A retrospective study of anlotinib in patients with persistent, recurrent or metastatic cervical and endometrial cancer

Introduction

The morbidity and mortality of gynecological cancers is growing rapidly worldwide, data from global cancer statistics demonstrated 341,831 and 97,370 new cases of death respectively for cervical cancer and endometrial cancer in 2020 (1). For the newly diagnosed cervical and endometrial cancer patients, the surgery, chemotherapy, and radiotherapy are preferred treatments (2,3). However, for patients with persistent, recurrent, and metastatic cervical and endometrial cancers, the therapeutic strategy is limited and the prognosis is poor (4). Thus, there is unmet need for effective therapeutic regimens for persistent, recurrent, and metastatic cervical and endometrial cancers.

Angiogenesis is an indispensable process of tumor aggressiveness which triggers the development of anti-angiogenesis therapy (5). Anti-angiogenesis therapies target on angiogenic factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), angiogenin (Ang), hepatocyte growth factor (HGF), hypoxia-inducible factor (HIF), insulin-like growth factor (IGF), transforming growth factor-β (TGF-β), matrix metalloproteinase (MMP), and tumor necrosis factor (TNF) to reduce tumor blood supply and normalize tumor blood vessels, which facilitate conventional treatments (6-9). Since the Food and Drug Administration (FDA) approval of the first antiangiogenic drug (bevacizumab), anti-angiogenesis treatment has enlightened new perspectives and gained remarkable benefits in anti-cancer therapy (10). Until now, bevacizumab is the only anti-angiogenic agent approved for cervical cancer, and no anti-angiogenic agent is approved for endometrial cancer (11). Moreover, previous study indicated that resistance to bevacizumab might attribute to enhanced secretion of other angiogenic factors (12). Therefore, there is growing need for agents targeting multiple angiogenesis pathways.

Anlotinib, a novel multitarget tyrosine kinase inhibitor (TKI) developed in China, inhibits the VEGF receptors 1–3, FGF receptors 1–4, EGF receptor, PDGF receptor, c-kit and c-Met to achieve anti-cancer effect through anti-angiogenesis, regulating tumor microenvironment and promoting tumor cell apoptosis (13,14). Anlotinib has been approved for treating non-small cell lung cancer, small cell lung cancer, and soft tissue sarcoma in China (15-17). A phase II, single-arm, prospective study showed that the objective response rate (ORR) and disease control rate (DCR) of anlotinib were 24.4% and 58.5% in Chinese patients with recurrent or metastatic cervical cancer (18). A phase II clinical trial by Wei et al. demonstrated robust therapeutic benefits of anlotinib plus sintilimab [anti-programmed death-1 (anti-PD-1) antibody] in endometrial cancer with an ORR of 73.9% and DCR of 91.3% (19). Given the heterogeneity between real-world practice and clinical trials, and among different centers, we retrospectively investigated the efficacy and safety of anlotinib in cervical and endometrial cancers in our center. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-272/rc).

Methods

Patients and treatments

In this study, we retrospectively enrolled patients with pathological or cytological confirmed persistent, recurrent or metastatic cervical and endometrial cancers receiving anlotinib as second- or later-line treatment in the General Hospital of Chinese People’s Liberation Army (PLA) between March 2020 and June 2023. The inclusion criteria were as follows: pathological or cytological confirmed persistent, recurrent or metastatic cervical and endometrial cancers, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2, at least one measurable lesion. The exclusion criteria were as follows: high bleeding risk, serious autoimmune diseases, grade III hypertension, cardiac insufficiency, gastrointestinal dysfunction, intestinal obstruction, failed to be followed up, incomplete clinical information, no measurable lesion. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethics Committee of General Hospital of Chinese PLA (No. S2021-553-01), the informed consent was waived according to the nature of retrospective study. The demographic and clinical characteristics, such as age, gender, diagnosis, stage, pathology subtypes, presence of liver or brain metastasis, ECOG PS, previous treatment lines and regimens, laboratory and radiological data and adverse events (AEs) were summarized.

Anlotinib was orally taken 8 or 12 mg once daily for 14 consecutive days and withdrawn for 7 days, the initial dosage was determined by the oncologist or gynecologist according to the patient’s condition and adjusted if intolerance occurred. The combined regimens were prescribed according to the National Comprehensive Cancer Network or Chinese Society of Clinical Oncology guidelines. The last follow-up was on October 1, 2023. Median follow-up time was 14.8 months (range, 3.1–43.3 months).

Assessments

The clinical benefit of anlotinib was evaluated every two cycles. The efficacy indicators were evaluated according to the Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1 by two independent doctors (20), and classified as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). ORR was calculated as the proportion of CR + PR; DCR was calculated as the percentage of CR + PR + SD. Clinical benefit was defined as patients achieving CR or PR or SD as best response. Non-clinical benefit was defined as patients experienced PD as best response. Progression-free survival (PFS) was defined as the time from anlotinib administration to disease progression or death due to any cause; overall survival (OS) was defined as the time from anlotinib administration to death. The AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE 5.0).

Statistical analysis

The statistical analysis was conducted by SPSS version 26.0 (IBM Corp., Armonk, NY, USA) and PRISM version 9.0 (GraphPad Software, La Jolla, CA, USA). Continuous data were expressed as mean and 95% confidence interval (CI). Countable data were expressed as frequency or percentage (%). PFS and OS were estimated by the Kaplan-Meier method. The comparison between two or three groups was assessed by the chi-squared test. The survival data between different groups were compared by the log-rank test. The significant difference was defined as P<0.05 (two-tails).

Results

Baseline demographics and clinical characteristics of patients

A total of 34 patients were screened for the study, five patients were excluded due to loss of follow-up. Thus, 29 patients were recruited in this study. The median age was 58 years (range, 36–73 years). There were 93.10% (27/29) of patients with stage IV per International Federation of Gynecology and Obstetrics (FIGO) stage system. There were 16 patients diagnosed with cervical cancer, and 13 with endometrial cancer. As for the pathological type, there were 11 and 14 patients with squamous cell carcinoma and adenocarcinoma respectively. Of the whole patients, 86.21% (25/29) were with ECOG PS ≤1, 68.97% (20/29) received two or more lines of previous treatment, and 55.17% (16/29) received anlotinib combined with immunotherapy. The baseline characteristics are summarized in Table 1.

Efficacy

Of the whole patients, seven gained PR, nine gained SD, and 13 experienced PD, yielding the ORR of 24.14% and DCR of 55.17%. The ORR in patients with cervical cancer and endometrial cancer were 25.00% and 23.08%, and the DCR were 56.25% and 53.85% (Table 2). There was no different anti-tumor effect of anlotinib between patients with cervical cancer and endometrial cancer. Thus, all patients were integrated as a whole for subsequent analysis, given the small sample size of each cancer.

To identify patients most likely benefit from anlotinib, the patients were divided into two groups by achieving clinical benefit or not. The patients received anlotinib combined with immunotherapy had significantly higher rate of clinical benefit than those receiving anlotinnb alone (P=0.04). There were no different rates of clinical benefit between patients in subgroups of age (P=0.53), FIGO stage (P=0.10), liver metastases (P=0.08), brain metastases (P=0.78), pathological types (P=0.19), ECOG PS (P=0.82), number of previous treatment lines (P=0.10) (Table 3).

Subsequently, patients were grouped by receiving combined immunotherapy or not. The baseline characteristics were comparable between patients with immunotherapy and without immunotherapy (Table 4). The ORR was higher in patients treated with anlotinib combined with immunotherapy than those without immunotherapy (31.25% vs. 15.38%, P=0.32); while, the DCR was significantly higher in patients with immunotherapy comparing to those without immunotherapy (75.00% vs. 30.76%, P=0.02) (Table 5).

The overall median PFS and OS were 12.2 months (95% CI: 6.6–17.8) and 22.3 months (95% CI: 20.9–23.7), respectively (Figure 1A,1B). The 6-month survival rates of PFS and OS were 51.7% and 82.8%, the 12-month survival rates of PFS and OS were 34.5% and 51.7%, and the 18-month survival rates of PFS and OS were 17.2% and 37.9%. For patients with cervical cancer, the median PFS and OS were 13.1 months (95% CI: 6.9–19.3) and 24.0 months (95% CI: 20.3–27.7); for patients with endometrial cancer, the median PFS and OS were 8.2 months (95% CI: 0–17.0) and 22.3 months (95% CI: 10.7–33.9). The patients receiving anlotinib combined with immunotherapy had significant longer OS than those without immunotherapy [not reached vs. 12.5 months; hazard ratio (HR): 0.32 (95% CI: 0.1–0.99); P=0.04]. In addition, the PFS was also longer in patients receiving anlotinib with immunotherapy comparing to those without immunotherapy, though not significant [12.2 vs. 5.6 months; HR: 0.76 (95% CI: 0.30–1.96); P=0.58] (Figure 1C,1D).

Figure 1 The Kaplan-Meier curves of PFS and OS of all patients and immunotherapy stratified patients. (A) The Kaplan-Meier curves of overall mPFS of patients. (B) The Kaplan-Meier curves of overall mOS of patients. (C) The Kaplan-Meier curves of PFS of patients stratified by with or without immunotherapy. (D) The Kaplan-Meier curves of OS of patients stratified by with or without immunotherapy. mPFS, median progression-free survival; CI, confidence interval; PFS, progression-free survival; mOS, median overall survival; OS, overall survival; HR, hazard ratio.

Safety

The AEs were reported in 23 (79.3%) patients, and there was no treatment-related death and anlotinib discontinuation. The seven most common AEs were fatigue (41.4%), hand-foot syndrome (17.2%), oral mucositis (17.2%), neutropenia (17.2%), anemia (13.8%), hoarseness (13.8%), and hypertension (13.8%). Grade 3–4 AEs were observed in 4 (13.8%) patients treated with anlotinib combined with immunotherapy; three suffered grade 3 hypertension and were managed well by antihypertensive drugs, one suffered grade 4 anemia and received transfusion and dose reduction. All the safety data are summarized in Table 6.

Discussion

Persistent, recurrent, or metastatic gynecological cancers are associated with poor prognosis and have limited treatment options (21-23). For the recurrent or metastatic cervical cancer, the 5-year survival rate is 17%; for the stage IV endometrial cancer, the 5-year survival rate ranges from 15% to 17% (24,25). Novel antitumor strategies remain an unmet clinical need. In our study, anlotinib exhibited compelling antitumor effect with ORR of 24.14% and DCR of 55.17% in patients with cervical cancer and endometrial cancer. Moreover, anlotinib plus immunotherapy demonstrated synergistic antitumor effect.

Sufficient clinical trials have confirmed the efficacy of anti-angiogenic therapy in solid tumors. In our study, the efficacy outcomes are similar with previous studies. As for cervical cancer, the ORR and DCR were comparable to those reported by Zhu et al. (18). In endometrial cancer, our results showed an ORR of 23.08% and DCR of 53.85%, which were slightly inferior to those reported by Cui et al. (26) and Wei et al. (19). The differences might attribute to the followings: firstly, the sample size of endometrial cancer in our study was relatively small; secondly, in the study by Wei et al., all patients were treated with anlotinib plus immunotherapy and lower proportion of patients received three or more lines of previous treatments (19). However, the survival benefits of our study are superior to previous studies. In present study, the median PFS and OS were 13.1 and 24.0 months in cervical cancer; while, the median PFS and OS were 8.2 and 22.3 months in patients with endometrial cancer. In Gynecologic Oncology Group (GOG) 240 trial, bevacizumab combined with chemotherapy achieved 17 months of median OS and 8.2 months of median PFS in patients with refractory, recurrent, or metastatic cervical cancer (27). Cui et al. reported the median PFS and OS of anlotinib in endometrial cancer were 6 and 13.3 months respectively (26). The promising survival benefit demonstrated the efficacy of anlotinib, while the difference due to small sample size cannot be ruled out.

Immunotherapy, especially for anti-PD-1/programmed death ligand-1 (PD-L1) blockades, has achieved remarkable success in solid tumors and revolutionized the treatment of cancers in recent years (28). In gynecological cancers, efficacy of immunotherapy has been validated by numerous studies (29,30), especially in endometrial cancer patients harboring deficient mismatch repair or high microsatellite instability (31,32). Thus, immunotherapy is recommended as the first-line treatment for advanced or metastatic endometrial cancer (33). Furthermore, anti-angiogenic therapy combined with immunotherapy shows synergistic anti-tumor effects, for the anti-angiogenic therapy could alleviate immunosuppression by T-cell infiltration, decrease regulatory T cells, and downregulate PD-L1 expression (34,35). As reported by Xu et al. (36), anlotinib plus sintilimab showed promising efficacy with ORR of 54.5% and DCR of 100% in patients with persistent, recurrent, or metastatic cervical cancer. Yang et al. showed that the anlotinib plus sintilimab achieved an ORR of 40% and a DCR of 100% in patients with persistent, recurrent, or metastatic cervical cancer as second-line treatment (37). In the KEYNOTE-146 study (38), lenvatinib plus pembrolizumab showed compelling antitumor activity with an ORR of 38% in patients with advanced or metastatic endometrial cancer regardless of microsatellite status. In line with above-mentioned studies, our study showed that the ORR and DCR were also superior in patients treated with anlotinib plus immunotherapy. The patients receiving anlotinib plus immunotherapy had longer PFS and OS than those without immunotherapy, which are similar to results reported by Wei et al. (19). Thus, anlotinib plus immunotherapy might be a promising regimen in cervical and endometrial cancers.

In our study, the most common AEs were fatigue (41.4%), hand-foot syndrome (17.2%), oral mucositis (17.2%), neutropenia (17.2%), anemia (13.8%), hoarseness (13.8%), and hypertension (13.8%), all of which were typical AEs of anlotinib reported in previous studies, and no unreported complications and death occurred. In present study, three patients suffered treatment-related grade 3 hypertension, which was reported ranging from 39% to 68% in previous studies (39-41), and all the three patients were managed well. Furthermore, all the grade 3–4 AEs were observed in patients treated with anlotinib plus immunotherapy, suggesting that the combination therapy might increase the incidence of grade 3–4 AEs. However, our study showed that anlotinib exhibited well tolerability and low toxicity.

Some limitations should be noted. First, the small sample size and self-limitation of single-center retrospective study lower the significant power, and further large-scale prospective studies are needed to confirm our findings. Second, prognostic indicators involving the microsatellite status, PD-L1 expression, and genetic status were not analyzed in this study, which could help to identify patients more likely to benefit from anlotinib with immunotherapy.

Conclusions

Anlotinib might be a promising therapy for persistent, recurrent, or metastatic cervical and endometrial cancers with low toxicity. Moreover, anlotinib combined with immunotherapy showed synergistic antitumor effects in persistent, recurrent, or metastatic cervical and endometrial cancers.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-272/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-272/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-272/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-272/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of General Hospital of Chinese PLA (No. S2021-553-01), the informed consent was waived according to the nature of retrospective study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
2. Chargari C, Peignaux K, Escande A, et al. Radiotherapy of cervical cancer. Cancer Radiother 2022;26:298-308. [Crossref] [PubMed]
3. Makker V, MacKay H, Ray-Coquard I, et al. Endometrial cancer. Nat Rev Dis Primers 2021;7:88. [Crossref] [PubMed]
4. Ferron G, Bataillon G, Martinez A, et al. Gynecological sarcomas, surgical management: primary, metastatic, and recurrent disease. Int J Gynecol Cancer 2024;34:393-402. [Crossref] [PubMed]
5. Li X, Zhou J, Wang X, et al. New advances in the research of clinical treatment and novel anticancer agents in tumor angiogenesis. Biomed Pharmacother 2023;163:114806. [Crossref] [PubMed]
6. Ye ZW, Yu ZL, Chen G, et al. Extracellular vesicles in tumor angiogenesis and resistance to anti-angiogenic therapy. Cancer Sci 2023;114:2739-49. [Crossref] [PubMed]
7. Shoeibi S, Mozdziak P, Mohammadi S. Important signals regulating coronary artery angiogenesis. Microvasc Res 2018;117:1-9. [Crossref] [PubMed]
8. Liu ZL, Chen HH, Zheng LL, et al. Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal Transduct Target Ther 2023;8:198. [Crossref] [PubMed]
9. Choi Y, Jung K. Normalization of the tumor microenvironment by harnessing vascular and immune modulation to achieve enhanced cancer therapy. Exp Mol Med 2023;55:2308-19. [Crossref] [PubMed]
10. Garcia J, Hurwitz HI, Sandler AB, et al. Bevacizumab (Avastin®) in cancer treatment: A review of 15 years of clinical experience and future outlook. Cancer Treat Rev 2020;86:102017. [Crossref] [PubMed]
11. Choi HY, Chang JE. Targeted Therapy for Cancers: From Ongoing Clinical Trials to FDA-Approved Drugs. Int J Mol Sci 2023;24:13618. [Crossref] [PubMed]
12. Huang M, Lin Y, Wang C, et al. New insights into antiangiogenic therapy resistance in cancer: Mechanisms and therapeutic aspects. Drug Resist Updat 2022;64:100849. [Crossref] [PubMed]
13. Shen G, Zheng F, Ren D, et al. Anlotinib: a novel multi-targeting tyrosine kinase inhibitor in clinical development. J Hematol Oncol 2018;11:120. [Crossref] [PubMed]
14. Song F, Hu B, Cheng JW, et al. Anlotinib suppresses tumor progression via blocking the VEGFR2/PI3K/AKT cascade in intrahepatic cholangiocarcinoma. Cell Death Dis 2020;11:573. [Crossref] [PubMed]
15. Han B, Li K, Wang Q, et al. Effect of Anlotinib as a Third-Line or Further Treatment on Overall Survival of Patients With Advanced Non-Small Cell Lung Cancer: The ALTER 0303 Phase 3 Randomized Clinical Trial. JAMA Oncol 2018;4:1569-75. [Crossref] [PubMed]
16. Wu D, Nie J, Hu W, et al. A phase II study of anlotinib in 45 patients with relapsed small cell lung cancer. Int J Cancer 2020;147:3453-60. [Crossref] [PubMed]
17. Chi Y, Fang Z, Hong X, et al. Safety and Efficacy of Anlotinib, a Multikinase Angiogenesis Inhibitor, in Patients with Refractory Metastatic Soft-Tissue Sarcoma. Clin Cancer Res 2018;24:5233-8. [Crossref] [PubMed]
18. Zhu J, Song C, Zheng Z, et al. Anlotinib in Chinese Patients With Recurrent Advanced Cervical Cancer: A Prospective Single-Arm, Open-Label Phase II Trial. Front Oncol 2021;11:720343. [Crossref] [PubMed]
19. Wei W, Ban X, Yang F, et al. Phase II trial of efficacy, safety and biomarker analysis of sintilimab plus anlotinib for patients with recurrent or advanced endometrial cancer. J Immunother Cancer 2022;10:e004338. [Crossref] [PubMed]
20. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47. [Crossref] [PubMed]
21. Adiga D, Eswaran S, Pandey D, et al. Molecular landscape of recurrent cervical cancer. Crit Rev Oncol Hematol 2021;157:103178. [Crossref] [PubMed]
22. Sun Z, Sun L, He M, et al. Low BCL7A expression predicts poor prognosis in ovarian cancer. J Ovarian Res 2019;12:41. [Crossref] [PubMed]
23. Kuhn TM, Dhanani S, Ahmad S. An Overview of Endometrial Cancer with Novel Therapeutic Strategies. Curr Oncol 2023;30:7904-19. [Crossref] [PubMed]
24. Capozzi VA, Scarpelli E, De Finis A, et al. Optimal Management for Stage IVB Endometrial Cancer: A Systematic Review. Cancers (Basel) 2023;15:5123. [Crossref] [PubMed]
25. Marret G, Borcoman E, Le Tourneau C. Pembrolizumab for the treatment of cervical cancer. Expert Opin Biol Ther 2019;19:871-7. [Crossref] [PubMed]
26. Cui Q, Mao Y, Hu Y, et al. Anlotinib in recurrent or metastatic endometrial cancer. Int J Gynecol Cancer 2022;ijgc-2022-003345. [Crossref] [PubMed]
27. Tewari KS, Sill MW, Penson RT, et al. Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). Lancet 2017;390:1654-63. [Crossref] [PubMed]
28. Abbott M, Ustoyev Y. Cancer and the Immune System: The History and Background of Immunotherapy. Semin Oncol Nurs 2019;35:150923. [Crossref] [PubMed]
29. Monk BJ, Coleman RL, Fujiwara K, et al. ATHENA (GOG-3020/ENGOT-ov45): a randomized, phase III trial to evaluate rucaparib as monotherapy (ATHENA-MONO) and rucaparib in combination with nivolumab (ATHENA-COMBO) as maintenance treatment following frontline platinum-based chemotherapy in ovarian cancer. Int J Gynecol Cancer 2021;31:1589-94. [Crossref] [PubMed]
30. Makker V, Colombo N, Casado Herráez A, et al. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. N Engl J Med 2022;386:437-48. [Crossref] [PubMed]
31. Di Donato V, Giannini A, Bogani G. Recent Advances in Endometrial Cancer Management. J Clin Med 2023;12:2241. [Crossref] [PubMed]
32. D'Oria O, Giannini A, Besharat AR, et al. Management of Endometrial Cancer: Molecular Identikit and Tailored Therapeutic Approach. Clin Exp Obstet Gynecol 2023;50:210. [Crossref]
33. Bogani G, Monk BJ, Powell MA, et al. Adding immunotherapy to first-line treatment of advanced and metastatic endometrial cancer. Ann Oncol 2024;35:414-28. [Crossref] [PubMed]
34. Liu S, Qin T, Liu Z, et al. anlotinib alters tumor immune microenvironment by downregulating PD-L1 expression on vascular endothelial cells. Cell Death Dis 2020;11:309. [Crossref] [PubMed]
35. Palakurthi S, Kuraguchi M, Zacharek SJ, et al. The Combined Effect of FGFR Inhibition and PD-1 Blockade Promotes Tumor-Intrinsic Induction of Antitumor Immunity. Cancer Immunol Res 2019;7:1457-71. [Crossref] [PubMed]
36. Xu Q, Chen C, Sun Y, et al. 865P A phase II study of sintilimab plus anlotinib for Chinese patients (pts) with persistent, recurrent, or metastatic cervical cancer (CC). Ann Oncol 2020;31:S640. [Crossref]
37. Yang H, Sun S, Mei Z, et al. A Retrospective Cohort Study Evaluates Clinical Value of Anlotinib in Persistent, Metastatic, or Recurrent Cervical Cancer After Failure of First-Line Therapy. Drug Des Devel Ther 2021;15:4665-74. [Crossref] [PubMed]
38. Makker V, Taylor MH, Aghajanian C, et al. Lenvatinib Plus Pembrolizumab in Patients With Advanced Endometrial Cancer. J Clin Oncol 2020;38:2981-92. [Crossref] [PubMed]
39. Si X, Zhang L, Wang H, et al. Management of anlotinib-related adverse events in patients with advanced non-small cell lung cancer: Experiences in ALTER-0303. Thorac Cancer 2019;10:551-6. [Crossref] [PubMed]
40. Song Y, Xiao J, Fang W, et al. The relationship between treatment-induced hypertension and efficacy of anlotinib in recurrent or metastatic esophageal squamous cell carcinoma. Cancer Biol Med 2021; Epub ahead of print. [Crossref] [PubMed]
41. Zhou M, Chen X, Zhang H, et al. China National Medical Products Administration approval summary: anlotinib for the treatment of advanced non-small cell lung cancer after two lines of chemotherapy. Cancer Commun (Lond) 2019;39:36. [Crossref] [PubMed]