Pan-cancer efficacy and safety of anlotinib plus PD-1 inhibitor in refractory solid tumor: A single-arm, open-label, phase II trial
Bao-Dong Qin
Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
Search for more papers by this authorXiao-Dong Jiao
Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
Search for more papers by this authorZhan Wang
Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
Search for more papers by this authorKe Liu
Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
Search for more papers by this authorYing Wu
Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
Search for more papers by this authorYan Ling
Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
Search for more papers by this authorShi-Qi Chen
Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
Search for more papers by this authorXue Zhong
Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
Search for more papers by this authorXiao-Peng Duan
Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
Search for more papers by this authorWen-Xing Qin
Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
Search for more papers by this authorCorresponding Author
Lei Xue
Department of Thoracic Surgery, Changzheng Hospital, Naval Medical University, Shanghai, China
Correspondence
Lei Xue, Department of Thoracic Surgery, Changzheng Hospital, Naval Medical University, 415 Fengyang Road, Shanghai, 200003, China.
Email: [email protected]
Zhen-Hong Guo, National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, 800 Xiangyin Road, Shanghai, 200433, China.
Email: [email protected]
Yuan-Sheng Zang, Department of Medical Oncology, Changzheng Hospital, Naval Medical University, 64 Hetian Road, Shanghai, 200072, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Zhen-Hong Guo
National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, China
Correspondence
Lei Xue, Department of Thoracic Surgery, Changzheng Hospital, Naval Medical University, 415 Fengyang Road, Shanghai, 200003, China.
Email: [email protected]
Zhen-Hong Guo, National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, 800 Xiangyin Road, Shanghai, 200433, China.
Email: [email protected]
Yuan-Sheng Zang, Department of Medical Oncology, Changzheng Hospital, Naval Medical University, 64 Hetian Road, Shanghai, 200072, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Yuan-Sheng Zang
Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
Correspondence
Lei Xue, Department of Thoracic Surgery, Changzheng Hospital, Naval Medical University, 415 Fengyang Road, Shanghai, 200003, China.
Email: [email protected]
Zhen-Hong Guo, National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, 800 Xiangyin Road, Shanghai, 200433, China.
Email: [email protected]
Yuan-Sheng Zang, Department of Medical Oncology, Changzheng Hospital, Naval Medical University, 64 Hetian Road, Shanghai, 200072, China.
Email: [email protected]
Search for more papers by this authorBao-Dong Qin
Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
Search for more papers by this authorXiao-Dong Jiao
Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
Search for more papers by this authorZhan Wang
Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
Search for more papers by this authorKe Liu
Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
Search for more papers by this authorYing Wu
Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
Search for more papers by this authorYan Ling
Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
Search for more papers by this authorShi-Qi Chen
Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
Search for more papers by this authorXue Zhong
Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
Search for more papers by this authorXiao-Peng Duan
Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
Search for more papers by this authorWen-Xing Qin
Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
Search for more papers by this authorCorresponding Author
Lei Xue
Department of Thoracic Surgery, Changzheng Hospital, Naval Medical University, Shanghai, China
Correspondence
Lei Xue, Department of Thoracic Surgery, Changzheng Hospital, Naval Medical University, 415 Fengyang Road, Shanghai, 200003, China.
Email: [email protected]
Zhen-Hong Guo, National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, 800 Xiangyin Road, Shanghai, 200433, China.
Email: [email protected]
Yuan-Sheng Zang, Department of Medical Oncology, Changzheng Hospital, Naval Medical University, 64 Hetian Road, Shanghai, 200072, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Zhen-Hong Guo
National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, China
Correspondence
Lei Xue, Department of Thoracic Surgery, Changzheng Hospital, Naval Medical University, 415 Fengyang Road, Shanghai, 200003, China.
Email: [email protected]
Zhen-Hong Guo, National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, 800 Xiangyin Road, Shanghai, 200433, China.
Email: [email protected]
Yuan-Sheng Zang, Department of Medical Oncology, Changzheng Hospital, Naval Medical University, 64 Hetian Road, Shanghai, 200072, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Yuan-Sheng Zang
Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
Correspondence
Lei Xue, Department of Thoracic Surgery, Changzheng Hospital, Naval Medical University, 415 Fengyang Road, Shanghai, 200003, China.
Email: [email protected]
Zhen-Hong Guo, National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, 800 Xiangyin Road, Shanghai, 200433, China.
Email: [email protected]
Yuan-Sheng Zang, Department of Medical Oncology, Changzheng Hospital, Naval Medical University, 64 Hetian Road, Shanghai, 200072, China.
Email: [email protected]
Search for more papers by this authorBao-Dong Qin and Xiao-Dong Jiao contributed equally to this work.
Abstract
The combination of immunotherapy and antiangiogenic agents for the treatment of refractory solid tumor has not been well investigated. Thus, our study aimed to evaluate the efficacy and safety of a new regimen of anlotinib plus PD-1 inhibitor to treat refractory solid tumor. APICAL-RST is an investigator-initiated, open-label, single-arm, phase II trial in patients with heavily treated, refractory, metastatic solid tumor. Eligible patients experienced disease progression during prior therapy without further effective regimen. All patients received anlotinib and PD-1 inhibitor. The primary endpoints were objective response and disease control rates. The secondary endpoints included the ratio of progression-free survival 2 (PFS2)/PFS1, overall survival (OS) and safety. Forty-one patients were recruited in our study; 9 patients achieved a confirmed partial response and 21 patients had stable disease. Objective response rate and disease control rate were 22.0% and 73.2% in the intention-to-treat cohort, and 24.3% and 81.1% in the efficacy-evaluable cohort, respectively. A total of 63.4% (95% confidence interval [CI]: 46.9%-77.4%) of the patients (26/41) presented PFS2/PFS1 >1.3. The median OS was 16.8 months (range: 8.23-24.4), and the 12- and 36-month OS rates were 62.8% and 28.9%, respectively. No significant association was observed between concomitant mutation and efficacy. Thirty-one (75.6%) patients experienced at least one treatment-related adverse event. The most common adverse events were hypothyroidism, hand-foot syndrome and malaise. This phase II trial showed that anlotinib plus PD-1 inhibitor exhibits favorable efficacy and tolerability in patients with refractory solid tumor.
Graphical Abstract
What's new?
The combination of immunotherapy and antiangiogenic agents for the treatment of refractory solid tumors remains to be further investigated. Here, the authors conducted the prospective, single-arm, nonrandomized, phase II APICAL-RST trial to investigate the efficacy and safety of the oral multikinase inhibitor anlotinib plus PD-1 inhibitor in refractory solid tumors. The regimen demonstrated substantial clinical activity and manageable toxicity among heavily pretreated, pan-cancer patients. The clinical benefits were consistent across different histological or molecular subgroups. The results from the APICAL-RST trial support anlotinib plus PD-1 inhibitor as an effective regimen in heavily-treated, refractory, metastatic solid tumors.
CONFLICT OF INTEREST STATEMENT
All authors declare no conflict of interests.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of our study are available from the corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| ijc34546-sup-0001-Supinfo.pdfPDF document, 257.7 KB | Data S1. Supporting Information. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. 2018; 15(5): 325-340.
- 2Tian L, Goldstein A, Wang H, et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature. 2017; 544(7649): 250-254.
- 3Chu T, Zhong R, Zhong H, et al. Phase 1b study of Sintilimab plus Anlotinib as first-line therapy in patients with advanced NSCLC. J Thorac Oncol. 2021; 16(4): 643-652.
- 4Kawazoe A, Fukuoka S, Nakamura Y, et al. Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial. Lancet Oncol. 2020; 21(8): 1057-1065.
- 5Taylor MH, Lee CH, Makker V, et al. Phase IB/II trial of Lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. J Clin Oncol. 2020; 38(11): 1154-1163.
- 6Xu Q, Wang J, Sun Y, et al. Efficacy and safety of Sintilimab plus Anlotinib for PD-L1-positive recurrent or metastatic cervical cancer: a multicenter, single-arm, prospective phase II trial. J Clin Oncol. 2022; 40: 1795-1805.
- 7Shen G, Zheng F, Ren D, et al. Anlotinib: a novel multi-targeting tyrosine kinase inhibitor in clinical development. J Hematol Oncol. 2018; 11(1): 120.
- 8Li D, Chi Y, Chen X, et al. Anlotinib in locally advanced or metastatic medullary thyroid carcinoma: a randomized, double-blind phase IIB trial. Clin Cancer Res. 2021; 27(13): 3567-3575.
- 9Cheng Y, Wang Q, Li K, et al. Anlotinib vs placebo as third- or further-line treatment for patients with small cell lung cancer: a randomised, double-blind, placebo-controlled phase 2 study. Br J Cancer. 2021; 125(3): 366-371.
- 10Han 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(11): 1569-1575.
- 11Wang P, Fang X, Yin T, Tian H, Yu J, Teng F. Efficacy and safety of anti-PD-1 plus Anlotinib in patients with advanced non-small-cell lung cancer after previous systemic treatment failure-a retrospective study. Front Oncol. 2021; 11:628124.
- 12Yuan M, Zhu Z, Mao W, et al. Anlotinib combined with anti-PD-1 antibodies therapy in patients with advanced refractory solid tumors: a single-center, observational, prospective study. Front Oncol. 2021; 11:683502.
- 13Eisenhauer 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(2): 228-247.
- 14von Hoff DD, Stephenson JJ Jr, Rosen P, et al. Pilot study using molecular profiling of patients' tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol. 2010; 28(33): 4877-4883.
- 15Massard C, Michiels S, Ferte C, et al. High-throughput genomics and clinical outcome in hard-to-treat advanced cancers: results of the MOSCATO 01 trial. Cancer Discov. 2017; 7(6): 586-595.
- 16Mao X, Zhang Z, Zheng X, et al. Capture-based targeted ultradeep sequencing in paired tissue and plasma samples demonstrates differential subclonal ctDNA-releasing capability in advanced lung cancer. J Thorac Oncol. 2017; 12(4): 663-672.
- 17Jiao XD, Zhang XC, Qin BD, et al. Tumor mutation burden in Chinese cancer patients and the underlying driving pathways of high tumor mutation burden across different cancer types. Ann Transl Med. 2020; 8(14): 860.
- 18Le Tourneau C, Delord JP, Goncalves A, et al. Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial. Lancet Oncol. 2015; 16(13): 1324-1334.
- 19Chae YK, Hong F, Vaklavas C, et al. Phase II study of AZD4547 in patients with tumors harboring aberrations in the FGFR pathway: results from the NCI-MATCH trial (EAY131) subprotocol W. J Clin Oncol. 2020; 38(21): 2407-2417.
- 20Jhaveri KL, Wang XV, Makker V, et al. Ado-trastuzumab emtansine (T-DM1) in patients with HER2-amplified tumors excluding breast and gastric/gastroesophageal junction (GEJ) adenocarcinomas: results from the NCI-MATCH trial (EAY131) subprotocol Q. Ann Oncol. 2019; 30(11): 1821-1830.
- 21Hendry SA, Farnsworth RH, Solomon B, Achen MG, Stacker SA, Fox SB. The role of the tumor vasculature in the host immune response: implications for therapeutic strategies targeting the tumor microenvironment. Front Immunol. 2016; 7: 621.
- 22Allen E, Jabouille A, Rivera LB, et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci Transl Med. 2017; 9(385):eaak9679.
- 23Martinez-Usatorre A, Kadioglu E, Boivin G, et al. Overcoming microenvironmental resistance to PD-1 blockade in genetically engineered lung cancer models. Sci Transl Med. 2021; 13(606):eabd161.
- 24Fukuoka S, Hara H, Takahashi N, et al. Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer: an open-label, dose-escalation, and dose-expansion phase Ib trial (REGONIVO, EPOC1603). J Clin Oncol. 2020; 38(18): 2053-2061.
- 25Sweeney CJ, Zhu J, Sandler AB, et al. Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: a phase II trial in patients with metastatic nonsmall cell lung carcinoma. Cancer. 2001; 92(10): 2639-2647.
10.1002/1097-0142(20011115)92:10<2639::AID-CNCR1617>3.0.CO;2-8 CAS PubMed Web of Science® Google Scholar
- 26Bridgewater J, Lopes A, Wasan H, et al. Prognostic factors for progression-free and overall survival in advanced biliary tract cancer. Ann Oncol. 2016; 27(1): 134-140.
- 27Rugo HS, Cristofanilli M, Loibl S, et al. Prognostic factors for overall survival in patients with hormone receptor-positive advanced breast cancer: analyses from PALOMA-3. Oncologist. 2021; 26(8): e1339-e1346.
- 28Reck M, Thatcher N, Smit EF, et al. Baseline quality of life and performance status as prognostic factors in patients with extensive-stage disease small cell lung cancer treated with pemetrexed plus carboplatin vs. etoposide plus carboplatin. Lung Cancer. 2012; 78(3): 276-281.
- 29Wang JR, Habbous S, Espin-Garcia O, et al. Comorbidity and performance status as independent prognostic factors in patients with head and neck squamous cell carcinoma. Head Neck. 2016; 38(5): 736-742.
- 30Spigel DR, McCleod M, Jotte RM, et al. Safety, efficacy, and patient-reported health-related quality of life and symptom burden with nivolumab in patients with advanced non-small cell lung cancer, including patients aged 70 years or older or with poor performance status (CheckMate 153). J Thorac Oncol. 2019; 14(9): 1628-1639.
- 31Ardizzoni A, Azevedo S, Rubio-Viqueira B, et al. Primary results from TAIL: a global single-arm safety study of atezolizumab monotherapy in a diverse population of patients with previously treated advanced non-small cell lung cancer. J Immunother Cancer. 2021; 9(3):e001865.
- 32Dall'Olio FG, Maggio I, Massucci M, Mollica V, Fragomeno B, Ardizzoni A. ECOG performance status >/=2 as a prognostic factor in patients with advanced non small cell lung cancer treated with immune checkpoint inhibitors-a systematic review and meta-analysis of real world data. Lung Cancer. 2020; 145: 95-104.
- 33Sehgal K, Gill RR, Widick P, et al. Association of performance status with survival in patients with advanced non-small cell lung cancer treated with pembrolizumab monotherapy. JAMA Netw Open. 2021; 4(2):e2037120.
- 34Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019; 393(10183): 1819-1830.
- 35Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016; 375(19): 1823-1833.
- 36Kim ST, Cristescu R, Bass AJ, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med. 2018; 24(9): 1449-1458.
- 37Arkenau HT, Barriuso J, Olmos D, et al. Prospective validation of a prognostic score to improve patient selection for oncology phase I trials. J Clin Oncol. 2009; 27(16): 2692-2696.
- 38Guo G, Yu M, Xiao W, Celis E, Cui Y. Local activation of p53 in the tumor microenvironment overcomes immune suppression and enhances antitumor immunity. Cancer Res. 2017; 77(9): 2292-2305.
- 39Shatz M, Menendez D, Resnick MA. The human TLR innate immune gene family is differentially influenced by DNA stress and p53 status in cancer cells. Cancer Res. 2012; 72(16): 3948-3957.
- 40Zitvogel L, Kroemer G. CANCER. A p53-regulated immune checkpoint relevant to cancer. Science. 2015; 349(6247): 476-477.
- 41Jiang Z, Liu Z, Li M, Chen C, Wang X. Immunogenomics analysis reveals that TP53 mutations inhibit tumor immunity in gastric cancer. Transl Oncol. 2018; 11(5): 1171-1187.
- 42Scalera S, Mazzotta M, Corleone G, et al. KEAP1 and TP53 frame genomic, evolutionary, and immunologic subtypes of lung adenocarcinoma with different sensitivity to immunotherapy. J Thorac Oncol. 2021; 16(12): 2065-2077.
- 43Wang JY, Xiu J, Baca Y, et al. Distinct genomic landscapes of gastroesophageal adenocarcinoma depending on PD-L1 expression identify mutations in RAS-MAPK pathway and TP53 as potential predictors of immunotherapy efficacy. Ann Oncol. 2021; 32(7): 906-916.
- 44Xiao W, Du N, Huang T, et al. TP53 mutation as potential negative predictor for response of anti-CTLA-4 therapy in metastatic melanoma. EBioMedicine. 2018; 32: 119-124.
- 45Dong ZY, Zhong WZ, Zhang XC, et al. Potential predictive value of TP53 and KRAS mutation status for response to PD-1 blockade immunotherapy in lung adenocarcinoma. Clin Cancer Res. 2017; 23(12): 3012-3024.
- 46Liu Z, Jiang Z, Gao Y, Wang L, Chen C, Wang X. TP53 mutations promote immunogenic activity in breast cancer. J Oncol. 2019; 2019:5952836.
- 47Chen X, Wang D, Liu J, et al. Genomic alterations in biliary tract cancer predict prognosis and immunotherapy outcomes. J Immunother Cancer. 2021; 9(11):e003214.
- 48Dufresne A, Pivot X, Tournigand C, et al. Impact of chemotherapy beyond the first line in patients with metastatic breast cancer. Breast Cancer Res Treat. 2008; 107(2): 275-279.
- 49von Hoff DD. There are no bad anticancer agents, only bad clinical trial designs: twenty-first Richard and Hinda Rosenthal Foundation Award Lecture. Clin Cancer Res. 1998; 4(5): 1079-1086.
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