A pilot study of neoadjuvant combination of anti-PD-1 camrelizumab and VEGFR2 inhibitor apatinib for locally advanced resectable oral squamous cell carcinoma

Wu-tong Ju; Rong-hui Xia; Dong-wang Zhu; Sheng-jin Dou; Guo-pei Zhu; Min-jun Dong; Li-zhen Wang; Qi Sun; Tong-chao Zhao; Zhi-hang Zhou; Si-yuan Liang; Ying-Ying Huang; Yong Tang; Si-cheng Wu; Jing Xia; Shi-qing Chen; Yue-zong Bai; Jiang Li; Qi Zhu; Lai-ping Zhong

doi:10.1038/s41467-022-33080-8

journal article Open Access Sep 14, 2022

A pilot study of neoadjuvant combination of anti-PD-1 camrelizumab and VEGFR2 inhibitor apatinib for locally advanced resectable oral squamous cell carcinoma

Wu-tong Ju

Rong-hui Xia Dong-wang Zhu Sheng-jin Dou Guo-pei Zhu

Min-jun Dong Li-zhen Wang Qi Sun

Tong-chao Zhao Zhi-hang Zhou Si-yuan Liang Ying-Ying Huang Yong Tang

Si-cheng Wu Jing Xia

Shi-qing Chen Yue-zong Bai Jiang Li

Qi Zhu

Lai-ping Zhong

Nature Communications Vol. 13 No. 1 · Springer Science and Business Media LLC

View at Publisher Save 10.1038/s41467-022-33080-8

Abstract

Abstract
Novel neoadjuvant therapy regimens are warranted for oral squamous cell carcinoma (OSCC). In this phase I trial (NCT04393506), 20 patients with locally advanced resectable OSCC receive three cycles of camrelizumab (200 mg, q2w) and apatinib (250 mg, once daily) before surgery. The primary endpoints are safety and major pathological response (MPR, defined as ≤10% residual viable tumour cells). Secondary endpoints include 2-year survival rate and local recurrence rate (not reported due to inadequate follow-up). Exploratory endpoints are the relationships between PD-L1 combined positive score (CPS, defined as the number of PD-L1-stained cells divided by the total number of viable tumour cells, multiplied by 100) and other immunological and genomic biomarkers and response. Neoadjuvant treatment is well-tolerated, and the MPR rate is 40% (8/20), meeting the primary endpoint. All five patients with CPS ˃10 achieve MPR. Post-hoc analysis show 18-month locoregional recurrence and survival rates of 10.5% (95% CI: 0%–24.3%) and 95% (95% CI: 85.4%–100.0%), respectively. Patients achieving MPR show more CD4+ T-cell infiltration than those without MPR (P = 0.02), and decreased CD31 and ɑ-SMA expression levels are observed after neoadjuvant therapy. In conclusion, neoadjuvant camrelizumab and apatinib is safe and yields a promising MPR rate for OSCC.

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References

54

[1]

Head and neck squamous cell carcinoma

Daniel E. Johnson, Barbara Burtness, C. René Leemans et al.

Nature Reviews Disease Primers 2020 10.1038/s41572-020-00224-3

[2]

Specenier, P. & Vermorken, J. B. Optimizing treatments for recurrent or metastatic head and neck squamous cell carcinoma. Expert Rev. Anticancer Ther. 18, 901–915 (2018). 10.1080/14737140.2018.1493925

[3]

Funt, S. A. & Chapman, P. B. The role of neoadjuvant trials in drug development for solid tumors. Clin. Cancer Res. 22, 2323–2328 (2016). 10.1158/1078-0432.ccr-15-1961

[4]

Zhong, L. P. et al. Randomized phase III trial of induction chemotherapy with docetaxel, cisplatin, and fluorouracil followed by surgery versus up-front surgery in locally advanced resectable oral squamous cell carcinoma. J. Clin. Oncol. 31, 744–751 (2013). 10.1200/jco.2012.43.8820

[5]

Bossi, P. et al. Preoperative chemotherapy in advanced resectable OCSCC: long-term results of a randomized phase III trial. Ann. Oncol. 25, 462–466 (2014). 10.1093/annonc/mdt555

[6]

Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial

Tanguy Y Seiwert, Barbara Burtness, Ranee Mehra et al.

The Lancet Oncology 2016 10.1016/s1470-2045(16)30066-3

[7]

Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck

Robert L. Ferris, George Blumenschein, Jerome Fayette et al.

New England Journal of Medicine 2016 10.1056/nejmoa1602252

[8]

Liu, J. et al. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov. 6, 1382–1399 (2016). 10.1158/2159-8290.cd-16-0577

[9]

Chalabi, M. et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat. Med. 26, 566–576 (2020). 10.1038/s41591-020-0805-8

[10]

Huang, A. C. et al. A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma. Nat. Med. 25, 454–461 (2019). 10.1038/s41591-019-0357-y

[11]

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma

Timothy F. Cloughesy, Aaron Y. Mochizuki, Joey R. Orpilla et al.

Nature Medicine 2019 10.1038/s41591-018-0337-7

[12]

Forde, P. M. et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N. Engl. J. Med. 378, 1976–1986 (2018). 10.1056/nejmoa1716078

[13]

Schoenfeld, J. D. et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in untreated oral cavity squamous cell carcinoma: a phase 2 open-label randomized clinical trial. JAMA Oncol. 6, 1563–1570 (2020). 10.1001/jamaoncol.2020.2955

[14]

Wise-Draper, T. et al. 809 phase 2 trial of neoadjuvant and adjuvant PD-1 checkpoint blockade in local-regionally advanced, resectable HNSCC indicates pathological response is associated with high disease-free survival. J. Immunother. Cancer 8, A484–A485 (2020).

[15]

Li, Q. et al. Low-dose anti-angiogenic therapy sensitizes breast cancer to PD-1 blockade. Clin. Cancer Res. 26, 1712–1724 (2020). 10.1158/1078-0432.ccr-19-2179

[16]

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

Dai Fukumura, Jonas Kloepper, Zohreh Amoozgar et al.

Nature Reviews Clinical Oncology 2018 10.1038/nrclinonc.2018.29

[17]

Zaremba, A. et al. The concepts of rechallenge and retreatment with immune checkpoint blockade in melanoma patients. Eur. J. Cancer 155, 268–280 (2021). 10.1016/j.ejca.2021.07.002

[18]

Saeed, A., Park, R. & Sun, W. The integration of immune checkpoint inhibitors with VEGF targeted agents in advanced gastric and gastroesophageal adenocarcinoma: a review on the rationale and results of early phase trials. J. Hematol. Oncol. 14, 13 (2021). 10.1186/s13045-021-01034-0

[19]

Zhang, B. et al. Phase II clinical trial using camrelizumab combined with apatinib and chemotherapy as the first-line treatment of advanced esophageal squamous cell carcinoma. Cancer Commun. 40, 711–720 (2020). 10.1002/cac2.12119

[20]

Lan, C. et al. Camrelizumab plus apatinib in patients with advanced cervical cancer (CLAP): a multicenter, open-label, single-arm, phase II trial. J. Clin. Oncol. 38, 4095–4106 (2020). 10.1200/jco.20.01920

[21]

Xu, J. et al. Camrelizumab in combination with apatinib in patients with advanced hepatocellular carcinoma (RESCUE): a nonrandomized, open-label, phase II trial. Clin. Cancer Res. 27, 1003–1011 (2021). 10.1158/1078-0432.ccr-20-2571

[22]

Xu, J. et al. Anti-PD-1 antibody SHR-1210 combined with apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric junction cancer: an open-label, dose escalation and expansion study. Clin. Cancer Res. 25, 515–523 (2019). 10.1158/1078-0432.ccr-18-2484

[23]

Efficacy and safety of camrelizumab combined with apatinib in advanced triple-negative breast cancer: an open-label phase II trial

Jingmin Liu, Qiang Liu, Qian Li et al.

Journal for ImmunoTherapy of Cancer 10.1136/jitc-2020-000696

[24]

Inhestern, J. et al. A two-arm multicenter phase II trial of one cycle chemoselection split-dose docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy before two cycles of split TPF followed by curative surgery combined with postoperative radiotherapy in patients with locally advanced oral and oropharyngeal squamous cell cancer (TISOC-1). Ann. Oncol. 28, 1917–1922 (2017). 10.1093/annonc/mdx202

[25]

Licitra, L. et al. Primary chemotherapy in resectable oral cavity squamous cell cancer: a randomized controlled trial. J. Clin. Oncol. 21, 327–333 (2003). 10.1200/jco.2003.06.146

[26]

Yen, C. J. et al. Sequential therapy of neoadjuvant biochemotherapy with cetuximab, paclitaxel, and cisplatin followed by cetuximab-based concurrent bioradiotherapy in high-risk locally advanced oral squamous cell carcinoma: final analysis of a phase 2 clinical trial. Head. Neck 41, 1703–1712 (2019). 10.1002/hed.25640

[27]

Uppaluri, R. et al. Biomarker and tumor responses of oral cavity squamous cell carcinoma to trametinib: a phase II neoadjuvant window-of-opportunity clinical trial. Clin. Cancer Res. 23, 2186–2194 (2017). 10.1158/1078-0432.ccr-16-1469

[28]

Duhen, R. et al. Neoadjuvant anti-OX40 (MEDI6469) therapy in patients with head and neck squamous cell carcinoma activates and expands antigen-specific tumor-infiltrating T cells. Nat. Commun. 12, 1047 (2021). 10.1038/s41467-021-21383-1

[29]

Uppaluri, R. et al. Neoadjuvant and adjuvant pembrolizumab in resectable locally advanced, human papillomavirus-unrelated head and neck cancer: a multicenter, phase II trial. Clin. Cancer Res. 26, 5140–5152 (2020). 10.1158/1078-0432.ccr-20-1695

[30]

Tewari, K. S. 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 390, 1654–1663 (2017). 10.1016/s0140-6736(17)31607-0

[31]

Zheng, Y. et al. Effect of apatinib plus neoadjuvant chemotherapy followed by resection on pathologic response in patients with locally advanced gastric adenocarcinoma: a single-arm, open-label, phase II trial. Eur. J. Cancer 130, 12–19 (2020). 10.1016/j.ejca.2020.02.013

[32]

Ferris, R. L. et al. Neoadjuvant nivolumab for patients with resectable HPV-positive and HPV-negative squamous cell carcinomas of the head and neck in the CheckMate 358 trial. J. Immunother. Cancer 9, e002568 (2021). 10.1136/jitc-2021-002568

[33]

Hecht, M. et al. Safety and efficacy of single cycle induction treatment with cisplatin/docetaxel/ durvalumab/tremelimumab in locally advanced HNSCC: first results of CheckRad-CD8. J. Immunother. Cancer 8, e001378 (2020). 10.1136/jitc-2020-001378

[34]

Leidner, R. et al. Neoadjuvant immunoradiotherapy results in high rate of complete pathological response and clinical to pathological downstaging in locally advanced head and neck squamous cell carcinoma. J. Immunother. Cancer 9, e002485 (2021). 10.1136/jitc-2021-002485

[35]

Borel, C., Jung, A. C. & Burgy, M. Immunotherapy breakthroughs in the treatment of recurrent or metastatic head and neck squamous cell carcinoma. Cancers 12, 2691 (2020). 10.3390/cancers12092691

[36]

Tetzlaff, M. T. et al. Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma. Ann. Oncol. 29, 1861–1868 (2018). 10.1093/annonc/mdy226

[37]

Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC)

T.R. Cottrell, E.D. Thompson, P.M. Forde et al.

Annals of Oncology 2018 10.1093/annonc/mdy218

[38]

Merlino, D. J. et al. Discordant responses between primary head and neck tumors and nodal metastases treated with neoadjuvant nivolumab: correlation of radiographic and pathologic treatment effect. Front. Oncol. 10, 566315 (2020). 10.3389/fonc.2020.566315

[39]

iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics

Lesley Seymour, Jan Bogaerts, Andrea Perrone et al.

The Lancet Oncology 2017 10.1016/s1470-2045(17)30074-8

[40]

Provencio, M. et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 21, 1413–1422 (2020). 10.1016/s1470-2045(20)30453-8

[41]

Comprehensive genomic characterization of head and neck squamous cell carcinomas

Nature 2015 10.1038/nature14129

[42]

Vos, J. L. et al. Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma. Nat. Commun. 12, 7348 (2021). 10.1038/s41467-021-26472-9

[43]

Parra, E. R. et al. Effect of neoadjuvant chemotherapy on the immune microenvironment in non-small cell lung carcinomas as determined by multiplex immunofluorescence and image analysis approaches. J. Immunother. Cancer 6, 48 (2018). 10.1186/s40425-018-0368-0

[44]

Kim, S. R. et al. The implications of clinical risk factors, CAR index, and compositional changes of immune cells on hyperprogressive disease in non-small cell lung cancer patients receiving immunotherapy. BMC Cancer 21, 19 (2021). 10.1186/s12885-020-07727-y

[45]

Ragusa, S. et al. Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice. J. Clin. Invest. 130, 1199–1216 (2020). 10.1172/jci129558

[46]

Mancuso, M. R. et al. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J. Clin. Invest. 116, 2610–2621 (2006). 10.1172/jci24612

[47]

Tian, L. et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 544, 250–254 (2017). 10.1038/nature21724

[48]

Song, Y. et al. Anti-angiogenic agents in combination with immune checkpoint inhibitors: a promising strategy for cancer treatment. Front. Immunol. 11, 1956 (2020). 10.3389/fimmu.2020.01956

[49]

Huang, Y. et al. Improving immune-vascular crosstalk for cancer immunotherapy. Nat. Rev. Immunol. 18, 195–203 (2018). 10.1038/nri.2017.145

[50]

Lee, W. S., Yang, H., Chon, H. J. & Kim, C. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Exp. Mol. Med. 52, 1475–1485 (2020). 10.1038/s12276-020-00500-y

Showing 50 of 54 references

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Details

Published: Sep 14, 2022
Vol/Issue: 13(1)
License: View

Authors

Department of Chemical Engineering and Materials Science, University of CaliforniaDavis, Davis, California 95616

Chinese PLA General Hospital

Funding

National Natural Science Foundation of China Award: 82103043

Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine

Cite This Article

Wu-tong Ju, Rong-hui Xia, Dong-wang Zhu, et al. (2022). A pilot study of neoadjuvant combination of anti-PD-1 camrelizumab and VEGFR2 inhibitor apatinib for locally advanced resectable oral squamous cell carcinoma. Nature Communications, 13(1). https://doi.org/10.1038/s41467-022-33080-8

A pilot study of neoadjuvant combination of anti-PD-1 camrelizumab and VEGFR2 inhibitor apatinib for locally advanced resectable oral squamous cell carcinoma

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