Background: Front-line therapy with immunotherapy combinations is standard of care for metastatic ccRCC, with ipilimumab/nivolumab (IO/IO) and several combinations of a VEGFR-targeted tyrosine kinase inhibitor with a PD-1 inhibitor (TKI/IO) showing superior efficacy to TKI monotherapy. PFS-2 evaluates the ability to be salvaged by 2^nd line therapy and is a surrogate for overall survival (OS). PFS-2 was compared in patients receiving 1^st line IO/IO vs TKI/IO for metastatic ccRCC. Methods: A retrospective analysis was performed on patients with ccRCC treated at Memorial Sloan Kettering Cancer Center between 1/1/2014 and 12/30/2020, in cohorts defined by 1^st line: IO/IO or TKI/IO. PFS-2 is defined as time from start of 1^st line to progression on next therapy, or death. Patients without a PFS-2 event were censored at a prespecified cutoff date. Objective response rate to 1^st (ORR_1st) and 2^nd (ORR_2nd) line are compared with the Fisher’s exact test. OS, PFS-2, and time on therapy are estimated with the Kaplan-Meier method and compared with the log-rank test. Results: One hundred seventy-three patients received 1^st line IO/IO (N = 90) or 1^st line TKI/IO (N = 83); respectively, 52 and 40 patients had a PFS-2 event. 1^st line TKI/IO regimens included: 34% axitinib/pembrolizumab, 29% lenvatinib/pembrolizumab, 25% axitinib/avelumab, 11% other. More IO/IO patients had brain metastases and intermediate/poor MSKCC risk category (respectively p = 0.007, p < 0.001). ORR_1st and median months on 1^st line were higher with TKI/IO vs IO/IO (65% vs 39%, p < 0.001; 16.1 vs 5.1, p < 0.001). ORR_2nd was higher with IO/IO vs TKI/IO (47% vs 13%, p < 0.001), and median months on 2^nd line was not significantly different (7.7 vs 7.1, p = 0.30). Median PFS-2 for TKI/IO was 44 months (95% CI: 27, 53) vs 23 months (95% CI: 16, 47) for IO/IO, p = 0.13. For TKI/IO and IO/IO groups, respective PFS-2 at 12 months was 86% (95% CI 77, 92) and 74% (95% CI 63, 82); PFS-2 at 36 months was 51% (95% CI 39, 63) and 42% (95% CI 30, 53). OS was not significantly different (p = 0.32; 3 year OS: IO/IO 60%, 95% CI 47, 71; TKI/IO 62%, 95% CI 49, 73). (Table) Conclusions: In patients receiving 1^st line IO/IO or TKI/IO, ORR_2nd was higher with IO/IO and median PFS-2 was numerically higher with TKI/IO, but no statistically significant difference in PFS-2 or OS was seen. These findings suggest that IO/IO and TKI/O are both acceptable 1^st line treatment strategies in ccRCC.