Journal Article
. 2021 Jun; 22(7):946-958.
doi: 10.1016/S1470-2045(21)00241-2.

Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study

Chung-Han Lee 1 Amishi Yogesh Shah 2 Drew Rasco 3 Arpit Rao 4 Matthew H Taylor 5 Christopher Di Simone 6 James J Hsieh 7 Alvaro Pinto 8 David R Shaffer 9 Regina Girones Sarrio 10 Allen Lee Cohn 11 Nicholas J Vogelzang 12 Mehmet Asim Bilen 13 Sara Gunnestad Ribe 14 Musaberk Goksel 15 Øyvind Krohn Tennøe 16 Donald Richards 17 Randy F Sweis 18 Jay Courtright 19 Daniel Heinrich 20 Sharad Jain 21 Jane Wu 22 Emmett V Schmidt 23 Rodolfo F Perini 23 Peter Kubiak 24 Chinyere E Okpara 25 Alan D Smith 25 Robert J Motzer 26 
  • PMID: 34143969
  •     20 References
  •     11 citations


Background: Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients.

Methods: We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0-1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with (NCT02501096) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants.

Findings: Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3-28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8-89·3) of 22 treatment-naive patients, seven (41·2%, 18·4-67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7-65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 [21%] of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia).

Interpretation: Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC.

Funding: Eisai and Merck Sharp & Dohme.

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Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes.
Robert Roskoski.
Pharmacol Res, 2015 Nov 04; 103. PMID: 26529477
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Preclinical trial of the multi-targeted lenvatinib in combination with cellular immunotherapy for treatment of renal cell carcinoma.
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Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model.
Takayuki Kimura, Yu Kato, +10 authors, Kenichi Nomoto.
Cancer Sci, 2018 Nov 18; 109(12). PMID: 30447042    Free PMC article.
Systemic Therapy for Metastatic Renal-Cell Carcinoma.
Toni K Choueiri, Robert J Motzer.
N Engl J Med, 2017 Jan 26; 376(4). PMID: 28121507
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Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial.
Robert J Motzer, Thomas E Hutson, +14 authors, James Larkin.
Lancet Oncol, 2015 Oct 21; 16(15). PMID: 26482279
Highly Cited.
Renal cell carcinoma.
James J Hsieh, Mark P Purdue, +6 authors, Vincenzo Ficarra.
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Tyrosine kinase inhibitors and immunotherapy combinations in renal cell carcinoma.
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David F McDermott, Jae-Lyun Lee, +16 authors, Michael B Atkins.
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Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma.
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N Engl J Med, 2018 Mar 22; 378(14). PMID: 29562145    Free PMC article.
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Robert J Motzer, Konstantin Penkov, +25 authors, Toni K Choueiri.
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iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics.
Lesley Seymour, Jan Bogaerts, +16 authors, RECIST working group.
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Evaluation of the Safety and Efficacy of Immunotherapy Rechallenge in Patients With Renal Cell Carcinoma.
Praful Ravi, Charlene Mantia, +14 authors, Toni K Choueiri.
JAMA Oncol, 2020 May 30; 6(10). PMID: 32469396    Free PMC article.
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Signal pathways of melanoma and targeted therapy.
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Single-cell transcriptomics reveals a low CD8+ T cell infiltrating state mediated by fibroblasts in recurrent renal cell carcinoma.
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First-line Immune Checkpoint Inhibitor Combinations in Metastatic Renal Cell Carcinoma: Where Are We Going, Where Have We Been?
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Immunotherapy in Genitourinary Malignancy: Evolution in Revolution or Revolution in Evolution.
Kevin Lu, Kun-Yuan Chiu, Chen-Li Cheng.
Cancer Treat Res, 2022 May 14; 183. PMID: 35551661