.74

ECOG PS Eastern cooperative oncology group performance status, VEGFR vascular endothelial growth factor receptor, TKI tyrosine kinase inhibitor

Table 4.

Univariate analysis of overall survival (OS)

Characteristic	OS(months)	95%CI	P value
Gender
Male	8.4	4.35–12.44	0.092
Female	5.0	1.67–8.32
Age(years)
< 65	11.1	5.40–16.79	0.367
≥ 65	6.0	2.76–9.23
Smoking status
Smoker	11.2	0.41–21.98	0.268
Never smoker	7.5	3.97–11.02
ECOG PS
≤ 1	–	–	0.005
> 1	6.0	1.76–2.55
Stage
Limited	8.4	–	0.061
Extensive	7.5	5.21–9.78
Number of distant metastases
< 2	8.4	3.45–13.34	0.590
≥ 2	6.0	2.27–9.72
Brain metastases
Yes	7.5	2.02–12.97	0.833
No	8.4	3.83–12.96
Liver metastases
Yes	4.1	2.93–5.26	0.001
No	11.1	7.09–15.10
Number of previous chemotherapy lines
= 2	7.8	14.63–10.95	0.839
> 2	11.1	0.99–21.20
Time from end of first-line chemotherapy to relapse
≤ 3 months	10.5	1.04–19.96	0.972
> 3 months	7.8	1.60–10.94
History of radiotherapy
Yes	11.1	6.53–15.66	0.042
No	3.7	1.11–6.28
Previous radiotherapy site
No previous radiotherapy	3.7	1.11–6.28	0.090
Previous thoracic radiotherapy	6.0	0.00–12.93
Previous radiotherapy of metastases	5.0	3.26–6.76
Previous radiotherapy of thorax + metastases	4.8	–
History of VEGFR-TKI treatment
Yes	6.0	2.32–9.68	0.233
No	10.5	6.61–14.38

ECOG PS Eastern cooperative oncology group performance status, VEGFR vascular endothelial growth factor receptor, TKI tyrosine kinase inhibitor

Table 5.

Cox regression analysis of progression-free survival and overall survival

Groups	PFS		OS
	P value	95% CI	P value	95% CI
ECOG PS	0.042	1.034–6.051	0.052	0.989–13.185
Number of distant metastases	0.092	0.885–5.132	–	–
Liver metastases	0.033	0.154–0.926	0.047	0.119–0.986
History of radiotherapy	–	–	0.713	0.426–3.479

CI confidence interval, ECOG PS Eastern cooperative oncology group performance status

Fig. 2.

Kaplan–Meier survival curves of progression-free survival (PFS) and overall survival (OS) from different patient subgroups. Kaplan–Meier plot of PFS (A) and OS (B) for patients with or without liver metastases. Kaplan–Meier plot of PFS (C) and OS (D) for patients with Eastern Cooperative Oncology Group performance status (ECOG PS) score of ≤ 1 and > 1

Safety

All of the patients (n = 40) treated with anlotinib were assessed for toxicity. Fourteen patients (35.0%) experienced treatment-related adverse events (Grade 1–3) (Table 6). No grade ≥ 4 adverse events were recorded. The most common adverse event with anlotinib antiangiogenic treatment was hypertension, which was observed in 17.5% of patients (n = 7) and could be well controlled by anti-hypertensive drugs. Grade 3 hypertension was observed in 7.5% of patients (n = 3). Other common AEs included fatigue (15%), anorexia (15%), cough (10%), rash (7.5%) and nausea (7.5%). One patient stopped anlotinib treatment due to repeated grade 1 epistaxis at the third cycle. No anlotinib treatment-related death was observed in this study.

Table 6.

Anlotinib-related adverse events of all grades and grades ≥ 3

Adverse events	Patients (N/%)
	Any grade	Grade 1–2	Grade ≥ 3
Hypertension	7 (17.5%)	4 (10.0%)	3 (7.5%)
Fatigue	6 (15%)	6 (15.0%)	0
Anorexia	6 (15%)	6 (15%)	0
Cough	4 (10%)	4 (10%)	0
Rash	3 (7.5%)	3 (7.5%)	0
Nausea	3 (7.5%)	3 (7.5%)	0
Hand-foot syndrome	1 (2.5%)	2 (5%)	0
Epistaxis	1 (2.5%)	1 (2.5%)	0

Discussion

Therapeutic options for patients with relapsed SCLC have remained unchanged for about three decades. The only Food and Drug Administration-approved chemotherapy agent for recurrent or progressive SCLC is topotecan which only showed a modest response rate and survival advantages in refractory SCLC (Saltos and Antonia 2020; Baize et al. 2020). Although ICIs have been recently approved for the treatment of relapsed SCLC, its limited response rate and unsatisfying survival benefit still remained to be further improved. More effective therapies and drugs in SCLC are urgently needed. As one of the major hallmarks of cancer, angiogenesis plays a significant role in the development, invasion, and metastasis of cancer (Hanahan 2011). VEGF signaling is a key promoting pathway that stimulates the proliferation and motility of vascular endothelial cells and thus the budding of new vessels (Hicklin 2005; Ferrara 2003). In addition to VEGF, platelet-derived growth factor (PDGF) induces the migration of both vascular pericytes and fibroblasts which are responsible for further vascular maturation and stabilization (Andrae et al. 2008). Another growth factor, fibroblast growth factor (FGF) is also involved in cellular growth and differentiation as well as angiogenesis (Ahmad et al. 2012). It has been reported that angiogenesis mediated by VEGF and PDGF was associated with unfavorable prognosis in non-small cell lung cancer (NSCLC) (Ferrara 2003). Meanwhile, the expression level of VEGF in cancer tissue was demonstrated to be closely correlated with the prognosis of SCLC (Lucchi et al. 2002; Zhan et al. 2009). As a novel multiple tyrosine kinase inhibitor that targets VEGFR1, VEGFR2, VEGFR3, c-Kit, PDGFR-α, and the FGF receptors (FGFR1, FGFR2, and FGFR3), anlotinib inhibits cell migration and the formation of capillary-like tubes induced by VEGF/PDGF-BB/FGF-2 in endothelial cells and suppresses VEGF/PDGF-BB/FGF-2 induced angiogenesis both in vitro and in vivo (Shen et al. 2018). Importantly, the inhibition of the above targets by anlotinib has been shown to be even stronger than other anti-angiogenic TKIs, such as nintedanib, sorafenib, and sunitinib (Xie et al. 2018; Lin et al. 2018). Based on the positive results of ALTER 0303 and ALTER 1202 studies, anlotinib monotherapy has been approved for the third- and later-line treatment in NSCLC and SCLC, respectively ( Han et al. 2018; Cheng et al. 2018). In contrast to the failure of other anti-angiogenic agents, the approval of anlotinib for refractory SCLC treatment brought novel therapeutic options and survival hope to patients in China.

In the multicenter, randomized, double-blind phase II trial ALTER 1202, a total of 121 SCLC patients were treated with anlotinib or placebo after disease progression on at least two lines of previous chemotherapy. The median PFS was 4.1 months (95% CI 2.8 to 4.2 months) in anlotinib arm and only 0.7 months (95% CI 0.7 to 0.8 months) in placebo arm, respectively (HR, 0.19; 95% CI 0.12 to 0.32, p < 0.0001) (Cheng et al. 2018). The DCR and ORR in the anlotinib group were 71.6% and 4.9%, respectively. And the median OS in the anlotinib group was 7.3 months compared to 4.9 months in the placebo group (Cheng et al. 2019a, b). Based on these positive results, anlotinib has been approved as the third- or later-line treatment for refractory SCLC in China since August 2019.

In the current retrospective study of a real-world setting, we revealed a shorter median PFS of 3.0 months, but a slightly longer OS of 7.8 months compared with the results from ALTER 1202 trial. At the same time, DCR in this study was only 45.0% compared with 71.6% in ALTER 1202, as shown in Table 7 (Cheng et al. 2018, 2019a, b; Chung et al. 2020; Ready et al. 2019). We presume the following reasons may contribute to above differences. First and most importantly, 88.9% of the patients receiving anlotinib treatment in the ALTER 1202 trial were with ECOG score ≤ 1 while only 27.5% of patients in our study were with ECOG score ≤ 1. Second, more patients were with brain metastases upon the first diagnosis in our study compared with ALTER 1202 (27.5% vs 25.9%) (Cheng et al. 2019a, b). The poorer physical condition and larger percentage of patients with brain metastases might contribute to the shorter PFS and lower ORR of the present refractory SCLC cohort in a real-world setting. As for treatments after progression beyond anlotinib which could significantly influence overall survival, we observed that 15% of patients (n = 6) were treated with ICIs and 5% of patients (n = 2) were treated with other chemotherapy. The information of treatments beyond anlotinib in ALTER 1202 was not available and thus we could not make a direct comparison between each other. It is possible that more patients have used immunotherapy in the current cohort of patients from June 2018 to July 2020 compared with patients recruited in ALTER 1202 from 2017 to early 2018. This might be the reason for the slightly better overall survival observed in our study. Compared with the placebo group in ALTER 1202 trial, mOS and mPFS of patients with refractory SCLC have been significantly improved with the treatment of anlotinib. And this retrospective study further confirmed that anlotinib could be considered as a feasible treatment option for patients with refractory SCLC who have experienced multi-line treatment failure.

Table 7.

Selected studies assessing efficacy of third- or further-line treatment of SCLC

Study name	Phase	Treatment	ORR (%)	DCR (%)	mPFS (months)	mOS (months)	References
ALTER 1202	II	Anlotinib	4.9	71.6	4.1	7.3	(Cheng et al. 2018) (Cheng et al. 2019a, b)
Present study	N/A	Anlotinib	0	45.0	3.0	7.8	N/A
KEYNOTE 028/158	Ib/II	Pembrolizumab	19.3	37.4	2.0	7.7	(Chung et al. 2020)
CheckMate 032	I/II	Nivolumab	11.9	34.8	1.4	5.6	(Ready et al. 2019)

ORR objective response rater, DCR disease control rate, mPFS median progression-free survival, mOS median overall survival

In the subgroup analysis of the current study, the mPFS and mOS of patients without or with brain metastases was 3.0 months versus 3.0 months and 8.4 months versus 7.5 months, respectively. There was no statistically significant difference in PFS or OS between patients with or without brain metastases. According to a data update of ALTER 1202 in 2019, the mPFS and mOS of patients with brain metastases were 3.84 months and 6.08 months, respectively, which were similar to the results in this real-world cohort (Cheng et al. 2019a, b). Our data further supported the survival benefit of anlotinib in SCLC patients with baseline brain metastases. On the contrary, Cox regression analysis showed that the mPFS and mOS of the patients with or without liver metastases upon anlotinib treatment were 1.9 months versus 3.9 months and 4.1 versus 11.1 months retrospectively. The survival differences were statistically significant for both PFS and OS, which proved the dismal prognosis of SCLC patients with liver metastases and suggested that the activity of anlotinib was quite limited in this group of patients. Therefore, anlotinib-based combination therapy might be of potential value in the treatment of SCLC patients with liver metastases. However, it must be realized that the sample size of patients with liver metastasis was very small with only 9 patients and thus the efficacy predicting role of liver metastasis for anlotinib in refractory SCLC should be further validated in studies with larger sample sizes. Cox regression analysis also revealed that the patients with ECOG PS ≤ 1 had longer PFS (5.6 months vs 2.6 months), which indicated that anlotinib was more effective in patients with ECOG PS ≤ 1. The mOS has not reached yet in patients with ECOG PS ≤ 1, which was significantly longer than the mOS of 6.0 months in patients with ECOG PS > 1. This result suggested that anlotinib brought more survival benefits in patients with better physical status.

There were no new anlotinib-related adverse events observed in this study and the toxic profile was similar to the other studies of anlotinib in SCLC and NSCLC. Like other VEGFR-TKIs, the most frequent AEs of anlotinib revealed in this study were hypertension which could be generally well controlled by angiotensin receptor blockers or calcium antagonists. As one of the serious AEs with antiangiogenic treatment, bleeding could be fatal which has ever been reported in previous studies. Thus, administration of anlotinib in patients with high risk factors of bleeding needs cautious consideration and intense surveillance at all times. However, only one patient with repeated grade 1 epistaxis was recorded in this study. In short, the toxicity profile recorded in our study indicated that anlotinib seemed to be safe for later-line treatment in refractory SCLC.

With the increasing usage of anlotinib in SCLC treatment in the future, several significant prospects need to be considered to optimize the anticancer potential of this novel agent. First, the synergistic effect between anti-angiogenic therapy and chemotherapy was redefined according to recent findings that anti-angiogenic agents could stabilize and mature tumor vasculature and could thus further reduce tumor hypoxia and improve the delivery of chemotherapy agents to tumor tissue (Heinhuis et al. 2019). Combined treatment of anlotinib plus chemotherapy (platinum-based agent and etoposide) as first-line treatment of SCLC has been studied in phase II clinical trials (Kong et al. 2021). The current data provided a promising ORR of 90% and PFS of 10 months with anlotinib plus etoposide and cisplatin/carboplatin (Kong et al. 2021). With the support of these encouraging preliminary results, phase III trial of anlotinib plus etoposide and platinum (cisplatin/carboplatin) in treatment-naive SCLC has already begun in China.

Furthermore, with the development of cancer immunotherapy, ICIs have entered the treatment armamentarium for SCLC (Paz-Ares et al. 2019). Anti-PD-1 antibody nivolumab and pembrolizumab has been approved for later-line treatment of refractory SCLC by the Food and Drug Administration of America based on the preliminary survival results of CheckMate-032 and KEYNOTE 028/158 trials (Ready et al. 2019; Ott et al. 2017), as shown in Table 7. However, the SCLC indications of both ICIs have been recently withdrawn by pharmaceutical companies due to failure of confirmatory Phase III trials (Owonikoko et al. 2021; Spigel et al. 2021; Rudin et al. 2020). Nevertheless, both nivolumab and pembrolizumab are still optional later-line treatment therapies in refractory SCLC according to treatment guidelines in America and China. During data collection of our study, we found only three patients who had received later-line anti-PD-1 antibody treatment before anlotinib treatment. All of them had received no more than two cycles of immunotherapy due to “disease progression” in the first response evaluation. Furthermore, all three patients had experienced various immune-related adverse events. To prevent confounding factors that whether anlotinib or anti-PD-1 antibody induced therapeutic response and adverse events, we excluded these three patients from analysis. In Table 7, the ORR, DCR and survival data of anlotinib treatment in this study could be easily compared with historical ICI treatments. It is quite meaningful to further study the role of anlotinib treatment for refractory SCLC in the era of immunotherapy in future.

Importantly, it has been demonstrated that anti-angiogenesis therapy could normalize the tumor immune microenvironment which increases the infiltration of immune effector cells into tumors and converted the intrinsically immunosuppressive tumor microenvironment (Popat et al. 2020). And thus integrated treatment solution combining anti-angiogenesis agents and ICIs may improve the therapeutic responsiveness and survival in cancers, which has already been proved in multiple clinical trials in NSCLC, hepatocellular carcinoma, kidney cancer and so on. The potential benefits of anlotinib combined with ICIs as first-line treatment are now being intensively investigated for ES-SCLC in China.

As a retrospective study, some inevitable limitations still existed in our study. First, the number of patients included in this retrospective study was relatively small and all the patients come from one single medical center. Thus, larger prospective clinical trials in the future are needed to confirm the efficacy and safety of anlotinib as a standard third-line treatment for SCLC in China. Furthermore, the enrolled patients in this study received different forms of previous therapy, which may influence the actual efficacy and safety of anlotinib. Third, due to the small sample size and bias of the retrospective analysis, the incidence of AEs we recorded in this study may be lower than the actual data in the real world.

In conclusion, in this retrospective study of a real-world setting, we revealed that anlotinib was beneficial for refractory SCLC as third- or further-line treatment, especially in patients without liver metastasis and with better physical status. Treatment-related adverse effects were tolerable and manageable. In future, the potential therapeutic role of first-line anlotinib in combination with chemotherapy or immunotherapy is worthy of further study.

Author contributions

JSL and XM contributed conception and design of the study; XTG and LZ organized the database; XTG and BL performed the statistical analysis; XTG and JSL wrote the first draft of the manuscript, KH, LP and CHY reviewed and edited the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.

Funding

This work was funded by the National Natural Science Foundation of China (81972864); Academic Promotion Program of Shandong First Medical University (2019RC002); Science and Technology Support Plan for Youth Innovation Teams of Universities in Shandong Province (2019KJL001); Science and Technology Plan of Jinan (201907113); Shandong Provincial Natural Science Foundation (ZR2020LZL018); Taishan Scholars Program (No. tsqn202103174).

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Conflict of interest

No authors report any conflict of interest.

Ethical approval

The Ethics Committee of Shandong Cancer Hospital (Shandong Province, China) approved this study. In this retrospective study, the privacy and personal information of all patients were protected, and all the procedure was performed in accordance with the Declaration of Helsinki.