Use of a pharmaceutical composition for the manufacture of a medicament for maintenance treatment of ES-SCLC patients with disease control after first line chemotherapy

Abstract

The application provides a kind of drug composition in the preparation for the application of the drug for the maintenance treatment of disease control ES-SCLC after first-line chemotherapy, belong to the biomedicine technical field.The drug composition is carimab and apatinib.The application finds that carimab is combined with apatinib as maintenance treatment, shows encouraging efficacy and acceptable safety in ES-SCLC patient who is not in progress after first-line chemotherapy, the median overall survival (OS) is 25.00 months, and the 12-month OS rate is 71.4%.This strategy of simultaneously targeting PD-1 and VEGFR2 provides a novel and reasonable solution for extending the disease control period in malignant tumors with limited treatment options after induction therapy, not only solves the key needs of ES-SCLC patients for more effective maintenance treatment, but also provides important insights into the biological principles of anti-angiogenic therapy combined with immunotherapy.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and more particularly to the use of a pharmaceutical composition in the preparation of a medicament for maintenance therapy in ES-SCLC patients whose disease is controlled after first-line chemotherapy. Background Technology

[0002] Extensive-stage small cell lung cancer (ES-SCLC) is one of the most challenging malignant tumors to treat, characterized by rapid progression and poor prognosis. Although immune checkpoint inhibitors (ICIs) have been successfully integrated into first-line platinum-etoposide chemotherapy regimens, median progression-free survival (PFS) (still only 4-5 months) and overall survival (OS) remain unsatisfactory. Most patients experience disease progression within months of completing the initial 4-6 cycles of induction therapy. This underscores the urgent need to develop effective post-induction therapy strategies to prolong disease control and survival.

[0003] Maintenance therapy is a promising approach in the treatment of ES-SCLC, addressing the limitations of first-line therapy. However, previous treatments with cytotoxic drugs, targeted therapies, or ICIs as monotherapy have largely failed to achieve the expected results. Recent studies have explored innovative maintenance therapy regimens for ES-SCLC, including combinations of anti-angiogenic drugs and immunotherapy (such as anlotinib combined with durvalumab or bemosubib), chemotherapy combined with immunotherapy (such as rubicatin combined with durvalumab), and other strategies (such as talatumab combined with durvalumab). These studies highlight the potential of maintenance therapy in improving the prognosis of ES-SCLC patients. The ETER701 study evaluated the efficacy of anlotinib (an anti-angiogenic drug) combined with bemosubib and platinum-based etoposide chemotherapy (a four-drug combination) as first-line treatment for ES-SCLC. Although this regimen showed good efficacy, its high incidence of adverse reactions hindered its widespread clinical application. Furthermore, the overall response rate (ORR) of the four-drug combination therapy in the induction phase was not significantly improved compared to immunochemotherapy, suggesting that the improvement in overall survival (OS) may mainly come from the addition of anti-angiogenic drugs in the maintenance therapy phase. Therefore, using immunochemotherapy in the induction phase and anti-angiogenic drugs combined with immunotherapy in the maintenance therapy phase is an optimized model to improve the efficacy and reduce the toxicity of ES-SCLC. Anti-angiogenic therapies targeting vascular endothelial growth factor receptor (VEGFR) have shown the potential to regulate the tumor immune microenvironment by inhibiting tumor angiogenesis and reducing immunosuppressive factors. Currently, clinical trials on the combined use of VEGFR and immunotherapy for small cell lung cancer (SCLC) patients are still relatively scarce. Summary of the Invention

[0004] Chemotherapy combined with immunotherapy is the standard first-line treatment for ES-SCLC. However, the median progression-free survival (PFS) remains only 4-5 months, and not all patients benefit. This invention aims to evaluate the efficacy and safety of camrelizumab (anti-PD-1) combined with apatinib (VEGFR-2 inhibitor) as maintenance therapy for ES-SCLC patients whose disease is controlled after first-line chemotherapy, and to provide a novel pharmaceutical composition for maintenance therapy.

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides the use of a pharmaceutical composition in the preparation of a medicament for maintenance therapy in patients with ES-SCLC whose disease is controlled after first-line chemotherapy, wherein the pharmaceutical composition is camrelizumab and apatinib.

[0006] Preferably, the dosage of camrelizumab is 200 mg every 3 weeks, and the dosage of apatinib is 250 mg / day.

[0007] Preferably, the camrelizumab is administered via intravenous injection, and the apatinib is administered via oral administration.

[0008] Preferably, the drug composition is administered within 3-8 weeks after the last chemotherapy session for ES-SCLC patients, and the ES-SCLC patients have completed 4-6 cycles of first-line platinum-based chemotherapy combined with etoposide or irinotecan chemotherapy, while induction chemotherapy has achieved disease control.

[0009] Beneficial effects: Anti-angiogenic therapy combined with immunotherapy is a promising maintenance therapy for ES-SCLC, but current research is limited, and the biological mechanisms underlying the synergistic effect of anti-angiogenic therapy and immunotherapy are not fully elucidated. To fill this gap, we conducted a phase II clinical trial (CAMERA trial) to evaluate the efficacy of camrelizumab (an anti-PD-1 monoclonal antibody) combined with apatinib (a highly selective VEGFR-2 inhibitor) as maintenance therapy for ES-SCLC patients whose disease was controlled after first-line chemotherapy. This combination regimen demonstrated encouraging efficacy and acceptable safety in ES-SCLC patients whose disease had not progressed after first-line chemotherapy, with a median overall survival (OS) of 25.00 months and a 12-month OS rate of 71.4%. This strategy of simultaneously targeting PD-1 and VEGFR-2 provides a novel and rational option for prolonging disease control in malignancies with limited treatment options after induction therapy. It not only meets the critical need of ES-SCLC patients for more effective maintenance therapy but also provides important insights into the biological principles of the combination of anti-angiogenic therapy and immunotherapy. Identifying key biomarkers associated with treatment response and drug resistance may provide guidance for future treatment strategies to improve the prognosis of SCLC patients. Attached Figure Description

[0010] Figure 1 Patient enrollment flowchart.

[0011] Figure 2 Treatment efficacy assessment. (A) Progression-free survival (PFS); (B) Overall survival (OS).

[0012] Figure 3 Genomic and transcriptomic biomarker analysis. (A) Baseline ctDNA mutation profile and prognostic gene characteristics; (B) Progression-free survival (PFS) of patients with SMAD4, EPHA3, PIK3CA, or RET mutations and wild-type patients; (CF) Hallmark pathway enrichment analysis of responders (R) and non-responders (NR); (HK) Kaplan-Meier curves of PFS stratified by high / low enrichment scores of key immune features; (LM) Kaplan-Meier curves of PFS stratified by angiogenesis-related features; (N) Predictive model for efficacy of integrated immune and anti-angiogenic biomarkers.

[0013] Figure 4Olink proteomic biomarker analysis. (A) Heatmap of differentially expressed proteins (DEPs) in responders (R) and non-responders (NR); (B) Level changes of key DEPs in Figure (A); (C) KEGG pathway enrichment analysis of DEPs in responders; (D) Heatmap of DEPs in patients with long PFS (>median PFS) and short PFS (≤median PFS); (E) Level changes of key DEPs in Figure (D); (F) KEGG pathway enrichment analysis of DEPs in the long PFS group. Detailed Implementation

[0014] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0015] Example 1

[0016] 1. Study Design and Subjects

[0017] The main inclusion criteria include: age 18-75 years; histologically / cytologically confirmed extensive-stage small cell lung cancer (meeting the definition of the U.S. Veterans Affairs Staging System); The patient has completed 4-6 cycles of first-line platinum-based chemotherapy (cisplatin or carboplatin) combined with etoposide or irinotecan; after induction chemotherapy, the patient achieved disease control [complete response (CR), partial response (PR), or stable disease (SD)] according to the Evaluation Criteria for the Treatment of Solid Tumors (RECIST) version 1.1; ECOG performance status score (PS) of 0-1; and good organ function.

[0018] Patients with untreated / symptomatic brain metastases, or those who had previously received immunotherapy or anti-angiogenic drug therapy, were excluded.

[0019] This study was approved by the ethics committees of all participating centers (including Henan Cancer Hospital, approval number: 2019269) and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP). This trial is registered on ClinicalTrials.gov (registration number: NCT04901754). All enrolled patients signed written informed consent forms.

[0020] 2. Operating Procedures

[0021] Patients begin maintenance therapy 3–8 weeks after their last chemotherapy session. The treatment regimen consists of camrelizumab (200 mg) administered intravenously every 3 weeks and apatinib (250 mg) orally once daily. Treatment continues until disease progression, intolerable toxicity, withdrawal of informed consent, or investigator's decision to discontinue. Dosage adjustments for apatinib (interruption or reduction to 250 mg every other day) and delays in camrelizumab treatment are outlined in the toxicity management protocol.

[0022] Tumor assessments were performed at baseline (within 28 days prior to the first maintenance dose), every 9 weeks (±1 week) for the first 54 weeks, and then every 12 weeks (±1 week). Efficacy assessments were performed by investigators according to RECIST v1.1 criteria. Safety assessments were ongoing and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.

[0023] The primary endpoint was investigator-assessed progression-free survival (PFS), defined as the time from the start of maintenance therapy to the first recorded disease progression or death from any cause according to RECIST v1.1, whichever comes first. Secondary endpoints included overall survival (OS) (time from the start of maintenance therapy to death from any cause), objective response rate (ORR) (defined as the proportion of patients achieving CR or PR with the best response), disease control rate (DCR, i.e., the proportion of patients achieving CR, PR, or SD with the best response), safety, and biomarker analysis.

[0024] 3. Statistical Analysis

[0025] Sample size was calculated using a one-sample log-rank test. Assuming the combination therapy could extend median progression-free survival (mPFS) from 2.1 months (historical control group) to 3.7 months, and setting a two-sided α value of 0.05 and a power of 80%, 30 evaluable patients were required. Considering a 20% dropout rate, 38 patients were planned for enrollment. Efficacy and safety analyses were performed only on all patients who received at least one dose of study therapy. Median follow-up time was analyzed using the reverse Kaplan-Meier method. Overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method and expressed as median with a 95% confidence interval (CI).

[0026] 4. Results

[0027] 4.1 Patient characteristics and treatment exposure

[0028] Between July 2021 and May 2025, a total of 35 patients were enrolled at the three participating centers in China. Figure 1 All patients were included in the full analysis set and the safety set. Baseline demographic characteristics are summarized in Table 1. The median age of enrolled patients was 63 years (range 45–75 years), with 28 males (80.0%) and 21 patients (60.0%) having an ECOG performance status score of 1. Regarding smoking history, 15 patients (42.8%) were former smokers and 10 patients (28.6%) were current smokers. At enrollment, the proportions of patients with liver metastases, bone metastases, and brain metastases were 20.0%, 20.0%, and 11.4%, respectively.

[0029] As of July 20, 2025, 2 patients (5.7%) were still receiving treatment. The median treatment duration was 5.2 months (range: 0.5–18.3 months). 33 patients discontinued treatment, with disease progression being the primary reason for discontinuation (n=27, 77.1%). The median follow-up time was 15.01 months (95% confidence interval: 8.57–25.00 months).

[0030] Table 1. Baseline patient characteristics (N=35) Some patients have multiple metastatic lesions. 4.2 Therapeutic effect Thirty-two patients underwent at least one post-baseline tumor assessment. Best outcomes during maintenance therapy included one complete response (CR), three partial responses (PR), and 24 stable disease (SD). Four patients achieved best outcomes with disease progression (PD).

[0031] In the ITT population (n=35), the median progression-free survival (PFS) was 5.78 months (95% CI, 3.29–9.23). Figure 2 A), the 6-month and 12-month PFS rates were 48.6% and 25.7%, respectively. The median overall survival (OS) was 25.00 months (95% CI, 10.91 - not reached). Figure 2 B), the 12-month overall survival (OS) rate was 71.4% (95% CI, 53.9-85.8%).

[0032] 4.3 Security

[0033] All 35 patients were included in the safety analysis. 32 patients (91.4%) experienced any grade of treatment-related adverse events (TRAEs), of which 18 (51.4%) reported grade 3 or 4 TRAEs. The most common grade 3 / 4 TRAE was abnormal liver function (elevated transaminases; n=7, 20%). Other significant grade 3 / 4 TRAEs included hyperglycemia (n=3, 8.6%), diarrhea (n=2, 5.7%), and elevated serum alkaline phosphatase (n=2, 5.7%). One patient each experienced grade 3 / 4 decreased lymphocyte count, pancreatitis, hyponatremia, decreased neutrophil count, fatigue, diabetes, hypertension, and neurological impairment. No grade 5 TRAEs occurred (Table 2).

[0034] Table 2. Incidence of treatment-related adverse events (TRASs) ≥10% (N=35)

[0035] Four patients discontinued treatment due to adverse events (AEs): one patient experienced worsening of coronary artery disease (considered possibly unrelated to the study drug); one patient experienced fatigue; one patient experienced infectious encephalitis (considered possibly unrelated to the study drug); and one patient experienced hyperglycemia.

[0036] Eighteen patients (51.4%) experienced immune-related adverse events (irAEs), of which seven (20.2%) experienced grade ≥3 irAEs, including reactive cutaneous capillary endothelial hyperplasia (RCCEP, n=1, 2.9%), hypothyroidism (n=5, 14.3%), and hepatitis (n=3, 8.6%). Most irAEs were grade 1–2 (Table 3).

[0037] Table 3. Immune-related adverse events (irAEs) (N=35)

[0038] Eleven patients (31.4%) had their apatinib dose interrupted or reduced due to adverse events (TRAEs) that occurred during treatment, and three patients (8.6%) permanently discontinued apatinib. Two patients (5.7%) discontinued camrelizumab due to TRAEs.

[0039] Example 2

[0040] 1. Biomarker Analysis

[0041] Baseline tissue samples and dynamic blood samples from enrolled patients during baseline / treatment were collected for biomarker analysis.

[0042] The circulating tumor DNA (ctDNA) analysis workflow is as follows: Blood samples were collected from enrolled patients during the baseline maintenance therapy period and after two cycles of treatment. Cell-free DNA was extracted using the QIAamp circulating nucleic acid extraction kit (Qiagen). Targeted next-generation sequencing was performed using a commercial 168-gene sequencing kit (LungPlasma). Somatic variants were identified using the BWA-GATK-VarScan standard workflow.

[0043] 2. Transcriptome Analysis: Transcriptome sequencing (WTS) was performed on formalin-fixed and paraffin-embedded (FFPE) tumor tissue samples obtained before first-line chemotherapy. RNA was extracted using the AllPrep DNA / RNA FFPE kit (Qiagen). Enrichment scores for 273 predefined oncogenic and immunological signatures (including 50 core Hallmark pathways) were calculated using gene expression data through single-sample gene set enrichment analysis (ssGSEA). Immune cell infiltration scores were assessed using CIBERSORT.

[0044] 3. Proteomics Analysis: Blood samples were collected at baseline during maintenance therapy and after two cycles of treatment. The plasma concentrations of 92 immuno-oncology-related proteins were simultaneously detected using the OlinkTarget96 immuno-oncology assay panel (OlinkProteomics AB, Uppsala, Sweden) via proximity extension technology. Data were standardized and presented as normalized protein expression (NPX) values.

[0045] 4. Statistical Analysis

[0046] The Mann-Whitney U test was used to analyze the association between biomarkers and clinical outcomes. Patients were divided into high and low biomarker score groups based on their biomarker scores (with the median or upper quartile as the cutoff value), and the log-rank test was used to compare progression-free survival (PFS) between groups. All tests were two-tailed, and P < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 24.0 and SAS version 9.4 (SAS Institute Inc.).

[0047] 5. Results of Exploratory Biomarker Research

[0048] Multi-omics analysis results consistently indicate that the "inflammatory" tumor microenvironment (TME) is a key determinant of the efficacy benefit of maintenance therapy with PD-1 inhibitors combined with VEGFR2 inhibitors, as detailed below.

[0049] Negative predictor: Figure 3 A shows the distribution of somatic mutations detected in baseline plasma circulating tumor DNA (ctDNA) (n=28), among which mutations in the SMAD4, EPHA3, PIK3CA, or RET genes were associated with poorer PFS (Pursuit of Failure). Figure 3 B). Although these four genes involve different biological pathways (TGF-β, RTK, PI3K), they have synergistic effects in function, promoting tumor cell plasticity, enhancing drug resistance, and forming an immunosuppressive microenvironment. Paired ctDNA analysis of 26 patients showed that patients who achieved ctDNA "clearance" during maintenance therapy C3 had numerically improved ORR and PFS.

[0050] Transcriptome-proteome association characteristics: Data analysis of pre-treatment tumor tissue RNA sequencing (n=29) and plasma proteomics showed that responders (CR / PR patients) exhibited "inflammatory" TME characteristics [CD8]. + T cells ( Figure 3 C), MHC-I ( Figure 3 D) Upregulation of interferon-α signal ( Figure 3 E), EMT signal down ( Figure 3[F], elevated levels of proteins associated with immune activation and cytotoxicity (FASLG, IL12RB1, IL33, PDCD1, TRAIL), and decreased levels of the immunosuppressive protein Galectin-1 (Gal-1). Figure 4 AC). Baseline expression of high levels of CD8. + T cells, activated memory CD4 + Patients with T-cell or NK-cell characteristics have significantly longer PFS ( Figure 3 HK). Plasma proteomics analysis also showed that prolonged PFS was associated with elevated IL18 and enrichment of antigen presentation and T cell receptor signaling pathways. Figure 4 DF). Conversely, non-responders were characterized by epithelial-mesenchymal transition (EMT) and upregulated TGF-β signaling, and the joint predictive model indicated that the "low TGF-β / high CD8" subgroup had the longest PFS ( Figure 3 (LM), which highlights the synergistic effect of "inflammatory" and non-fibrotic TME on the benefits of combination therapy.

[0051] In summary, the CAMERA trial demonstrated that maintenance therapy with camrelizumab in combination with apatinib showed encouraging efficacy and manageable safety in ES-SCLC patients who achieved disease control after first-line platinum-etoposide chemotherapy. It was significantly superior to the median PFS of 5.78 months and historical data from immunotherapy monotherapy maintenance therapy (approximately 2-3 months). This maintenance therapy strategy using a combination of PD-1 / VEGFR2 inhibitors after induction chemotherapy provides an effective direction for ES-SCLC patients with extremely limited treatment options.

[0052] In the Phase 3 ETER701 clinical trial, the four-drug combination regimen of anlotinib (anti-angiogenic), bemosubibumab (anti-PD-L1), and chemotherapy achieved a median overall survival (OS) of 19.3 months, setting a new OS record for ES-SCLC. However, the four-drug combination significantly increased toxicity, limiting its widespread clinical application. Furthermore, compared to induction therapy with immunotherapy combined with chemotherapy, the four-drug combination did not further improve patient response rates. This suggests that using immunotherapy combined with chemotherapy during the induction phase and immunotherapy combined with anti-angiogenic therapy during the maintenance phase is an optimized treatment strategy to prolong patient survival and reduce treatment toxicity. The Camera study adopted this maintenance therapy model, consistent with previous exploratory maintenance regimens such as durvalumab combined with anlotinib or olaparib. These studies consistently demonstrate that "immunotherapy combined with anti-angiogenic maintenance after immunotherapy induction" is a reasonable and feasible treatment strategy that balances efficacy and toxicity.

[0053] This invention provides the biological mechanism of combined use of PD-1 inhibitors and VEGFR-2 inhibitors. First-line chemotherapy may induce immunogenic cell death, potentially initiating an anti-tumor immune response. However, the residual tumor microenvironment is typically characterized by hypoxia and VEGF-driven immunosuppression. Apatinib, by blocking VEGFR-2, may normalize the tumor vascular system, reduce hypoxia, and decrease the immunosuppressive cell population, thereby creating a favorable environment for PD-1 blockade by camrelizumab, achieving a synergistic effect.

[0054] This invention analyzes multiple sets of biological markers, confirming that CD8 is the most effective biomarker. + The "inflammatory" tumor microenvironment (TME), characterized by T-cell infiltration and upregulation of interferon-α signaling, forms the basis of treatment response. TGF-β and epithelial-mesenchymal transition (EMT) are key features of the unresponsive "cold" TME, providing a direct mechanistic basis for the combined use of apatinib: VEGFR2 inhibition can counteract the angiogenesis and immunosuppressive pathways associated with these resistance phenotypes. The prognostic value of SMAD4 (a TGF-β pathway mediator) mutations further strengthens this association. Our proteomic data further confirm this conclusion, indicating that systemic immune activation (such as elevated IL-12 / IL-18 / TRAIL levels) is associated with better prognosis. Therefore, biomarkers from tumor tissue and peripheral blood consistently identify the "inflammatory" TME as a subgroup of patients with good prognosis, providing a clear direction for precision medicine.

[0055] The safety profile of this invention is as expected and consistent with the known safety profiles of other drugs. The incidence of grade 3 / 4 hepatic dysfunction was relatively high (20%), requiring close monitoring and aggressive management, including timely administration of corticosteroids and dose adjustment. Other noteworthy toxicities (such as hypertension, proteinuria, and hand-foot skin reactions, common side effects of VEGFR inhibitors) were relatively rare or mild in this study, and no treatment-related deaths occurred. This indicates that this combination therapy regimen is feasible for maintenance therapy under appropriate supervision.

[0056] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. The use of a pharmaceutical composition in the preparation of a medicament for maintenance therapy in patients with ES-SCLC whose disease is controlled after first-line chemotherapy, characterized in that, The drug composition is camrelizumab and apatinib.

2. The application as described in claim 1, characterized in that, The dosage of camrelizumab is 200 mg every 3 weeks, and the dosage of apatinib is 250 mg / day.

3. The application as described in claim 1, characterized in that, The administration route of the camrelizumab is intravenous injection, and the administration route of the apatinib is oral administration.

4. The application as described in claim 1, characterized in that, The drug composition is administered within 3-8 weeks after the last chemotherapy session for ES-SCLC patients, provided that the ES-SCLC patients have completed 4-6 cycles of first-line platinum-based chemotherapy combined with etoposide or irinotecan, and that induction chemotherapy has achieved disease control.

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