Phase IB/II Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors

Overview

Journal J Clin Oncol

Specialty Oncology

Date 2020 Jan 22

PMID 31961766

Citations 212

Authors

Matthew H Taylor

Chung-Han Lee

Vicky Makker

Drew Rasco

Corina E Dutcus

Jane Wu

Daniel E Stepan

Robert C Shumaker

Robert J Motzer

Affiliations

Soon will be listed here.

Abstract

Purpose: Modulation of vascular endothelial growth factor-mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. We report results from the dose-finding and initial phase II expansion of a phase Ib/II study of lenvatinib plus pembrolizumab in patients with selected advanced solid tumors.

Methods: Eligible patients had metastatic renal cell carcinoma (RCC), endometrial cancer, squamous cell carcinoma of the head and neck (SCCHN), melanoma, non-small-cell lung cancer (NSCLC), or urothelial cancer. The primary objective of phase Ib was to determine the maximum tolerated dose (MTD) for lenvatinib plus pembrolizumab (200 mg intravenously every 3 weeks). In the preplanned phase II cohort expansion, the primary objective was objective response rate at week 24 (ORR) at the recommended phase II dose.

Results: Overall, 137 patients were enrolled during phase Ib (n = 13) and the initial phase II expansion (n = 124). Two dose-limiting toxicities (DLTs; grade 3 arthralgia and grade 3 fatigue) were reported in the initial dose level (lenvatinib 24 mg/d plus pembrolizumab). No DLTs were observed in the subsequent dose-de-escalation cohort, establishing the MTD and recommended phase II dose at lenvatinib 20 mg/d plus pembrolizumab. ORR was as follows: RCC, 63% (19/30; 95% CI, 43.9% to 80.1%); endometrial cancer, 52% (12/23; 95% CI, 30.6% to 73.2%); melanoma, 48% (10/21; 95% CI, 25.7% to 70.2%); SCCHN, 36% (8/22; 95% CI, 17.2% to 59.3%); NSCLC, 33% (7/21; 95% CI, 14.6% to 57.0%); and urothelial cancer 25% (5/20; 95% CI, 8.7% to 49.1%). The most common treatment-related adverse events were fatigue (58%), diarrhea (52%), hypertension (47%), and hypothyroidism (42%).

Conclusion: Lenvatinib plus pembrolizumab demonstrated a manageable safety profile and promising antitumor activity in patients with selected solid tumor types.

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References

Kato Y, Tabata K, Kimura T, Yachie-Kinoshita A, Ozawa Y, Yamada K . Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS One. 2019; 14(2):e0212513. PMC: 6392299. DOI: 10.1371/journal.pone.0212513. View

Motzer R, Hutson T, Glen H, Michaelson M, Molina A, Eisen T . Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015; 16(15):1473-1482. DOI: 10.1016/S1470-2045(15)00290-9. View

Herbst R, Baas P, Kim D, Felip E, Perez-Gracia J, Han J . Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2015; 387(10027):1540-1550. DOI: 10.1016/S0140-6736(15)01281-7. View

Medina P, Adams V . PD-1 Pathway Inhibitors: Immuno-Oncology Agents for Restoring Antitumor Immune Responses. Pharmacotherapy. 2016; 36(3):317-34. PMC: 5071694. DOI: 10.1002/phar.1714. View

Schachter J, Ribas A, Long G, Arance A, Grob J, Mortier L . Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017; 390(10105):1853-1862. DOI: 10.1016/S0140-6736(17)31601-X. View

Sato K, Tsuchiya N, Sasaki R, Shimoda N, Satoh S, Ogawa O . Increased serum levels of vascular endothelial growth factor in patients with renal cell carcinoma. Jpn J Cancer Res. 1999; 90(8):874-9. PMC: 5926146. DOI: 10.1111/j.1349-7006.1999.tb00829.x. View

Matsui J, Yamamoto Y, Funahashi Y, Tsuruoka A, Watanabe T, Wakabayashi T . E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer. 2007; 122(3):664-71. DOI: 10.1002/ijc.23131. View

Rini B, Powles T, Atkins M, Escudier B, Mcdermott D, Suarez C . Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019; 393(10189):2404-2415. DOI: 10.1016/S0140-6736(19)30723-8. View

Tohyama O, Matsui J, Kodama K, Hata-Sugi N, Kimura T, Okamoto K . Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J Thyroid Res. 2014; 2014:638747. PMC: 4177084. DOI: 10.1155/2014/638747. View

10.

Rini B, Plimack E, Stus V, Gafanov R, Hawkins R, Nosov D . Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019; 380(12):1116-1127. DOI: 10.1056/NEJMoa1816714. View

11.

Garon E, Rizvi N, Hui R, Leighl N, Balmanoukian A, Eder J . Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015; 372(21):2018-28. DOI: 10.1056/NEJMoa1501824. View

12.

Wolchok J, Hoos A, ODay S, Weber J, Hamid O, Lebbe C . Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009; 15(23):7412-20. DOI: 10.1158/1078-0432.CCR-09-1624. View

13.

Ott P, Bang Y, Berton-Rigaud D, Elez E, Pishvaian M, Rugo H . Safety and Antitumor Activity of Pembrolizumab in Advanced Programmed Death Ligand 1-Positive Endometrial Cancer: Results From the KEYNOTE-028 Study. J Clin Oncol. 2017; 35(22):2535-2541. DOI: 10.1200/JCO.2017.72.5952. View

14.

Bellmunt J, de Wit R, Vaughn D, Fradet Y, Lee J, Fong L . Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017; 376(11):1015-1026. PMC: 5635424. DOI: 10.1056/NEJMoa1613683. View

15.

Matsui J, Funahashi Y, Uenaka T, Watanabe T, Tsuruoka A, Asada M . Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res. 2008; 14(17):5459-65. DOI: 10.1158/1078-0432.CCR-07-5270. View

16.

Robert C, Schachter J, Long G, Arance A, Grob J, Mortier L . Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015; 372(26):2521-32. DOI: 10.1056/NEJMoa1503093. View

17.

Lieu C, Heymach J, Overman M, Tran H, Kopetz S . Beyond VEGF: inhibition of the fibroblast growth factor pathway and antiangiogenesis. Clin Cancer Res. 2011; 17(19):6130-9. PMC: 5562355. DOI: 10.1158/1078-0432.CCR-11-0659. View

18.

Ott P, Hodi F, Buchbinder E . Inhibition of Immune Checkpoints and Vascular Endothelial Growth Factor as Combination Therapy for Metastatic Melanoma: An Overview of Rationale, Preclinical Evidence, and Initial Clinical Data. Front Oncol. 2015; 5:202. PMC: 4585112. DOI: 10.3389/fonc.2015.00202. View

19.

Schlumberger M, Jarzab B, Cabanillas M, Robinson B, Pacini F, Ball D . A Phase II Trial of the Multitargeted Tyrosine Kinase Inhibitor Lenvatinib (E7080) in Advanced Medullary Thyroid Cancer. Clin Cancer Res. 2015; 22(1):44-53. DOI: 10.1158/1078-0432.CCR-15-1127. View

20.

Reck M, Rodriguez-Abreu D, Robinson A, Hui R, Csoszi T, Fulop A . Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016; 375(19):1823-1833. DOI: 10.1056/NEJMoa1606774. View