Abstract
BACKGROUND: Lenvatinib is a tyrosine kinase inhibitor (TKI) that targets both vascular endothelial growth factor (VEGF) receptor and fibroblast growth factor receptor. It has demonstrated efficacy both in the upfront and refractory disease settings. However, there is a lack of data surrounding the efficacy of TKIs post-lenvatinib exposure. In this study, we investigate the activity of therapies post-lenvatinib in patients with aRCC. METHODS: We conducted a retrospective analysis utilizing the International Metastatic Database Consortium (IMDC). Patients having received treatment post-lenvatinib exposure were eligible and divided into two cohort: patients post-1(st) line lenvatinib (2(nd) line cohort) and patients post-2(nd) line lenvatinib (3(rd) line cohort). The primary objective was objective response rate (ORR) and time to treatment failure (TTF). ORR was summarized with 95% two-sided exact binomial confidence interval. TTF was defined as time from treatment initiation to drug cessation for any reason censored at the date of last follow-up. RESULTS: Overall, 84 patients received 1(st) line lenvatinib of whom 43 (51%) remain on therapy, 20 (24%) received 2(nd) line treatment, and 21 (25%) received no subsequent treatment. The median duration of prior lenvatinib was 9.7 months. All patients received 1(st) line pembrolizumab + lenvatinib (ORR 50%, median TTF 19.7 months). Reason for lenvatinib discontinuation was progression (50%), progression + toxicity (20%), toxicity (15%), or other (15%). For the 2(nd) line cohort, median age was 61 years, most patients were male (85%), had prior nephrectomy (75%), clear cell histology (85%), and were IMDC intermediate/poor risk (55%). 2(nd) line therapy regimens included TKI monotherapy (80%), TKI-IO (5%), and other (15%). The median follow up from 2(nd)-line treatment initiation was 4.9 months. The ORR to 2(nd) line treatment was 5% (95% CI 0.2-25) and median TTF was 5.8 months (95% CI 1.9-14.9). Of 2(nd) line lenvatinib-exposed patients (n=84), 24 (29%) remain on treatment, 34 (40%) received 3(rd) line treatment, and 26 (31%) did not receive additional therapy. The median duration of prior lenvatinib was 5.9 months. Most patients received 2(nd) line everolimus + lenvatinib (97%) (ORR 31%, median TTF 9.2 months). Reason for lenvatinib discontinuation was progression (59%), progression + toxicity (9%), toxicity (12%), or other (21%). For the 3(rd) line cohort, median age was 67 years, most patients were male (68%), had prior nephrectomy (88%), clear cell histology (68%), and were IMDC intermediate/poor risk (77%). 3(rd) line treatments included TKI alone (50%), IO-TKI (38%), and other (12%). The median follow up from 3(rd)-line treatment initiation was 14.9 months. The ORR to 3(rd) line treatment was 12% (95% CI 3.3-27) and median TTF was 2.8 months (95% CI 1.9-7.4). CONCLUSIONS: In this analysis, we demonstrate modest activity of TKI-based therapy post-lenvatinib exposure. Our study highlights the need for improved treatment options for patients progressing on lenvatinib-based therapies.