Anlotinib plus oral fluoropyrimidine S-1 in treating patients with refractory or relapsed small-cell lung cancer (SALTER TRIAL): an open-label, multicenter, single-arm, phase II trial

doi:10.21203/rs.3.rs-4457908/v1

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Anlotinib plus oral fluoropyrimidine S-1 in treating patients with refractory or relapsed small-cell lung cancer (SALTER TRIAL): an open-label, multicenter, single-arm, phase II trial

https://doi.org/10.21203/rs.3.rs-4457908/v1

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published 01 Sep, 2021

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Background

Patients with small-cell lung cancer (SCLC) have few treatment options and dismal overall survival (OS) after failed platinum-based chemotherapy.

Methods

The eligibility criteria of this phase II clinical trial included patients with measurable disease, age of 18 to 75 years, a confirmed diagnosis of disease progression or recurrence after prior platinum-based chemotherapy with a pathologically proven diagnosis of SCLC. Patients were treated with anlotinib at a dosage of 12mg once daily (QD) and S-1 at 60mg twice daily (BID) for 2 weeks, followed by a 1-week treatment-free interval. After six cycles of above treatment, patients were continued the maintenance therapy using S-1 monotherapy at 60mg/ BID for 2 weeks, followed by a 1-week treatment-free interval until disease progression.

Results

From March 2019 to June 2020, a total of 71 patients were initially assessed for eligibility in this study. Out of these, 52 patients who met the inclusion criteria were enrolled, and 48 patients received at least two doses of the study drug. The median follow-up time was 25.1 months. The ORR was seen in 21 patients (43.8%). The median PFS was 4.5 months (95% CI, 3.5–5.5 months), and the median OS was 5.9 months (95% CI, 4.6–7.3 months). The most common grade 3–4 treatment-related adverse events were thrombocytopenia (16.7%), anemia (14.6%), neutropenia (14.6%), and hypertension (10.4%). No treatment-related death occurred.

Conclusions

Treatment of anlotinib combined with oral fluoropyrimidine S-1 was active for relapsed or refractory SCLC in terms of ORR, having an acceptable and manageable safety profile.

Trial Registration

This trial was registered with ClinicalTrial.gov (NCT03823118) on 3 January 2019.

small-cell lung cancer

antiangiogenic TKIs

oral fluoropyrimidine S-1

relapse

treatment outcome

Small cell lung cancer (SCLC) is a highly metastatic and recalcitrant carcinoma, which accounts for approximately 10–13% of all lung cancers^[1–3]. Platinum-based chemotherapy has been the backbone of SCLC treatment over the past decades. While in addition of extensive-stage SCLC, the programmed death-ligand 1 (PD-L1) inhibitors has demonstrated a sustained overall survival (OS) benefit and currently is considered as the standard first-line treatment^{[4, 5]}. Unfortunately, most patients inevitably develop resistance to these therapies. There is an absence of effective therapies for recurrent and progressive diseases.

Angiogenesis plays an important role in tumor initiation and progression in SCLC, and the therapeutic activity of single-agent vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) by targeting VEGFRs has been shown a disheartening outcomes from previous phase 2 studies in second or later line treatment for SCLC^[6–8].. Anlotinib, a potent novel oral multi-target anti-angiogenesis receptor tyrosine kinase (RTK) inhibitor, inhibits tumor angiogenesis by inhibiting VEGFRs and PDGFR. It also suppresses tumor cell proliferation by blocking c-Kit, PDGFR, Ret, c-FMS, Aurora-B, and discoidin domain receptor 1 (DDR1)^[9]. Several clinical trials demonstrated that anlotinib had robust antitumor efficacy in many types tumor, therefore, It has been approved by the Chinese FDA to treat several types of cancer as a second or later-line option, such as non-small cell lung cancer^[10], advanced or metastatic medullary thyroid carcinoma^[11], and refractory metastatic soft-tissue sarcoma^[12]. In a multinational, randomized phase Ⅱ study (ALTER 1202), anlotinib monotherapy significantly improved overall response rate (ORR) ( 4.9% vs. 2.6%) compared with placebo in patients with progression SCLC who has been given at least two lines of chemotherapy, and median progression-free survival (PFS) was 4.1 and 0.7 months, respectively^[13]. However, whether the combination of anlotinib and chemotherapy can improve outcome in second-line or later setting is unknown.

S-1, a new oral fluoropyrimidine cytotoxic anticancer drug, is a combination of three pharmacological compounds tegafur (prodrug of 5-fluorouracil), gimeracil, and oteracil potassium in a molar ratio of 1:0.4:1. S-1 was approved in Europe for the treatment of patients with non-small cell lung cancer (NSCLC) and gastrointestinal tumors. In a Japanese phase II trial enrolled 26 patients with relapsed SCLC who were treated with S-1 monotherapy, only one patient (3.8%) had an overall response, with a median PFS of 1.1 months^[14].

Our previous basic research found that the treatment of combination of antitumor angiogenesis agent anlotinib with chemotherapy drug 5-FU may have synergistic cytotoxicity to SCLC in vitro and in vivo. This treatment modality reduced cell proliferation and migration via Src/AKT pathway^[15]. We conducted this open-label, multicenter, Phase II Trial (SALTER TRIAL, NCT03823118) to assess the efficacy and safety of anlotinib in combination with oral fluoropyrimidine S-1 in patients with refractory or relapsed SCLC.

3.1 Study Design and Eligibility criteria

SALTER TRIAL was an open-label, multicenter, single arm phase II study designed to evaluate the efficacy and safety of anlotinib in combination with oral fluoropyrimidine S-1 in patients with relapsed or refractory SCLC (ClinicalTrial.gov number, NCT03823118).

Patients eligible for enrollment were required to meet the following criteria: histologically or cytologically confirmed diagnosis of SCLC; patients with platinum-resistant (relapse < 90 days after or during chemotherapy) or platinum-sensitive (relapse ≥ 90 days after chemotherapy) whose disease progression after at least one previous platinum-based chemotherapy regimen, for platinum-sensitive population whose disease progression after at least two chemotherapy regimens. another line chemotherapy is required; aged 18 to75 years; an estimated life expectancy of at least three months; adequate organ function per protocol; at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 ^[16]; the Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2.

Key exclusion criteria included tumour histology that was predominantly NSCLC, mixed small cell, or a combination of both histologies; previous treatment with anti-angiogenesis (VEGF/VEGFR) inhibitor; active symptomatic brain or meningeal metastases (a brain magnetic resonance imaging scan was mandatory); history of malignancy within the last 5 years except for in basal cell carcinoma or situ cervical carcinoma.

This study was approved by the Institutional Review Boards at each participating institution, and was carried out in accordance with Good Clinical Practices and the Declaration of Helsinki^[17], and local ethical and legal requirements. All patients provided written informed consent before their participation in the study.

3.2 Treatment

Patients were treated with oral anlotinib (12mg, QD) plus oral fluoropyrimidine S-1 (60mg, BID). Each cycle was defined as consecutive 2 weeks on-treatment follow by 1 week off-treatment^[9]. After six cycles of combined treatment, S-1 single-agent maintenance treatment was continually followed (3-week as a cycle, 2 week on-treatment follow by 1 week off-treatment) unless the occurrence of disease progression, unacceptable toxicity, withdrawal of consent, or study completion.

3.3 Endpoints and Assessments

The primary endpoint was investigator-assessed ORR. Key secondary endpoints were PFS, OS and treatment-related adverse events (TRAEs). Tumor response was assessed by at least two study investigators using RECIST criteria v1.1 ^[16]. Investigator-assessed ORR was defined as the proportion of patients achieving a complete response (CR) or partial response (PR). PFS was defined at the time from initiation of therapy to the date of first documented tumor progression according to RECIST criteria v1.1^[16], or death due to any cause. OS was defined as the time between initiation of therapy and the date of death or censoring on the day of the last follow-up visit. Disease control rate (DCR) was defined as the proportion of patients who achieved a best ORRs of CR, PR, or stable disease (SD). TRAEs were assessed and graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.

3.4 Sample Size and Statistical Analysis

We planned to enroll 37 patients to accept the hypothesis that the true ORR was 50% of with 80% power and to reject the hypothesis that the ORR was < 20%, with a two-sided alpha level of 5%. Considering a 20% drop-off rate, the total number of patients was estimated to be 45.

Descriptive statistics were used for baseline characteristics of included patients, tumor-response data analysis, and summary statistics for TRAEs. PFS and OS were calculated using the Kaplan-Meier method. Statistical analyses were performed using GraphPad Prism software (Version 9, GraphPad Software) and R software (version 4.1.3, R Foundation for Statistical Computing). Two-sided values of p ≤ .05 were considered statistically significant

4.1 Patients and Baseline Characteristics

Between March 2019 to June 2020, a total of 71 patients with relapsed or refractory SCLC were reviewed for eligibility. Among those eligible, 19 patients were excluded (12 patients did not meet the eligibility criteria, 5 patients declined to participate and 2 patients with others), and 4 patients were excluded from the final analysis because of inadequate data (two patients because of received only one course combination treatment, two patients were not received response assessment). Therefore, a total of 48 patients were included for final analysis in the study, including 44 men (91.70%) and 4 women (8.30%) (Fig. 1). Their median age was 65 (range 37–75) years. Among those 48 patients, 47 (95.8%) were extensive-stage SCLC, and 27 (56.30%) were platinum resistant (progression during or 90 days after platinum). The baseline characteristics are shown in Table 1.

Table 1

Patient demographics and baseline characteristics
	Number (%)
Age, median (range), years	65 (37–75)
Sex
male	44 (91.7%)
female	4 (8.3%)
ECOG performance status
0	5 (10.4%)
1	28 (58.3%)
2	15 (31.1%)
Smoking status
Current/former smoker	37 (77.1%)
Never smoked	11 (22.9%)
Disease classification at initial diagnosis
Limited disease	1 (4.2%)
Extensive disease	47 (95.8%)
Response to first-line therapy
Platinum sensitive	21 (43.7%)
Platinum resistant	27 (56.3%)
Central nervous system metastases
Yes	13 (27.1%)
No	35 (72.9%)
Liver metastases
Yes	18 (37.5%)
No	30 (62.5%)

Two-hundred one S-1 and anlotinib combination treatment courses in total were administered, with a median of three courses per patient, and 12 patients received S-1 single-agent maintenance treatment.

At data cut off April 17, 2021, median follow-up time was 25.1 months. According to the investigator assessment of all treated patients, the ORR was 43.8% (Fig. 2), all responses were PR. The DCR was 89.3%, including the 21 (43.8%) patients had PR, and 22 (45.5%) patients had SD. Antitumor activity by investigator assessment are summarized in Table 2.

Table 2

Summary of tumor response
Response	No. (%)
Objective response
Patients with response, n % of patients	21(43.8%)
Disease control rate, n % of patients	43 (89.3%)
Best overall response, n (%)
Complete response	0(%)
Partial response	21(43.8%)
Stable disease	22(45.5%)
Progressive disease	4(4.2%)
Could not be determined	1(2.0%)

The Kaplan-Meier estimates for PFS and OS were shown in Fig. 3. Investigator-assessed median PFS was 4.5 months (95% CI, 3.5–5.5 months), median OS was 6.3 months (95% CI, 4.6–7.3 months).

In subgroup analyses, the ORR was 47.6% in platinum sensitive (chemotherapy-free interval of 90 days or more 90 days) and 40.7% in platinum resistance patients (chemotherapy-free interval of less than 90 days). The median PFS and OS for the platinum-sensitive were 4.7 months and 6.6 months, the median PFS and OS for the platinum-resistant were 4.3 months and 5.9 months.

4.2 Safety

Three patients had a dose reduction of 10mg per day, one patient had a dose reduction to 8mg in anlotinib treatment, and one patient had S-1 dose reduction to 40mg per day due to anemia. Both anlotinib and S-1 dose administration was reduced in 1 (2.0%) patient, and 1 patient had anlotinib dose reduced only because of TRAEs.

A safety summary of TRAEs was presented in Table 3 (grade 1–2 TRAEs that reported ≥ 10% of patients and all grade 3–4 TRAEs). At least one TRAE was reported in all 48 patients (100%), the most frequently reported TRAEs of any grade were hematological AEs (62.5%), hypertension (47.9%), skin hyperpigmentation (37.5%), fatigue (35.4%), appetite decrease (35.4%), weight loss (31.2%) and hyperbilirubinaemia (20.8%).

Table 3

Treatment-related adverse events occurring in ≥ 10% of patients
	Any grade	Grade 3 or 4
	48 (100.0%)	19 (39.6%)
Hematologic
Leukopenia	22 (45.8%)	4 (8.3%)
Neutropenia	14 (29.2%)	7 (14.6%)
Lymphopenia	17 (35.4%)	3 (6.3%)
Thrombocytopenia	25 (52.1%)	8 (16.7%)
Anemia	37 (77.1%)	7 (14.6%)
Non-hematologic
Fatigue	17 (35.4%)	4 (8.3%)
Appetite decreases (anorexia)	17 (35.4%)	3 (6.3%)
Nausea	4 (8.3%)	0
Vomiting	5 (10.4%)	0
Constipation	5 (10.4%)	0
Weight loss	15 (31.2%)	1 (2.8%)
Hand-food skin reaction	13 (27.1%)	2 (4.2%)
Hypertension	23 (47.9%)	5 (10.4%)
proteinuria	7 (14.5%)	1
Skin hyperpigmentation	18 (37.5%	1
blurred vision	6 (12.5%)	1
Hemoptysis	5 (10.4%)	1
Hyperbilirubinaemia	10 (20.8%)	none

Grade 3 or 4 TRAES were observed in 19 (39.6%) patients, the most common grade 3 or 4 TRAEs were hematologcial (18.8%), hypertension (10.4%), fatigue (8.3%), hand-foot syndrome (4.2%), anorexia (6.3) and blurred vision (4.2%). All TRAEs during trial were controlled after dose modification or symptomatic treatment and no patients had discontinued treatment because of TRAEs. No treatment-related deaths occurred.

The SALTER Trial meets its primary endpoint of improved ORR versus histological report standard treatment as second-line or later treatment in patients with SCLC whose disease progression after at least one platinum-based chemotherapy^{[18, 19]}. Results from this study demonstrated that S-1 in combination with anlotinib had robust antitumor activity in ≥ 2L patients with SCLC.

The present study confirmed that the combination therapy of anlotinib and S-1 had more potent clinical activity than anlotinib or S-1 monotherapy in relapsed or refractory SCLC. An objective response was obtained in only 1 patient (3.8%) from S-1 monotherapy ¹⁴ and 4.9% in anlotinib monotherapy as previous clinical trials reported¹³. In addition, the ORR was significantly higher than immune-based treatment strategies and traditional cytotoxic chemotherapy for relapsed SCLC^[20–22]. The FDA approves oral or intravenous topotecan as a subsequent treatment for patients with SCLC who had disease progression after the initial response to systemic therapy, and the ORRs do not typically exceed 25%^{[18, 23, 24]}. Moreover, immune-based treatment strategies, for example, Checkmate 331, a randomized phase 3 trial showed response rate was only 13.6% for nivolumab.¹⁹ Similarly, lurbinectedin monotherapy showed an ORR of 45% and lurbinectedin plus irinotecan showed an ORR of 62%, single agent amrubicin showed 31% ORRs. Olaparib, a PARP inhibitors in combination with temozolomide showed a confirmed overall response rate of 41.7%^[25], temozolomide in combination with another PARP inhibitor veliparib achieved 39%^[26]. In a phase 2 trial by Fan et al, the combination of PD-1 immune checkpoint inhibitor camrelizumab with anti-VEGFR inhibitor apatinib showed an ORR of 34.0%^[27]. The ORR of the present trial was also higher than other anti-VEGFR-TIKs monotherapy such as sorafenib^[6], pazopanib^[7], apatinib^[8] in relapsed or refractory SCLC. Table 4 summarized outcomes of anlotinib for relapsed SCLC from selected studies.

Table 4

Outcomes of anlotinib for relapsed SCLC from selected studies
	Study design	Treatment scheme	Number of Patients	Treatment Line	ORR	DCR	Median PFS (months)	Median OS (months)
Present study (NCT03823118)	Phase 2, pro	Anlo + S-1	48	≥ 2L	43.8%	89.3%	4.5	5.9
Chen et al.^[13] (NCT03059797)	Phase 2, RCT	Anlo placebo	81 36	≥ 3L	4.9% 2.6%	71.6% 13.2%	4.1 0.7	7.3 4.9
Wu et al.^[31] (NCT03732846)	Phase 2	Anlo	45	≥ 3L	11.0%	67.0%	4.1	6.1
Gao et al.^[32]	Retrospective	Anlo	40	≥ 3L	10.0%	45.0%	3.0	7.8
Xia et al.^{[33, 34]} (NCT04757779)	Phase 2	Anlo + irinotecan/docetaxel	24	2L(relapsed ≤ 6mon)	47.6%	90.5%	4.0	7.5
Ma et al. ^[35] (NCT04055792)	Phase 2	Anlo + sintilimab	26	≥ 2L	45.5%	86.4%	5.7	11.4
Zhang et al.^[36] (NCT04203719)	Phase 2	Anlo + Penpulimab	20	2L	50.0%	75.0%	4.7	/
Wang et al.^[37]	Retrospective	Anlo Chemo	28 27	≥ 3L	/	/	3.6 2.7	5.3 6..6
Hao et al.^[38]	Retrospective	Anlo + PD(L)1i	36	≥ 2L	27.8%	80.6%	4.6	9.3
Chen et al.^[39]	Retrospective	Anlo Anlo + ICI	58 62	3L	6.9% 19.4%	72.4% 87.1%	4.6 4.5	/
RCT, randomized controlled trial; anlo, anlotinib; chemo, chemotherapy; ICI, immune checkpoint inhibitor

Our findings showed that the addition of oral fluoropyrimidine S-1 and anlotinib in the ≥ 2L patients with SCLC led to significant improvement of ORR, which, however, did not translate into significant PFS and OS benefits. Previous studies have shown that the OS outcome highly depends on the time from initial therapy to relapse and subsequent therapy options for patients with SCLC who have relapsed progression^[28]. Several reasons may account for this: firstly, in the present study, approximately 56.3% of patients had a treatment-free interval of fewer than 90 days at study entry; Secondly, most patients (95.8%) were at an extensive stage at initial diagnosis; thirdly, 56.7% of the patients in the present study received third-line therapy; lastly, patients had a higher rate of brain metastasis (27.1%) and liver metastases (37.5%). Predictive markers that identify patients with an enhanced likelihood of clinical benefit from this combination regimen need to be further investigated.

In subgroup analysis, the ORR was similar in platinum-sensitive group and platinum-resistance group (47.6% vs. 40.7%) in the present study. These results was different from other studies that reported resistance patients had inferior ORR to sensitive patients. A systematic analysis included twenty-one clinical studies that showed the ORR was 27.7% in the sensitive group and 14.8% in the resistant group^[28]. Treatment with the multi-kinase inhibitor sorafenib resulted in an ORR of 11% in the platinum-sensitive and 2% in the platinum-refractory stratum^[6]. The median PFS (4.7m vs. 4.3m, HR = 1.09, p > 0.05) and OS (6.6m vs. 5.9m, HR = 0.50. p > 0.05) in platinum-sensitive and platinum-resistance subgroup in the current study. The sensitive disease derived more clinical benefit from subsequent system treatment compared than resistant/refractory disease both in terms of PFS and OS. A system analysis showed the median OS was 7.73 months for sensitive SCLC and 5.45 months for refractory disease^[28].

The toxicity was safe and acceptable in the present study. The toxicity profile of the present combination regimen was similar to the previous report with component monotherapy or combination therapy^{[7, 14, 29]}. Any grade TRAEs and grade 3 and grade 4 TRAEs were 100% and 39.6% in our study, it has seemly occurred more frequently than the previous report and grade 3 or 4 toxicities occurred slightly higher than S-1 or anlotinib monotherapy. A phase II study from Japanese population reported single-agent S-1 treatment for relapsed SCLC, the grade 3 or 4 AE rate was 7.7%^[14] and the frequency of G3/G4 TRAEs was 35.8% in anlotinib monotherapy by another trial ^[7]. The grade 3 or 4 TRAEs are more frequent than the previous report, which anlotinib plus S-1 in patients with EGFR-mutation NSCLC population^[30].

The impact of this study is limited by the single-arm study designed with no control group and heterogeneity of the enrolled patient population. Fresh tumor specimens before treatment were not obtained for further biomarker analyses.

The combination therapy of anlotinib and oral fluoropyrimidine S-1 provided robust antitumor activity and had an acceptable and manageable safety profile as a second or later-line treatment for the recurrence or refractory SCLC. These results suggest that this combination strategy is an effective second or later-line treatment for this population.

Ethics approval and consent to participate

The study was approved by the Institutional Review Boards at each participating institution and was carried out in accordance with Good Clinical Practices and the Declaration of Helsinki, and local ethical and legal requirements. All patients provided written informed consent before their participation in the study. This trial was registered with ClinicalTrial.gov (NCT03823118).

Consent for publication

This work was original research that has not been published previously. All the authors listed have approved the manuscript and have agreed to publish this manuscript.

Authors' contributions

Wei Wang: Data analysis; Accessed and verified the underlying data; Manuscript writing & final approval of manuscript.

Guixian Wu: Data analysis; Accessed and verified the underlying data; Manuscript writing & final approval of manuscript.

Wujun Luo: Data analysis; Accessed and verified the underlying data; Manuscript writing & final approval of manuscript.

Ziran Chen: Provision of study materials or patient; Collection and assembly of data, writing & final approval of manuscript.

Ling Lin: Provision of study materials or patient; Collection and assembly of data, writing & final approval of manuscript.

Chao Zhou: Provision of study materials or patient; Collection and assembly of data, writing & final approval of manuscript.

Guifei Yao: Provision of study materials or patient; Collection and assembly of data, writing & final approval of manuscript.

Meifang Chen: Provision of study materials or patient; Collection and assembly of data, writing & final approval of manuscript.

Xiaomai Wu: Collection and assembly of data, writing & final approval of manuscript

Junhui Ye: Conception and design; Administrative support; Collection and assembly of data; Accessed and verified the underlying data writing & final approval of manuscript.

Haihua Yang: Conception and design; Administrative support; Collection and assembly of data; Accessed and verified the underlying data writing & final approval of manuscript.

Dongqing Lv: Conception and design; Administrative support; Collection and assembly of data; Accessed and verified the underlying data writing & final approval of manuscript.

Acknowledgments

We thank the patients, their families, and the participating trial teams for making this trial possible.

Funding

Medicine and Health Science and Technology Project of Zhejiang Province（2024KY1829）

Competing interests

The authors declare no competing interests.

Availability of data and materials

The de-identified datasets created and analyzed during the current study are available with investigator support, after approval of a proposal and with a signed data access agreement.

Disclosure

Part of this work was presented at the European Society for Medical Oncology (ESMO) Virtual Annual Meeting, September 16-21, 2021.

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Anlotinib plus oral fluoropyrimidine S-1 in treating patients with refractory or relapsed small-cell lung cancer (SALTER TRIAL): an open-label, multicenter, single-arm, phase II trial

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Introduction

Study design and Methods

3.1 Study Design and Eligibility criteria

3.2 Treatment

3.3 Endpoints and Assessments

3.4 Sample Size and Statistical Analysis

Results

4.1 Patients and Baseline Characteristics

4.2 Safety

Discussion

Conclusions

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