Lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma (ITCC-050): a multicentre, open-label, multicohort, phase 1/2 study
Open accessAbstract
Background Tyrosine kinase inhibitors have shown activity in osteosarcoma and might enhance the efficacy of chemotherapy. We aimed to determine the recommended phase 2 dose and antitumour activity of lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma.Methods This multicentre, open-label, multicohort, phase 1/2 trial was done at 17 hospitals in six countries. Eligible patients were aged 2-25 years, had relapsed or refractory osteosarcoma, measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors version 1.1, Lansky play-performance score or Karnofsky performance score of 50% or higher, up to one previous VEGF or VEGF receptor-targeted therapy, and a life expectancy of at least 3 months. This study includes a combination dose-finding phase 1 part (cohort 3A) and a phase 2 combination expansion in patients with osteosarcoma (cohort 3B). Lenvatinib was administered orally at a starting dose of 11 mg/m 2 per day, capped at 24 mg per day, and etoposide (100 mg/m 2 per day) plus ifosfamide (3000 mg/m 2 per day) were administered intravenously on days 1-3 of each 21-day cycle for a maximum of five cycles. Lenvatinib monotherapy continued after these five cycles until disease progression, toxic effects, or patient choice to discontinue. The phase 1 primary endpoint was to determine the recommended phase 2 dose by evaluating dose-limiting toxicity and the phase 2 primary endpoint was progression-free survival at 4 months. Progression-free survival was measured in the full analysis set, which included all patients enrolled for efficacy outcomes; safety was assessed in all patients who received any study drug. This study is registered with ClinicalTrials.gov, NCT02432274.Findings 30 patients were screened for enrolment into cohort 3A between May 9, 2016, and June 3, 2019, and 22 patients for enrolment into cohort 3B between Sept 13, 2018, and July 18, 2019. Eight patients from cohort 3A and two from cohort 3B were ineligible for enrolment in the study. In phase 1, dose-limiting toxicities were observed in three patients (one in the lenvatinib 11 mg/m 2 combination group and two in the 14 mg/m 2 combination group) and the recommended phase 2 dose was determined as lenvatinib 14 mg/m 2 per day (with daily dose cap of 24 mg) and etoposide 100 mg/m 2 per day plus ifosfamide 3000 mg/m 2 per day administered intravenously on days 1-3 of each 21-day cycle for a maximum of five cycles. 35 patients from phase 1 (cohort 3A; n=15) and phase 2 (cohort 3B; n=20) were treated at the recommended phase 2 dose and their results were pooled. Progression-free survival at 4 months was 51% (95% CI 34-69) in 18 of 35 patients per the binomial estimate. The most common grade 3-4 treatment-emergent adverse events were neutropenia (27 [77%] of 35), thrombocytopenia (25 [71%]), anaemia (19 [54%]), and decreased white blood cell count (19 [54%]). 26 [74%] of 35 patients had serious treatment-emergent adverse events and no treatment-related deaths occurred.Interpretation Lenvatinib with etoposide plus ifosfamide shows promising antitumour activity with no new safety signals in patients with refractory and relapsed osteosarcoma. These findings warrant further investigation in an ongoing randomised phase 2 study (NCT04154189).Funding Eisai and Merck Sharp & Dohme.
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The rationale for combining tyrosine kinase inhibitors with ifosfamide/etoposide was initially proposed by Gaspar et al. with the idea that inhibition of angiogenesis may increase uptake of ifosfamide/etoposide into tumor tissue through vascular normalization.
“The rationale for combining TKIs with IE, including lenvatinib plus IE, was initially proposed by Gaspar et al.11–13 with the idea of inhibition of angiogenesis may increase uptake of IE into tumor tissue through vascular normalization.”
Almost all progressions in the ITCC-050 study occurred after the cessation of IE chemotherapy.
“almost all progressions in the ITCC-050 study occurred after the cessation of IE chemotherapy12”
The progression-free survival estimate for lenvatinib plus ifosfamide and etoposide was based on the single-arm Study 207, which examined a more heavily pretreated population.
“First, the PFS estimate for LEN-IE was based on the single-arm Study 207,26,28 which examined a more heavily pretreated population (26% of patients in the pooled lenvatinib 14 mg/m2 combination group had ≥3 prior lines of therapy vs 0% in OLIE).”
From Lenvatinib Plus Ifosfamide and Etoposide in Children and Young Adults With Relapsed Osteosarcoma (2024) · cites this paper as [26]
The progression-free survival estimate for lenvatinib plus ifosfamide and etoposide was based on the single-arm Study 207, which examined a more heavily pretreated population.
“First, the PFS estimate for LEN-IE was based on the single-arm Study 207,26,28 which examined a more heavily pretreated population (26% of patients in the pooled lenvatinib 14 mg/m2 combination group had ≥3 prior lines of therapy vs 0% in OLIE).”
From Lenvatinib Plus Ifosfamide and Etoposide in Children and Young Adults With Relapsed Osteosarcoma (2024) · cites this paper as [28]
The overall safety profile of lenvatinib plus ifosfamide and etoposide in OLIE was consistent with the known safety profiles of the individual agents and the safety profile previously observed for lenvatinib plus ifosfamide and etoposide in relapsed or refractory osteosarcoma in pediatric and young adult patients, with no new safety signals detected.
“The overall safety profile of LEN-IE in OLIE was consistent with known safety profiles of the individual agents and the safety profile previously observed for LEN-IE in relapsed or refractory osteosarcoma in pediatric and young adult patients (Study 207), with no new safety signals detected.”
From Lenvatinib Plus Ifosfamide and Etoposide in Children and Young Adults With Relapsed Osteosarcoma (2024) · cites this paper as [28]
In Study 207, lenvatinib monotherapy demonstrated activity in the relapsed or refractory osteosarcoma cohort, with 37.8% alive and progression free at 4 months, median progression-free survival of 3.0 months, and objective response rate of 6.7%.
“In Study 207, results of lenvatinib monotherapy demonstrated activity in the relapsed or refractory osteosarcoma cohort (patients alive and progression free at 4 months by Kaplan-Meier estimate, 37.8% [95% CI, 20.0%-55.4%]; median progression-free survival [PFS], 3.0 months [95% CI, 1.8-5.4 months]; objective response rate [ORR], 6.7% [95% CI, 0.8%-22.1%]).”
From Lenvatinib Plus Ifosfamide and Etoposide in Children and Young Adults With Relapsed Osteosarcoma (2024) · cites this paper as [26]
In the lenvatinib plus ifosfamide and etoposide cohort of Study 207, progression-free survival at 4 months was 51%, median progression-free survival was 8.7 months, and median overall survival was 16.3 months.
“In the LEN-IE cohort of Study 207, PFS at 4 months (primary end point, per binomial proportion) was 51% (95% CI, 34%-69%), median PFS was 8.7 months (95% CI, 4.5-12.0 months), and median overall survival (OS) was 16.3 months (95% CI, 12.6 months to not estimable [NE]).”
From Lenvatinib Plus Ifosfamide and Etoposide in Children and Young Adults With Relapsed Osteosarcoma (2024) · cites this paper as [28]
The phase I trial of ifosfamide and etoposide plus lenvatinib demonstrated tolerability and a 4-month PFS of 51%.
“The phase I trial of this combination demonstrated tolerability and a 4-month PFS of 51% 150 .”
From Osteosarcoma (2022) · cites this paper as [150]
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References 24 · Cited by 89
- Authors
- Gaspar, N., Venkatramani, R., Hecker-Nolting, S., Melcon, S. G., Locatelli, F., Bautista, F., Longhi, A., Lervat, C., Entz-Werle, N., Casanova, M., Aerts, I., Strauss, S. J., Thebaud, E., Morland, B., Nieto, A. C., Marec-Berard, P., Gambart, M., Rossig, C., Okpara, C. E., He, C., Dutta, L., & Campbell-Hewson, Q.
- Affiliations
- Institut Gustave Roussy (FR)
- Baylor College of Medicine (US)
- Bambino Gesù Children's Hospital (IT)
- Hospital Infantil Universitario Niño Jesús (ES)
- Istituto Ortopedico Rizzoli (IT)
- Centre Oscar Lambret (FR)
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
- Université Paris Sciences et Lettres (FR)
- University College Hospital (GB)
- Birmingham Children's Hospital (GB)
- Centre Hospitalier Universitaire de Toulouse (FR)
- Eisai (United Kingdom) (GB)
- Eisai (United States) (US)
- Corresponding author
- Gaspar, Nathalie
- ORCID
- Venue
- The Lancet Oncology
- Publisher
- Elsevier BV
- Published
- 2021-09
- Volume
- 22
- Issue
- 9
- Pages
- 1312-1321
- ISSN
- 1470-2045 (ISSN-L)
- OpenAlex
- W3195419801
- Cited by
- 89
- References
- 24
- Citations by year
- 2026: 3 · 2025: 14 · 2024: 23 · 2023: 25 · 2022: 22 · 2021: 2
- FWCI
- 11.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 180 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- The Lancet Oncology (acceptedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- National Institute for Health and Care Research
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Health Sciences › Medicine › Rheumatology › Bone Tumor Diagnosis and Treatments
- Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
- Keywords
- lenvatinib, etoposide, ifosfamide, osteosarcoma, tyrosine kinase inhibitors, VEGF receptor inhibition, combination chemotherapy, recommended phase 2 dose, dose-limiting toxicity, progression-free survival, antitumour activity
- MeSH terms
- Progression-Free Survival, Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols, Bone Neoplasms, Child, Child, Preschool, Etoposide, Female, Humans, Ifosfamide, Male, Neoplasm Recurrence, Local, Phenylurea Compounds, Quinolines, Osteosarcoma, Cohort Studies, Drug Resistance, Neoplasm, Protein Kinase Inhibitors, Young Adult, Drug-Related Side Effects and Adverse Reactions, Response Evaluation Criteria in Solid Tumors
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