Safety and Efficacy of Lucitanib Plus Toripalimab in Advanced Solid Tumors Refractory to Standard Therapies: An Open-Label, Multicenter, Phase II Study

Abstract

Lucitanib is a novel multi-target inhibitor of vascular endothelial growth factor receptor 1–3, fibroblast growth factor receptor 1–3, and platelet-derived growth factor receptor α/β. This open-label, multicenter, single-arm Phase II study evaluated lucitanib plus the anti-programmed cell death 1 (PD-1) antibody toripalimab in patients with advanced solid tumors refractory to standard therapies. Patients received lucitanib (10 mg) once daily plus toripalimab (240 mg) every 3 weeks until progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate (ORR) and secondary endpoints included disease control rate, duration of response, progression-free survival (PFS), overall survival, and safety. Among 131 patients across four cohorts (PD-1–treated recurrent/metastatic nasopharyngeal carcinoma [NPC], PD-1–naïve NPC, recurrent/metastatic endometrial cancer [EC], and other tumors), ORR was 34.1%, 45.8%, 38.5%, and 13.5%, respectively. Median PFS was 4.2 months (95% confidence interval [CI], 4.1–5.6), 6.5 months (95% CI, 4.0–not estimable [NE]), 5.6 months (95% CI, 2.78–11.21), and 9.7 months (95% CI, 5.4–NE). The most common Grade ≥ 3 treatment-related adverse events were hypertension (37.4%), proteinuria (10.7%), and thrombocytopenia (10.7%). Lucitanib plus toripalimab showed encouraging antitumor activity with manageable safety in heavily pretreated advanced solid tumors, supporting further randomized evaluation, particularly in NPC and EC.

Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2400087935

Keywords

efficacy / lucitanib / nasopharyngeal carcinoma / Phase II study / solid tumor / toripalimab

References

[1] R. Feng, Q. Su, X. Huang, T. Basnet, X. Xu, and W. Ye, “Cancer Situation in China: What Does the China Cancer Map Indicate From the First National Death Survey to the Latest Cancer Registration?,” Cancer Communications 43, no. 1 (2022): 75–86.

[2] C. Robert, “A Decade of Immune-Checkpoint Inhibitors in Cancer Therapy,” Nature Communications 11, no. 1 (2020): 3801.

[3] S. Bagchi, R. Yuan, and E. G. Engleman, “Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance,” Annual Review of Pathology 16 (2021): 223–249.

[4] Y. Yang, T. Zhou, X. Chen, et al., “Efficacy, Safety, and Biomarker Analysis of Camrelizumab in Previously Treated Recurrent or Metastatic Nasopharyngeal Carcinoma (CAPTAIN Study),” Journal for ImmunoTherapy of Cancer 9, no. 12 (2021): e003790.

[5] F. H. Wang, X. L. Wei, J. Feng, et al., “Efficacy, Safety, and Correlative Biomarkers of Toripalimab in Previously Treated Recurrent or Metastatic Nasopharyngeal Carcinoma: A Phase II Clinical Trial (POLARIS-02),” Journal of Clinical Oncology 39, no. 7 (2021): 704–712.

[6] W. Fang, Y. Yang, Y. Ma, et al., “Camrelizumab (SHR-1210) Alone or in Combination With Gemcitabine Plus Cisplatin for Nasopharyngeal Carcinoma: Results From Two Single-Arm, Phase 1 Trials,” Lancet Oncology 19, no. 10 (2018): 1338–1350.

[7] A. K. Green, J. Feinberg, and V. Makker, “A Review of Immune Checkpoint Blockade Therapy in Endometrial Cancer,” American Society of Clinical Oncology Educational Book 40 (2020): 1–7.

[8] A. Marabelle, D. T. Le, P. A. Ascierto, et al., “Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study,” Journal of Clinical Oncology 38, no. 1 (2020): 1–10.

[9] D. Fukumura, J. Kloepper, Z. Amoozgar, D. G. Duda, and R. K. Jain, “Enhancing Cancer Immunotherapy Using Antiangiogenics: Opportunities and Challenges,” Nature Reviews Clinical Oncology 15, no. 5 (2018): 325–340.

[10] Z. R. Huinen, E. J. M. Huijbers, J. R. van Beijnum, P. Nowak-Sliwinska, and A. W. Griffioen, “Anti-Angiogenic Agents—Overcoming Tumour Endothelial Cell Anergy and Improving Immunotherapy Outcomes,” Nature Reviews Clinical Oncology 18, no. 8 (2021): 527–540.

[11] T. A. Yap, E. E. Parkes, W. Peng, J. T. Moyers, M. A. Curran, and H. A. Tawbi, “Development of Immunotherapy Combination Strategies in Cancer,” Cancer Discovery 11, no. 6 (2021): 1368–1397.

[12] J. Liu, Q. Liu, Y. Li, et al., “Efficacy and Safety of Camrelizumab Combined With Apatinib in Advanced Triple-Negative Breast Cancer: An Open-Label Phase II Trial,” Journal for ImmunoTherapy of Cancer 8, no. 1 (2020): e000696.

[13] J. Lee, J. Koh, H. K. Kim, et al., “Bevacizumab Plus Atezolizumab After Progression on Atezolizumab Monotherapy in Pretreated Patients With NSCLC: An Open-Label, Two-Stage, Phase 2 Trial,” Journal of Thoracic Oncology 17, no. 7 (2022): 900–908.

[14] R. S. Finn, S. Qin, M. Ikeda, et al., “Atezolizumab Plus Bevacizumab in Unresectable Hepatocellular Carcinoma,” New England Journal of Medicine 382, no. 20 (2020): 1894–1905.

[15] B. I. Rini, E. R. Plimack, V. Stus, et al., “Pembrolizumab Plus Axitinib Versus Sunitinib for Advanced Renal-Cell Carcinoma,” New England Journal of Medicine 380, no. 12 (2019): 1116–1127.

[16] Y. Zhou, Y. Chen, L. Tong, et al., “AL3810, a Multi-Tyrosine Kinase Inhibitor, Exhibits Potent Anti-Angiogenic and Anti-Tumour Activity via Targeting VEGFR, FGFR and PDGFR,” Journal of Cellular and Molecular Medicine 16, no. 10 (2012): 2321–2330.

[17] R. Hui, A. Pearson, J. Cortes, et al., “Lucitanib for the Treatment of HR+/HER2- Metastatic Breast Cancer: Results From the Multicohort Phase II FINESSE Study,” Clinical Cancer Research 26, no. 2 (2020): 354–363.

[18] J. C. Soria, F. DeBraud, R. Bahleda, et al., “Phase I/IIa Study Evaluating the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Lucitanib in Advanced Solid Tumors,” Annals of Oncology 25, no. 11 (2014): 2244–2251.

[19] Y. Zhang, F. Luo, Y. X. Ma, et al., “A Phase Ib Study of Lucitanib (AL3810) in a Cohort of Patients With Recurrent and Metastatic Nasopharyngeal Carcinoma,” Oncologist 27, no. 6 (2022): e453–e462.

[20] X. L. Wei, C. Ren, F. H. Wang, et al., “A Phase I Study of Toripalimab, an Anti-PD-1 Antibody, in Patients With Refractory Malignant Solid Tumors,” Cancer Communications 40, no. 8 (2020): 345–354.

[21] B. B. Y. Ma, W. T. Lim, B. C. Goh, et al., “Antitumor Activity of Nivolumab in Recurrent and Metastatic Nasopharyngeal Carcinoma: An International, Multicenter Study of the Mayo Clinic Phase 2 Consortium (NCI-9742),” Journal of Clinical Oncology 36, no. 14 (2018): 1412–1418.

[22] C. Hsu, S. H. Lee, S. Ejadi, et al., “Safety and Antitumor Activity of Pembrolizumab in Patients With Programmed Death-Ligand 1-Positive Nasopharyngeal Carcinoma: Results of the KEYNOTE-028 Study,” Journal of Clinical Oncology 35, no. 36 (2017): 4050–4056.

[23] A. T. C. Chan, V. H. F. Lee, R. L. Hong, et al., “Pembrolizumab Monotherapy Versus Chemotherapy in Platinum-Pretreated, Recurrent or Metastatic Nasopharyngeal Cancer (KEYNOTE-122): An Open-Label, Randomized, Phase III Trial,” Annals of Oncology 34, no. 3 (2023): 251–261.

[24] E. P. Hui, B. B. Y. Ma, H. H. F. Loong, et al., “Efficacy, Safety, and Pharmacokinetics of Axitinib in Nasopharyngeal Carcinoma: A Preclinical and Phase II Correlative Study,” Clinical Cancer Research 24, no. 5 (2018): 1030–1037.

[25] L. Huang, X. Zhang, Y. Bai, et al., “Efficacy and Safety of Apatinib in Recurrent/Metastatic Nasopharyngeal Carcinoma: A Pilot Study,” Oral Oncology 115 (2021): 105222.

[26] X. Ruan, J. H. Liang, Y. Pan, et al., “Apatinib for the Treatment of Metastatic or Locoregionally Recurrent Nasopharyngeal Carcinoma After Failure of Chemotherapy: A Multicenter, Single-Arm, Prospective Phase 2 Study,” Cancer 127, no. 17 (2021): 3163–3171.

[27] L. Yuan, G. D. Jia, X. F. Lv, et al., “Camrelizumab Combined With Apatinib in Patients With First-Line Platinum-Resistant or PD-1 Inhibitor Resistant Recurrent/Metastatic Nasopharyngeal Carcinoma: A Single-Arm, Phase 2 Trial,” Nature Communications 14, no. 1 (2023): 4893.

[28] X. Ding, W. J. Zhang, R. You, et al., “Camrelizumab Plus Apatinib in Patients With Recurrent or Metastatic Nasopharyngeal Carcinoma: An Open-Label, Single-Arm, Phase II Study,” Journal of Clinical Oncology 41, no. 14 (2023): 2571–2582.

[29] N. Lu, Y. F. Jiang, W. X. Xia, et al., “Efficacy and Safety of Sintilimab Plus Bevacizumab in Metastatic Nasopharyngeal Carcinoma After Failure of Platinum-Based Chemotherapy: An Open-Label Phase 2 Study,” EClinicalMedicine 62 (2023): 102136.

[30] R. Bonneville, M. A. Krook, E. A. Kautto, et al., “Landscape of Microsatellite Instability Across 39 Cancer Types,” JCO Precision Oncology 2017 (2017): PO.17.00073.

[31] M. R. Mirza, D. M. Chase, B. M. Slomovitz, et al., “Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer,” New England Journal of Medicine 388, no. 23 (2023): 2145–2158.

[32] D. M. O'Malley, G. M. Bariani, and P. A. Cassier, “Pembrolizumab in Patients With Microsatellite Instability-High Advanced Endometrial Cancer: Results From the KEYNOTE-158 Study,” Journal of Clinical Oncology 40, no. 7 (2022): 752–761.

[33] A. Oaknin, L. Gilbert, A. V. Tinker, et al., “Safety and Antitumor Activity of Dostarlimab in Patients With Advanced or Recurrent DNA Mismatch Repair Deficient/Microsatellite Instability-High (dMMR/MSI-H) or Proficient/Stable (MMRp/MSS) Endometrial Cancer: Interim Results From GARNET—A Phase I, Single-Arm Study,” Journal for ImmunoTherapy of Cancer 10, no. 1 (2022): e003777.

[34] J. C. Dudley, M. T. Lin, D. T. Le, and J. R. Eshleman, “Microsatellite Instability as a Biomarker for PD-1 Blockade,” Clinical Cancer Research 22, no. 4 (2016): 813–820.

[35] C. Luchini, F. Bibeau, M. J. L. Ligtenberg, et al., “ESMO Recommendations on Microsatellite Instability Testing for Immunotherapy in Cancer, and Its Relationship With PD-1/PD-L1 Expression and Tumour Mutational Burden: A Systematic Review-Based Approach,” Annals of Oncology 30, no. 8 (2019): 1232–1243.

[36] S. Lheureux, D. E. Matei, P. A. Konstantinopoulos, et al., “Translational Randomized Phase II Trial of Cabozantinib in Combination With Nivolumab in Advanced, Recurrent, or Metastatic Endometrial Cancer,” Journal for ImmunoTherapy of Cancer 10, no. 3 (2022): e004233.

[37] V. Makker, N. Colombo, A. Casado Herráez, et al., “Lenvatinib Plus Pembrolizumab for Advanced Endometrial Cancer,” New England Journal of Medicine 386, no. 5 (2022): 437–448.

[38] S. Iwama, T. Kobayashi, Y. Yasuda, and H. Arima, “Immune Checkpoint Inhibitor-Related Thyroid Dysfunction,” Best Practice & Research Clinical Endocrinology & Metabolism 36, no. 3 (2022): 101660.

[39] J. Yu, Y. Zhang, L. H. Leung, L. Liu, F. Yang, and X. Yao, “Efficacy and Safety of Angiogenesis Inhibitors in Advanced Gastric Cancer: A Systematic Review and Meta-Analysis,” Journal of Hematology & Oncology 9, no. 1 (2016): 111.

[40] E. P. Hui, B. B. Y. Ma, A. D. King, et al., “Hemorrhagic Complications in a Phase II Study of Sunitinib in Patients of Nasopharyngeal Carcinoma Who Has Previously Received High-Dose Radiation,” Annals of Oncology 22, no. 6 (2011): 1280–1287.

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