Efficacy of targeted therapies (TT) after HIF-2⍺ inhibitor-based treatment in advanced renal cell carcinoma (aRCC).

508 Background: Hypoxia-inducible factor 2⍺ (HIF) inhibitors are active in renal cell carcinoma refractory to prior treatment with tyrosine kinase inhibitors (TKI) and immunotherapy, including anti-PD-1 monotherapy or combinations with anti-CTLA-4, and represent a new therapeutic option. However, the efficacy of TT after HIF-2⍺ inhibitors has not been assessed. Methods: A retrospective review of medical records from aRCC patients (pts) treated with HIF-2a inhibitors at five academic institutions was conducted. Pts who received subsequent treatment with TT were identified to collect outcomes in terms of best radiological response by RECIST 1.1 criteria (BRR), time to treatment failure (TTF), defined as treatment failure can be defined as one or a combination of events, including disease progression, discontinuation of treatment due to toxicity, or death from any cause; and overall survival (OS). This work was approved by an ethics board and all patients provided approval. Results: Data of 35 pts were available: 30 (85%) were male and 18 (51%) were metastatic at diagnosis. IMDC risk group was favorable, intermediate and poor in 11 (31%), 20 (57%) and 4 (11%) pts, respectively. Belzutifan was administered as monotherapy in 27 (77%) and in combination in 8 (22%) pts. Regarding first subsequent TT, 30 (85%) received TKI and 5 (14%) received mammalian target of rapamycin (mTOR). TT post HIF-2a was administered as second-line, third-line, fourth-line and beyond fourth-line in 3 (8%), 4 (9%), 18 (51%) and 10 (28%) pts, respectively. Treatment was interrupted due to progression in 28 (80%), 1 (3%) discontinued due to toxicity and 7 (20%) remained on treatment after data cut-off. Median follow-up was was 19 months.Median TTF on subsequent TT was 5.74 months (95% CI: 2.82–8.00). Median OS was 10,49 months (95% CI: 6,13-NR) with 17% pts alive at 1 year from the initiation of subsequent TT. Investigator-assessed BRR to subsequent TT was available for 33 out of 35 pts. Partial response and stable disease were observed in 7 (20%) and 12 (34%), respectively. Progressive disease was observed in 14 (40%) pts. Conclusions: Both VEGF/VEGFR and mTOR inhibitors have activity following HIF-2α blockade. However, 40% of patients will be refractory to treatment. This highlights the need for new drugs with distinct mechanisms of action.