Effectiveness and safety of anlotinib plus anti-programmed cell death 1/ligand 1 (anti-PD-1/PD-L1) antibodies as maintenance therapy after first-line chemotherapy combined with anti-PD-1/PD-L1 antibodies in extensive-stage small cell lung cancer: A real-world study

doi:10.21203/rs.3.rs-3595926/v1

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Effectiveness and safety of anlotinib plus anti-programmed cell death 1/ligand 1 (anti-PD-1/PD-L1) antibodies as maintenance therapy after first-line chemotherapy combined with anti-PD-1/PD-L1 antibodies in extensive-stage small cell lung cancer: A real-world study

https://doi.org/10.21203/rs.3.rs-3595926/v1

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Background

Currently, chemotherapy plus immunotherapy followed by maintenance therapy with immune monotherapy is the preferable first-line treatment option for extensive-stage small cell lung cancer (ES-SCLC), but with limited overall survival (OS) and progression-free survival (PFS) benefits. The combination of anti-angiogenic drugs with immunotherapy has shown encouraging anti-tumor activity and tolerability, with some degree of overcoming immune resistance. This study evaluated the effectiveness and safety of anlotinib plus anti-programmed cell death 1/ligand 1 (anti-PD-1/PD-L1) antibodies as maintenance therapy after first-line chemotherapy combined with immunotherapy in ES-SCLC.

Methods

Between June 2020 and December 2021, 12 patients with newly diagnosed ES-SCLC in our hospital were retrospectively analyzed. All patients without disease progression after 4–6 cycles of first-line platinum-containing chemotherapy plus anti-PD-1/PD-L1 antibodies received anlotinib (12 mg, days 1–14) plus anti-PD-1/PD-L1 antibodies as maintenance therapy. Several patients underwent chest radiotherapy (intensity-modulated radiotherapy using a 6MV X-ray) without disease progression before maintenance therapy. The effectiveness and safety of anlotinib plus anti-PD-1/PD-L1 antibodies as maintenance therapy after first-line chemotherapy combined with immunotherapy in ES-SCLC were evaluated.

Results

The median follow-up time was 31.1 months. During first-line treatment (including maintenance therapy), 1 patient achieved a complete response, 8 patients achieved a partial response (PR), and 3 patients had stable disease, with an objective response rate of 75.0% and a disease control rate of 100.0%. During maintenance therapy with anlotinib plus anti-PD-1/PD-L1 antibodies, 50.0% of patients achieved further lesion remission on the basis of the prior initial treatment, of which 1 patient achieved a PR. The median PFS was 13.6 (95% confidence interval [CI], 11.2–15.6) months, and the median OS was 19.5 (95% CI, 14.5–24.5) months. Treatment-related any grade and grade 3–4 adverse events (AEs) were reported in 100.0% and 58.3% of patients, respectively. No life-threatening AEs were observed. Grade 3–4 AEs included leukocytopenia (58.3%, 7/12), thrombocytopenia (33.3%, 4/12), nausea (33.3%, 4/12), anemia (16.7%, 2/12), and fatigue (8.3%, 1/12). All AEs during maintenance therapy were tolerated and were regarded as grade 1–2, with the majority being fatigue, nausea, rash, and hemoptysis.

Conclusion

The combination of anlotinib with anti-PD-1/PD-L1 antibodies demonstrated encouraging effectiveness and safety in treating patients with ES-SCLC, suggesting that it may be a preferable option for maintenance therapy after first-line chemotherapy combined with immunotherapy.

anlotinib

anti-programmed cell death 1/ligand 1 antibodies

maintenance therapy

small cell lung cancer

Small cell lung cancer (SCLC) originates from neuroendocrine cells in the lung epithelium and accounts for appropriately 15–20% of all lung cancer cases[1]. Due to the high malignancy of SCLC and its rapid progression and early metastasis characteristics, most patients present with obvious signs of metastasis at the time of initial diagnosis, resulting in a poor prognosis[2]. Data from 1983 to 2012 showed that the median overall survival (OS) of patients with SCLC was only 7 months, with a 5-year OS of only 1%-2%[3]. Based on the American Veterans Administration Lung Study Group (VALG) staging system, SCLC can be divided into limited-stage (LS-SCLC) and extensive-stage SCLC (ES-SCLC). The previous standard first-line treatment for patients with ES-SCLC was platinum-containing chemotherapy (carboplatin or cisplatin) combined with etoposide, with an objective response rate (ORR) of 60%-65% and a median OS of approximately 10 months[4, 5]. In recent years, although immune maintenance therapy after first-line immune checkpoint inhibitors (ICIs) combined with carboplatin and etoposide has shown superior OS compared with chemotherapy alone, the progression-free survival (PFS) benefit is limited[6, 7]. Moreover, the treatment options after disease relapse were extremely limited with a poor prognosis.

Abnormalities in the tumor vascular system are characterized by disordered, immature, disorganized, poorly perfused, and permeable vessels[8] and may be one of the mechanisms of immune resistance. It plays direct immunosuppressive roles, including inhibition of dendritic cells differentiation and maturation[9], reduction of T cell migration and tumor infiltration[10, 11], induction or maintenance of regulatory T cells and myeloid-derived suppressor cells[12, 13], recruitment of tumor-associated macrophages leading to T cell inactivation[14], up-regulation of programmed cell death 1 (PD-1) expression on T cells to induce T cell exhaustion[15], and direct inhibition of T cell proliferation and cytotoxic activity[16, 17].

Numerous studies indicate that anti-angiogenic therapies targeting vascular endothelial growth factor (VEGF) or VEGF receptor-2 (VEGFR-2) can modulate the tumor immunosuppressive microenvironment and may help to reverse immune resistance[18–20]. The combined blockade of PD-1 and VEGFR in mouse tumor models induces strong synergistic antitumor responses, such as inhibition of VEGF-A expression reduces T cell exhaustion in tumors[15, 21]. Anlotinib is a multitarget tyrosine kinase inhibitor (TKI) with anti-angiogenic, anti-tumor growth, proliferation, and migration properties by targeting VEGFR 1–3, platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and stem cell growth factor receptor (c-Kit)[22]. The ALTER 1202 trial assessed the anti-tumor activity of anlotinib as a third- or further-line treatment in patients with ES-SCLC. The results showed that anlotinib extended the median PFS by 3.4 months (p < 0.0001) and reduced the risk of disease progression by 81% compared to placebo[23]. Therefore, anlotinib was approved as a third-line therapy for SCLC by National Medical Products Administration (NMPA). However, the safety and efficacy of first-line maintenance therapy with anlotinib and anti-PD-1/programmed cell death ligand 1 (PD-L1) antibodies in ES-SCLC are still unknown. Thus, the retrospective study was conducted to evaluate the effectiveness and safety of anlotinib plus anti-PD-1/PD-L1 antibodies as maintenance therapy after first-line chemotherapy combined with anti-PD-1/PD-L1 antibodies in ES-SCLC.

Participants

Between June 2020 and December 2021, patients with newly diagnosed ES-SCLC in the Department of Respiratory and Critical Care Medicine, Southwest Hospital, Army Medical University (Third Military Medical University) were retrospectively analyzed. The main inclusion criteria included: 1) patients with histopathologically confirmed ES-SCLC according to the VALG staging system; 2) patients who did not receive systemic therapy for ES-SCLC; 3) patients with at least one measurable tumor lesion per Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1; 4) patients who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. Patients who were complicated with other malignant tumors, serious infections, tuberculosis, or poor cardiopulmonary function were excluded from this study. This study was conducted following the Declaration of Helsinki. Ethical approval was obtained from the Ethics Committee of the Southwest Hospital, Army Medical University (Third Military Medical University(NO. (B)KY2023090)). Informed consent from patients was exempted from the ethical review due to the retrospective design.

Procedures

Patients without disease progression after 4–6 cycles of first-line platinum-containing chemotherapy plus anti-PD-1/PD-L1 antibodies received anlotinib (12 mg, day 1–14; Chia-tai Tianqing Pharmaceutical Co., Ltd., Nanjing, China) plus anti-PD-1/PD-L1 antibodies as maintenance therapy. The anti-PD-1/PD-L1 antibodies included atezolizumab (F Hoffmann-La Roche Ltd, Switzerland), durvalumab (AstraZeneca, England), tislelizumab (BeiGene Co. Ltd, China), and sintilimab (Innovent Biologics, China). The choice of anti-PD-1/PD-L1 antibodies was mainly based on the approved drug indications, enrollment in phase III clinical trials, patient willingness, and drug accessibility. Several patients underwent chest radiotherapy (intensity-modulated radiotherapy using a 6MV X-ray) without disease progression before maintenance therapy. The use of chest radiotherapy was based on the 2020/2021 CSCO guidelines for the diagnosis and treatment of SCLC and patient selection. Maintenance therapy was continued until the disease progression or unacceptable toxicity.

Data collection and outcomes assessment

The medical records of each patient were retrospectively collected, including patients’ demographic characteristics, disease history, treatment history, laboratory test results, tumor biomarker levels, treatment modalities, efficacy, and safety. The primary endpoint was PFS. Secondary endpoints included OS, ORR, disease control rate (DCR), and safety. The tumor response was assessed as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) according to the RECIST version 1.1. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version 5.0).

Statistical analysis

The categorical variables were expressed as percentages and numbers, while the continuous variables were presented as mean with standard deviation or median with range. The PFS and OS were estimated using the Kaplan-Meier method and expressed as a median with a 95% confidence interval (CIs). The survival curve was generated using R Statistical Language (version 3.5.0). All statistical analyzes were performed using SPSS (version 27.0) software, and a p < 0.05 was considered statistically significant.

This article has been approved by the Ethics Committee of the Southwest Hospital, Army Medical University (Third Military Medical University) (NO. (B)KY2023090)

Patient and treatment

Between June 2020 and December 2021, 12 patients with newly diagnosed ES-SCLC were included in this study. The baseline demographic and clinical characteristics of patients are shown in Table 1. The majority of patients were male, with a male-to-female ratio of 7:3. The median age of the 12 patients was 57.0 (range, 35.0–72.0) years. 5 (41.7%) patients were aged > 60 years and 9 (75.0%) patients had a smoking history of ≥ 20 pack-years. Nearly half of the patients (5/12, 41.7%) had more than 3 metastatic sites. The proportions of patients treated with anti-PD-1 antibodies (tislelizumab and sintilimab) and anti-PD-L1 antibodies (atezolizumab and durvalumab) were 50.0% and 50.0%, respectively. 9 patients (75.0%) underwent chest radiotherapy after chemotherapy combined with immunotherapy (Table 1).

Table 1

Baseline characteristics of the study population
Characteristic	Patients (n = 12)
Age (year), median (range)	57 (35–72)
Sex, n (%)
Male	10 (83.3)
Female	2 (16.7)
ECOG performance status, n (%)
0–1	7 (58.3)
2	5 (41.7)
Smoking status, n (%)
≥ 20 pack-years	9 (75.0)
< 20 pack-years	3 (25.0)
Stage, n (%)
III	9 (75.0)
IV	3 (25.0)
Liver metastasis, n (%)
Yes	2 (16.7)
No	10 (83.3)
Metastasis sites, n (%)
≤ 3	7 (58.3)
> 3	5 (41.7)
Radiotherapy, n (%)
Yes	9 (75.0)
No	3 (25.0)
Anti-PD-1 or PD-L1 antibodies, n (%)
Atezolizumab	2 (16.7)
Durvalumab	4 (33.3)
Tislelizumab	4 (33.3)
Sintilimab	2 (16.7)
ECOG, Eastern Cooperative Oncology Group; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1

Efficacy

Up to the study cutoff date of May 11, 2023, the median follow-up time was 31.1 (95% CI, 14.8–47.5) months. During first-line treatment (including maintenance therapy), 1 patient achieved a CR, 8 patients achieved a PR, and 3 patients had SD, with an ORR of 75.0% and a DCR of 100.0%. During maintenance therapy with anlotinib plus anti-PD-1/PD-L1 antibodies, 50.0% of patients achieved further lesion remission on the basis of the prior initial treatment, of which 1 patient achieved a PR (Fig. 1). The median PFS was 13.6 (95% CI, 11.2–15.6) months and the median OS was 19.5 (95% CI, 14.5–24.5) months (Fig. 2A and 2B). At the time of the last follow-up, 8 (66.7%) patients had died, and 4 (33.3%) patients were still alive with the longest OS of 32.7 months.

Safety

Treatment-related AEs of any grade were reported in 100.0% of patients, the majority of which were regarded as grade 1–2 (Table 2). 7 (58.3%) patients experienced grade 3–4 treatment-related AEs. No life-threatening AEs were observed. Grade 3–4 AEs (Table 2) included leukocytopenia (58.3%, 7/12), thrombocytopenia (33.3%, 4/12), nausea (33.3%, 4/12), anemia (16.7%, 2/12), and fatigue (8.3%, 1/12). All AEs during maintenance therapy were tolerated and were regarded as grade 1–2, with the majority being fatigue, nausea, rash, and hemoptysis.

Table 2

Treatment-related adverse events occurring in > 10% of patients (n = 12)
Adverse events	All grades, n (%)	Grades 1–2, n (%)	Grades 3–4, n (%)
Any	12 (100.0)	12 (100.0)	7 (58.3)
Fatigue	11 (91.7)	10 (83.3)	1 (8.3)
Radiation pneumonitis	9 (75.0)	9 (75.0)	0
Leukocytopenia	11 (91.7)	4 (33.3)	7 (58.3)
Thrombocytopenia	8 (66.7)	4 (33.3)	4 (33.3)
Anemia	11 (91.7)	9 (75.0)	2 (16.7)
Nausea	8 (66.7)	4 (33.3)	4 (33.3)
Hand-foot syndrome	2 (16.7)	2 (16.7)	0
Hypothyroidism	1 (8.3)	1 (8.3)	0
Diarrhoea	1 (8.3)	1 (8.3)	0

Currently, there is no standard first-line maintenance treatment regimen for ES-SCLC. Although chemotherapy plus immunotherapy followed by maintenance therapy with immune monotherapy is the preferred first-line treatment option for ES-SCLC, the OS and PFS benefits are limited. The present study evaluated the effectiveness and safety of anlotinib plus immunotherapy as maintenance therapy after first-line chemotherapy combined with immunotherapy in ES-SCLC. The median PFS and OS of our patients were 13.6 (95% CI, 11.2–15.6) months and 19.5 (95% CI, 14.5–24.5) months, respectively, which were higher than those reported from chemotherapy plus immunotherapy followed by maintenance therapy with immune monotherapy. All AEs during maintenance therapy were tolerated and were regarded as grade 1–2, with the majority being fatigue, nausea, rash, and hemoptysis. Besides, no patients occurred treatment interruption due to AEs. These findings suggested that anlotinib plus immunotherapy might be a preferable first-line maintenance treatment option for ES-SCLC.

The IMPOWER-133, CASPIAN, ASTRUM-005, and CAPSTONE-1 trials demonstrated that adding anti-PD-1/PD-L1 antibodies to chemotherapy improved the OS of patients with ES-SCLC compared with chemotherapy alone, providing novel prospects for first-line treatment of patients with this disease. However, the immunotherapy combined with chemotherapy in the IMPOWER-133 (atezolizumab), CASPIAN (durvalumab), and CAPSTONE-1 (adebrelimab [SHR-1316])[24] trials only extended the median OS by 2.0-2.5 months compared to chemotherapy alone. Moreover, serplulimab plus chemotherapy improved median OS vs. chemotherapy alone by only 4.5 months in the ASTRUM-005 trial (Ying Cheng, et al.2022 ASCO. Abstract #8505). In the present study, the median PFS was 13.6 (95% CI, 11.2–15.6) months and the median OS was 19.5 (95% CI, 14.5–24.5) months, which were higher than those reported in the IMPOWER-133, CASPIAN, ASTRUM-005, and CAPSTONE-1 trials.

It has been shown that ICI monotherapy is unsatisfactory as first-line maintenance therapy for ES-SCLC. Results from the CheckMate 451 trial indicated that maintenance therapy with nivolumab plus ipilimumab (median PFS, 1.7 months; median OS, 9.2 months) or nivolumab monotherapy (median PFS, 1.9 months; median OS, 10.4 months) following first-line chemotherapy did not prolong the PFS and OS[25]. Gadgeel et al. conducted a single-arm phase II study to assess the efficacy of maintenance pembrolizumab in patients with ES-SCLC who had a response or SD after first-line platinum-etoposide chemotherapy, with an ORR of 11.1%, median PFS of 1.4 months, a 6-month PFS of 20.0%, a 12-month PFS of 13.0%, and a median OS of 9.6 months[26]. The exploratory analysis in the subset of patients who reached the maintenance phase from the IMPOWER-133 trial demonstrated a median PFS of 2.6 months for maintenance treatment with atezolizumab monotherapy[27]. These findings suggest the importance of maintenance therapy in the first-line setting of ES-SCLC and reflect that the survival benefits from first-line maintenance therapy with ICI monotherapy warrant to be further improvement.

Therefore, the excellent survival results in our study were considered to be attributable to the addition of anlotinib in the maintenance therapy. The unsatisfactory efficacy of ICI monotherapy maintenance therapy after first-line chemotherapy plus immunotherapy in ES-SCLC may be associated with the heterogeneity of SCLC as well as primary and secondary immune resistance[28]. Since anti-angiogenic therapies can modulate the tumor immunosuppressive microenvironment and eliminate immunosuppression, the combination of anti-angiogenic agents with immunotherapy might overcome primary and secondary immune resistance[29, 30]. Anlotinib is a multitarget TKI that facilitates tumor vessel normalization by improving the distribution of pericytes/endothelial cells[31] and increases the infiltration of immune cells by downregulating PD-L1 expression on the surface of endothelial cells[32]. In addition, anlotinib regulates immune cells to alleviate the immunosuppressive state in the tumor microenvironment[31, 33], and modulates cytokine levels to enhance the anti-tumor immune response[32, 34–35]. A single-arm phase II study revealed the encouraging efficacy of anlotinib plus toripalimab as maintenance treatment after first-line platinum-based chemotherapy in ES-SCLC, with an ORR of 6.7%, a DCR of 80.0%, and a median PFS of 12.5 months[36].

The real-world data from this study showed that the addition of anlotinib in the maintenance therapy did not increase the toxicity of ICI monotherapy and had a manageable safety profile. In the present study, grade 3–4 AEs were reported in 58.3% of patients, which was lower than that reported in the IMPOWER-133, CASPIAN, and CAPSTONE-1 trials (66.0%-86.0%). Moreover, no life-threatening AEs were observed. All AEs during maintenance therapy were tolerated and were regarded as grade 1–2, with the majority being fatigue, nausea, rash, and hemoptysis.

The main limitation of this study was the small sample size. Since there were few anti-PD-1/PD-L1 antibodies available for the first-line treatment of ES-SCLC between 2020 and 2021, and the high economic burden of the study drugs at that time, making only a small percentage of patients in the real-world setting received maintenance therapy with anlotinib and anti-PD-1/PD-L1 antibodies. However, with the approval of more immunologic drugs and the reduction in drug costs in recent years, the treatment regimen is accessible to more patients, allowing us to enlarge our sample size and follow-up more patients. Although the combination of anti-angiogenic agents with immunotherapy has been proven to be a promising therapeutic strategy in the treatment of a variety of solid tumors, there are still many issues that need to be resolved in clinical practice, such as determining the optimal beneficial populations, optimal dosage, and duration of administration, with the expectation of making the combination regimen more effective and safer, which is also a priority in future research.

The present study demonstrated that anlotinib plus anti-PD-1/PD-L1 antibodies as maintenance therapy after first-line chemotherapy combined with immunotherapy in ES-SCLC could significantly prolong PFS and OS with an acceptable safety profile, which brings new hope for the long-term survival of patients with this disease.

FUNDING

Our article has no funding support.

Availability of Data and Materials

The original data used for analysis in current study is available as you inquired for the corresponding author.

Ethics approval and consent to participate

This study was conducted following the Declaration of Helsinki. Ethical approval was obtained from the Ethics Committee of the Southwest Hospital, Army Medical University (Third Military Medical University(NO. (B)KY2023090)). The ethics committee has conducted a swift review of the research plan and other related projects. Overall, the committee believes that the research project membership is qualified, the submission materials are complete, and the clinical research plan and other materials meet ethical requirements. The committee agrees to proceed with the clinical research and to waive the need for informed consent.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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Effectiveness and safety of anlotinib plus anti-programmed cell death 1/ligand 1 (anti-PD-1/PD-L1) antibodies as maintenance therapy after first-line chemotherapy combined with anti-PD-1/PD-L1 antibodies in extensive-stage small cell lung cancer: A real-world study

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Patient and treatment

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