Anlotinib Combined with S-1 in Third- or Later-Line Stage IV Non-Small Cell Lung Cancer Treatment: A Phase II Clinical Trial.

LESSONS LEARNED: The combination of anlotinib and S-1 exhibited good antitumor activity in third- or later-line treatment for stage IV non-small cell lung cancer (NSCLC). Combination therapy of anlotinib with S-1 has manageable toxicities in patients with NSCLC.
BACKGROUND: This study aimed to evaluate the efficacy and safety of anlotinib combined with S-1 as a third- or later-line treatment for patients with stage IV non-small cell lung cancer (NSCLC). Anlotinib was approved in 2018 by the Chinese Food and Drug Administration (FDA) as a third-line treatment for patients with refractory advanced NSCLC and is under study in the U.S. and Europe.
METHODS: Simon's phase II clinical trial design with an α error of 5% and a power β of 80% was used, anticipating a 10% objective response rate (ORR) of anlotinib and a 30% ORR of anlotinib combined with S-1; the required sample size was 29. A total of 29 patients were enrolled in the clinical trial. Patients were treated with anlotinib plus S-1 over a 21-day treatment course until disease progression or unacceptable toxic effects. If the efficacy was assessed as stable disease, partial response, or complete response after six cycles, anlotinib was maintained until disease progression or death. The primary endpoint was the objective response rate. Somatic mutations were not required for study enrollment.
RESULTS: The median follow-up time was 11.1 months. Objective responses were observed in 11 of 29 (37.9%) patients making up the intention-to-treat population, which reached the target primary endpoint of 30% ORR. The median overall and progression-free survival were 16.7 and 5.8 months, respectively. The most common grade 3 adverse events (AEs) were gastrointestinal, including nausea, vomiting and diarrhea, fatigue, and hypertension. No grade 4 treatment-related AEs or treatment-related deaths occurred.
CONCLUSION: The combination of anlotinib with S-1 in the third- or later-line treatment of stage IV NSCLC shows promising antitumor activity and manageable toxicity in patients with NSCLC; phase III trials will be planned in the future. © AlphaMed Press; the data published online to support this summary are the property of the authors.

Discussion

Anlotinib is an oral, multitargeted tyrosine kinase (TK) receptor inhibitor, which was more effective than placebo in third‐line treatment of patients with advanced NSCLC. However, the ORR was only 9.2% and the overall survival (OS) time was prolonged only 3 months. In the U.S., ramucirumab is most similar to anlotinib, but it was not approved by the Chinese FDA for the treatment of NSCLC. The combination of multitargeted TK receptor inhibitors and chemotherapy is effective and well tolerated in patients with NSCLC and ovarian cancer. Therefore, we hypothesized that anlotinib combined with chemotherapy may be an effective treatment strategy for patients with stage IV NSCLC, leading to the present study combining anlotinib with S‐1. Oral S‐1 is a third‐generation fluorouracil derivative, with good efficacy and relatively low toxicity in the treatment of stage IV NSCLC.

This prospective study reached the target primary endpoint of 30% ORR; the ORR was 37.9%, and the disease control rate (DCR) was 62.1% in the 29 patients who participated in the study. Excluding four (13.8%) patients who did not undergo postbaseline evaluation because of adverse reactions, the ORR was 44%, and the DCR was 72% in 25 patients who had at least one postbaseline evaluation. The secondary endpoints were as follows: median progression‐free survival was 5.8 months and median overall survival was 16.7 months. The patient who achieved the best response (55% reduction by RECIST) also had the longest treatment time among all patients. The patient continued to show >30% decline from the baseline for 36 weeks. These results indicated that the combination of anlotinib and S‐1 exhibited good antitumor activity in third‐line or above treatment for stage IV NSCLC (Figs. 1 and 2).

Figure 1

(A): Waterfall plot for maximal percentage change in target lesion size. (B): Line chart of changes in the tumor size.

Figure 2

Kaplan‐Meier curves of overall survival (A) and progression‐free survival (B).

The most common grade 3 adverse events (AEs) were gastrointestinal (3 [10.3%]), fatigue (2 [6.9%]), and hypertension (2 [6.9%]). Most of the AEs were reversible. In addition, no grade 4 treatment‐related AEs or deaths were recorded. The toxicity was controllable, and the combination therapy did not significantly increase the adverse reactions.

Notably, both anlotinib and S‐1 are orally administered without the need for hospital admission or an infusion pump, which may improve patient compliance and reduce economic costs. In conclusion, the current study showed that the combination therapy of anlotinib with S‐1 has promising efficacy and manageable toxicities in patients with NSCLC, supporting planned phase III trials.

Trial Information

Drug Information

Patient Characteristics

Primary Assessment Method

Assessment, Analysis, and Discussion

Lung cancer is the second leading cause of cancer‐related morbidity and the leading cause of mortality worldwide, with an estimated 2.2 million new lung cancer cases and 1.8 million deaths in 2020 [1]. Non‐small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer [2], and most of the newly diagnosed patients present with metastatic disease [3]. Targeted therapy and immunotherapy play a critical role in the treatment of advanced NSCLC. However, drug resistance in the late stage of targeted therapy is a major concern, and because of its high cost, immunotherapy may not be available. Therefore, third‐line treatment has become a key area of research after the failure of second‐line chemotherapy or targeted drug therapy for patients with advanced NSCLC.

Tumor angiogenesis has been identified as a critical therapeutic target for a malignant tumor, and vascular endothelial growth factor and its receptors are involved in the core signaling pathway in angiogenesis‐related molecular mechanisms. Anlotinib is a new oral small‐molecule tyrosine kinase inhibitor that has a broad spectrum of inhibitory actions against tumor growth and angiogenesis [4, 5]. The ALTER‐0303 [6] trial showed that anlotinib was more effective than placebo in the third‐line treatment of patients with advanced NSCLC. Compared with the placebo group, the objective response rate (ORR) and disease control rate (DCR) of the patients in the anlotinib group were improved (ORR 9.18% vs. 0.7%, p < .0001; DCR 80.95% vs. 37.06%, p < .0001). In addition, anlotinib significantly prolonged the median PFS and OS compared with the placebo group (PFS 5.37 vs. 1.40 months, p < .0001; OS 9.63 vs. 6.30 months, p < .0001). Based on the ALTER‐0303 study, the Chinese Society of Clinical Oncology guidelines recommended anlotinib as the standard third‐line treatment for advanced NSCLC [7]. However, the ORR was only 9.18% and the OS time was prolonged by only 3 months.

The combination of multitargeted tyrosine kinase receptor inhibitors and chemotherapy is effective and well tolerated in patients with NSCLC and ovarian cancer [8, 9], suggesting that anlotinib combined with chemotherapy could be an effective treatment strategy for patients with stage IV NSCLC. S‐1 is an oral fluoropyrimidine formulation with high antitumor activity as a third‐line therapy for NSCLC. Nokihara et al. [10] reported that S‐1 had an ORR of 19% when used as a third‐line treatment for NSCLC. Ono et al. [11] reported the use of S‐1 as a third‐ or fourth‐line therapy for NSCLC, with an ORR of 5.7% in a retrospective analysis. A previous study reported [12] that when S‐1 was used as third‐line therapy, PFS was 3.3 months, and OS was 12.2 months. S‐1 is also well tolerated in elderly patients [13]. Oral S‐1 is a cost‐effective treatment option for patients with advanced NSCLC. However, the response rate of a single drug does not demonstrate sufficient activity for patients with advanced NSCLC.

At present, the effective rate of third‐line treatment for advanced NSCLC is low, and there are few effective options in the clinical setting. Both anlotinib and S‐1 are oral antitumor drugs and are more convenient for patients. They have proven efficacy in patients with third‐ and later‐line advanced NSCLC and good safety. One retrospective study [14] demonstrated that the combination of S‐1 and anlotinib prolonged OS compared with the anlotinib group (8.07 ± 0.56 vs. 6.17 ± 0.42 months), but no significant change was observed in PFS between the two groups (3.87 ± 0.29 months vs. 3.00 ± 0.24 months). The ORR (20.0% vs. 10.0%) and DCR (75.0% vs. 60.0%) of the combined therapy group were significantly higher than those of the anlotinib single group, but the difference was not statistically significant.

This prospective study reached the target primary endpoint of 30% ORR; the ORR was 37.9% (95% CI: 20.7–57.7), and the DCR was 62.1% (95% CI: 42.3–79.3) in the 29 patients who participated in the study. Excluding 4 (13.8%) patients who did not undergo postbaseline evaluation because of adverse reactions, the ORR was 44% (95% CI: 24.4–65.1), and the DCR was 72% (95% CI: 50.6–87.9) in 25 patients who had at least one postbaseline evaluation. The secondary endpoints were as follows: median progression‐free survival was 5.8 (95% CI: 2.9–8.7) months, and the median overall survival was 16.7 (95% CI: 14.9–18.6) months. In contrast, the patient who achieved the best ORR (55%) also had the longest treatment time among all patients. The patient continued to show >30% decline from the baseline for 36 weeks. These results indicated that the combination of anlotinib and S‐1 exhibited good antitumor activity in third‐line or above treatment for stage IV NSCLC. This prospective study achieved a better outcome than the retrospective study noted above [14]. We consider this likely to be due to the synergistic effect of anlotinib and chemotherapy.

Common adverse events (AEs) were fatigue, myelosuppression, gastrointestinal reaction, and hypertension. The common grade 3 AEs were gastrointestinal reaction (3 [10.3%]), fatigue (2 [6.9%]), and hypertension (2 [6.9%]). Most of the AEs were reversible. In addition, no grade 4 treatment‐related AEs or deaths were recorded. The toxicity was controllable, and the combination therapy did not significantly increase the adverse reactions.

Both anlotinib and S‐1 are orally administered without the need for hospital admission or an infusion pump, which may improve patient compliance and reduce economic costs.

Nevertheless, the present study had some limitations. First, it was a single‐arm study with no randomized control design, and hence, selection bias could not be ruled out. Second, the sample size of this study was small and recruited from a single institution. Third, at the beginning of the study, we did not evaluate the indicators, such as smoking status, brain metastasis, and previous treatment regimen, which might be related to the therapeutic effect.

In conclusion, the current study showed that the combination therapy of anlotinib with S‐1 has promising efficacy and manageable toxicities in patients with NSCLC, indicating a need for phase III trials.

Disclosures

The authors indicated no financial relationships.

Disease	Lung cancer ‐ NSCLC
Stage of Disease/Treatment	Metastatic/advanced
Prior Therapy	More than two prior regimens
Type of Study – 1	Phase II
Type of Study – 2	Single arm
Primary Endpoint	Overall response rate
Secondary Endpoint	Progression‐free survival, safety
Additional Details of Endpoints or Study Design
Study design: This phase II, single‐arm, prospective clinical trial was approved by the Ethics Committee of Mianyang Central Hospital, Sichuan, China (Number: S2019001) and was conducted according to the tenets of the Declaration of Helsinki and its later amendments. All participants provided written informed consent prior to participation. The study was registered at the Chinese Clinical Trial Registry (Number: ChiCTR1900020948), and its detailed rationale and methods have been published elsewhere [11]. Briefly, we enrolled patients with cytologically or histologically confirmed stage IV NSCLCfrom Mianyang Central Hospital in Sichuan province. The eligibility criteria were the following: (a) age 18–75 years; (b) pathologically diagnosed with stage IV NSCLC; (c) Eastern Cooperative Oncology Group performance status score 0–2 points; (d) disease progression after at least one line of chemotherapy and tyrosine kinase inhibitor therapy for patients with positive driver mutations epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement and at least two lines of chemotherapy for patients tested negative for driver mutations; (e) a measurable lesion based on the RECIST 1.1 criteria; (f) expected survival time ≥ 12 weeks; (g) normally functioning major organs.
Dosage regimen: Anlotinib: 12 mg, once daily, administered orally for 2 weeks on/1 week off over a 21‐day treatment course, until disease progression or unacceptable toxic effects. S‐1: 70 mg/m2, twice a day, administered orally for 2 weeks on/1 week off, over a 21‐day treatment course, for a maximum of six cycles. If the efficacies were assessed as stable disease, partial response, or complete response after six cycles, anlotinib was maintained until disease progression or death.
Efficacy and safety assessments: The primary endpoint was ORR, and the secondary endpoints were DCR, progression‐free survival (PFS), overall survival (OS), and safety. The treatment effect was assessed every two cycles by measuring the target lesions via computed tomography imaging. Tumor response was assessed according to the RECIST 1.1. The evaluation of adverse reactions was based on the guidelines of National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
Statistical analysis: We used Simon's phase II clinical trial design with an α error of 5% and a power β of 80%, given a 10% ORR of anlotinib, and an anticipated 30% ORR of anlotinib combined S‐1, and estimated the required sample size as 29 cases. The 30% ORR of anlotinib combined S‐1 is the target primary endpoint of the study. SPSS 22.0 statistical software (IBM, Armonk, NY) was used to analyze the data collected by the cutoff date of January 11, 2021. The ORR was calculated using the Clopper‐Pearson method. The ORRs with different clinical characteristics were compared using χ2 test. Multivariate analysis of the independent prognostic factors was performed using the Cox regression model. A log‐rank test was applied to evaluate the differences in PFS and OS between groups. The Kaplan‐Meier method was used to assess PFS and OS with 95% confidence intervals (CIs). Origin 9.0 software was used to draw waterfall and line charts. Two‐sided values of p ≤ .05 were considered statistically significant.
Investigator's Analysis	Active and should be pursued further

Generic Name	Anlotinib
Trade Name	Anlotinib
Company Name	Chia Tai Tianqing Pharmaceutical Co. Ltd
Drug Type	Small molecule
Drug Class	VEGFR
Dose	12 mg per flat dose
Route	p.o.
Schedule of Administration	12 mg, once daily, administered orally for 2 weeks on/1 week off over a 21‐day treatment course, until disease progression or unacceptable toxic effects. If the efficacy in any given patient was assessed as stable disease, partial response, or complete response after six cycles, anlotinib was maintained until disease progression or death.
Generic Name	S‐1
Trade Name	S‐1
Company Name	Lunan Pharmaceutical Group
Drug Type	Biological
Drug Class	Antimetabolite
Dose	70 mg/m2
Route	p.o.
Schedule of Administration	70 mg/m2, twice a day, oral for 2 weeks on/1 week off, 21 days as a course of treatment, until disease progression or unacceptable toxic effects, for a maximum of six cycles.

Number of Patients, Male	24
Number of Patients, Female	5
Stage	IV
Age	Median: 58 years
Number of Prior Systemic Therapies	Median (range): 2 (2–5)
Performance Status: ECOG	0 — 10 1 — 9 2 — 10 3 —0 Unknown —0
Cancer Types or Histologic Subtypes	Adenocarcinoma, 22 Squamous, 5 Adenosquamous, 2

Title	Objective response rate
Number of Patients Screened	29
Number of Patients Enrolled	29
Number of Patients Evaluable for Toxicity	29
Number of Patients Evaluated for Efficacy	25
Evaluation Method	RECIST 1.1
Response Assessment CR	n = 0 (0%)
Response Assessment PR	n = 11 (37.90%)
Response Assessment SD	n = 7 (24.05%)
Response Assessment PD	n = 7 (24.05%)
(Median) Duration Assessments PFS	5.8 months, CI: 95% CI: 2.9–8.7
(Median) Duration Assessments OS	16.7 days, CI: 95% CI: 14.9–18.6

Adverse Events

All Dose Levels, All Cycles
Name	NC/NA	1	2	3	4	5	All grades
Fatigue	45	34	14	7	0	0	55
Hemorrhage, pulmonary/upper respiratory	83	10	3	3	0	0	17
Hypertension	62	21	10	7	0	0	38
Nausea	64	18	7	11	0	0	36
Liver dysfunction/failure (clinical)	66	28	7	0	0	0	34
Proteinuria	83	14	3	0	0	0	17
Rash: hand‐foot skin reaction	79	7	7	7	0	0	21
Rash: acne/acneiform	93	3	3	0	0	0	7
Hypothyroidism	69	17	14	0	0	0	31

All data are presented as %.

Toxicities during treatment (n = 29).

Abbreviation: NC/NA, no change from baseline/no adverse event.

Completion	Study completed
Investigator's Assessment	Active and should be pursued further