For several years, targeted therapies have been part of the standard of care for most human cancers, many targeting epidermal growth factor receptors (EGFR) and vascular endothelial growth factors (VEGF), the two main control key intracellular pathways, governing fundamental processes in cancer cells. However, these therapies are not curative; relapse inevitably occurs. Lenvatinib (Lenvima®, Eisai, Tokyo, Japan), a small-molecule tyrosine kinase inhibitor, targets vascular endothelial growth factor (VEGF) and its receptors 1–3 (VEGFR1–3), fibroblast growth factor receptors 1–4 (FGFR-1–4), RET, c-kit, and platelet-derived growth factor receptor α (PDGFRα).1 It has demonstrated clinical activity in a variety of solid tumors in phase I and II clinical trials, and is approved by the US Food and Drug Administration (FDA) for the treatment of patients with recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer and following VEGF therapy in combination with everolimus for patients with advanced renal cell carcinoma (RCC).
Immune checkpoint inhibitors have also been the focus of considerable research in many cancer types as they can induce durable responses in a proportion of patients. The combination of immune checkpoint inhibitors and targeted therapy is therefore an attractive option. In a strategic collaboration, Eisai have teamed up with Merck & Co. for the clinical development of lenvatinib, both as monotherapy and in combination with Merck’s anti-PD-1 therapy, pembrolizumab (Keytruda®, Merck & Co., Kenilworth, NJ, US). The combination therapy has already been granted Breakthrough Therapy designation from the FDA for the treatment of patients with advanced and/or metastatic RCC, based on data from the RCC cohort of the ongoing phase Ib/II Study 111/KEYNOTE-146 trial (NCT02501096) that is investigating the combination in selected solid tumors. At 24 weeks, the combination therapy yielded an objective response rate (ORR) of 83% in patients who had not previously received treatment, and 50% in previously treated patients.2
The 54th Annual Meeting of the American Society of Clinical Oncology (ASCO), which was held in Chicago from June 1–5, 2018, featured poster presentations of data on lenvatinib in combination with pembrolizumab in multiple tumor types, including liver, kidney, endometrial and head/neck cancers. Study 116/KEYNOTE-524 (NCT03006926) is a phase Ib open-label, single-arm, multicenter study evaluating the tolerability and safety of lenvatinib (12 mg/day for patients weighing ≥60 kg, 8 mg/day for patients weighing <60 kg) plus pembrolizumab (200 mg intravenously every 3 weeks) in patients with unresectable hepatocellular carcinoma. Data from 30 patients were presented. At data cutoff, the ORR was 42.3%. A second scan, performed at least 4 weeks following the initial response, demonstrated a confirmed ORR of 26.9%. Median duration of progression-free survival (PFS) was 9.7 months. None of the treated patients experienced progressive disease. There were no incidences of dose-limiting toxicities, although four patients discontinued due to treatment emergent adverse events (TEAEs). The most common TEAEs (any grade) were decreased appetite (53.3%) and hypertension (53.3%), diarrhoea (43.3%) and fatigue (40.0%) On the basis of these data, the protocol has been amended to enroll approximately 94 patients to the Part 2 expansion cohort.3
Data were also presented from individual cohorts of the phase Ib/II study 111/KEYNOTE-526 (NCT02501096) “basket trial” evaluating the combination of lenvatinib (20 mg/day) with pembrolizumab (200 mg intravenously every 3 weeks) in patients with selected solid tumors. In the cohort with squamous cell carcinoma of the head and neck (n=22), the ORR at week 24 was 36.4%, overall ORR was 40.9% (including one complete response), and medial PFS was 8.2 months. This compares favorably with the ORRs for pembrolizumab of 18%, 15%, and 16%, in the KEYNOTE-012,4 KEYNOTE-040,5 and KEYNOTE-0556 studies, respectively. Grade 3 or 4 TEAEs occurred in 91% of patients (grade 4 AEs in 14%), and four patients (18%) discontinued study treatment due to TEAEs.7 According to lead author Matthew H Taylor, MD, of the Knight Cancer Institute, Oregon Health and Science University, Portland, “In a previous clinical trial, lenvatinib by itself had a response rate of less than 10%, so we think that it’s the combination that’s making the difference.”
In 30 patients with metastatic clear cell RCC, at data cutoff, ORR at week 24 was 63.3% by investigator review using Immune-related Response Evaluation Criteria In Solid Tumors (irRECIST), and by independent radiographic review using RECIST 1.1, ORR was 66.7%. The median PFS was 17.7 months. Grade 3 or 4 TEAEs occurred in 21 patients (70%); and, four patients (13%) discontinued treatment due to a TEAE.8 In 53 patients with metastatic endometrial cancer, ORR at week 24 was 50.0%, overall ORR was 36.7% and median PFS was 10.1 months. Grade 3 TEAEs were reported in in 32 patients (59%); there were no Grade 4 TEAEs, and 3 patients (6%) discontinued treatment due to a TEAE.9 The most common TEAEs (any grade) across all cohorts were fatigue (50–73%), hypertension (41–59%), hypothyroidism (35–70%), diarrhea (36–83-%), stomatitis (32–60%), and nausea (36–60%).
In another study investigating 41 candidate serum biomarkers in patients with advanced endometrial cancer, treatment with the combination was associated with changes in several substances, including interferon (IFN)-gamma and IFN-gamma-regulated chemokines (CXCL9, CXCL10, CXCL11; all p=0.05). In vivo preclinical experiments suggest that lenvatinib monotherapy may modulate tumor microenvironment by decreasing the local population of tumor-associated macrophages, while the combination of lenvatinib and pembrolizumab may have a different mechanism of action that includes the IFN signaling pathway.10
As a result of these promising findings, further studies are planned. A phase III trial comparing the efficacy and safety of lenvatinib in combination with everolimus or pembrolizumab versus sunitinib monotherapy for the first-line treatment of advanced RCC (CLEAR; NCT02811861) is currently recruiting. Alton Kremer, MD, PhD, Chief Clinical Officer and Chief Medical Officer, Oncology Business Group at Eisai, commented that these data have: “fueled our commitment to help meet the diverse healthcare needs of patients living with cancer, through clinical studies and research in specific tumor types that are notoriously difficult to treat and continue to have a significant need for new therapeutic options.”
Jeff Evans, of the University of Glasgow, UK, talks to us about the advances in the clinical development of lenvatinib and its potential use in combination with pembrolizumab for the treatment of hepatocellular carcinoma. Watch the interview here.
1. Cabanillas ME, Habra MA. Lenvatinib: Role in thyroid cancer and other solid tumors. Cancer Treat Rev. 2016;42:47–55.
2. Lee C, Makker V, Rasco D, et al. A phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with renal cell carcinoma. Presented at: European Society of Medical Oncology (ESMO) 2017 Congress, September 8–12, 2017, Madrid, Spain. Abstract 847O.
3. Ikeda M, Sung MW, Kudo M, et al. A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol. 2018;36:15(suppl):4076.
4. Seiwert TY, Burtness B, Mehra R, et al. 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. Lancet Oncol. 2016;17:956–65.
5. Cohen EE, Harrington KJ, Le Tourneau C, et al. Pembrolizumab (pembro) vs standard of care (SOC) for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC): Phase 3 KEYNOTE-040 trial. Ann Oncol. 2017;28:Issue suppl_5.
6. Bauml J, Seiwert TY, Pfister DG, et al. Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: results from a single-arm, phase II study. J Clin Oncol. 2017;35:1542–9.
7. Taylor MH, Rasco DW, Brose MS, et al. A phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with squamous cell carcinoma of the head and neck. J Clin Oncol. 2018;36:15(suppl):6016.
8. Lee C-H, Makker V, Rasco D, et al. Lenvatinib + pembrolizumab in patients with renal cell carcinoma: updated results. J Clin Oncol. 2018;36:15(suppl):4560.
9. Makker V, Rasco DW, Vogelzang NJ, et al. Lenvatinib + pembrolizumab in patients with advanced endometrial cancer: Updated results. J Clin Oncol. 2018;36:15(suppl):5596.
10. Makker V, Cohn AL, Taylor MH, et al. Biomarker results and preclinical rationale for combination lenvatinib and pembrolizumab in advanced endometrial carcinoma. J Clin Oncol. 2018;36: Abstr 5597.