Guohui Song,1,2,* Qinglian Tang,1,2,* Jinchang Lu,1,2,* Huaiyuan Xu,1,2 Anqi Wang,1,2 Chuangzhong Deng,1,2 Hao Wu,1,2 Jinxin Hu,1,2 Xiaojun Zhu,1,2 Jin Wang1,2 

1Department of Musculoskeletal Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 2State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Jin Wang; Xiaojun Zhu, Department of Musculoskeletal Oncology, Sun Yat-Sen University Cancer Center 651 Dongfeng East Road, Yuexiu District, Guangzhou, 510060, People’s Republic of China, Tel +86-20-87340519, Email wangjinr@sysucc.org.cn; zhuxj@sysucc.org.cn

Purpose: To explore the efficacy and safety of lenvatinib, either as a monotherapy or in combination with programmed death-1 (PD-1) blockades, as re-challenging treatment in patients with metastatic osteosarcoma following treatment failure with previous tyrosine kinase inhibitors (TKIs).
Patients and Methods: We retrospectively reviewed the data of 26 patients with metastatic osteosarcoma who received rechallenge treatment with lenvatinib monotherapy or lenvatinib plus PD-1 blockades after failure of the initial TKI treatment from January 2020 to June 2024 in our center. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), and safety.
Results: Of the 26 patients, ORR and CBR were 11.5% and 61.5%, respectively. The median duration of follow-up was 15 months (range, 4.3– 25.6) with a median PFS of 7.2 months (95% CI: 1.9– 12.5). A total of 14 patients received lenvatinib as a monotherapy, and 12 received a combination therapy of lenvatinib and PD-1 blockade. No significant differences were observed in ORR (0 vs 25%) and CBR (57.1 vs 66.7%) between the two groups. Additionally, the combination cohort exhibited a significantly longer PFS compared to the monotherapy cohort (8.6 [95% CI: 5.0– 12.1] vs 4.0 months [95% CI: 1.0– 7.0], p = 0.022). 96.2% of patients experienced grade 1 or more adverse events (AEs). Grade 3 adverse events occurred in 6 (23.1%) patients. The safety profiles of the lenvatinib and PD-1 blockade combination group were found to be comparable to those of the lenvatinib monotherapy group.
Conclusion: Our data indicated that patients with metastatic osteosarcoma could potentially benefit from lenvatinib rechallenge after progress with initial TKI treatment. The combination of lenvatinib and PD-1 blockade therapy demonstrated promising survival outcomes in patients with metastatic osteosarcoma, accompanied by a manageable toxicity profile.

Keywords: metastatic osteosarcoma, tyrosine kinase inhibitor, lenvatinib, PD-1 blockades, rechallenge