The selection of 2L TKI therapy was at the discretion of the treating physician. CI: 10.1, NA). Forty-five percent of subjects required a dose reduction, and twenty-seven percent of patients discontinued treatment due to toxicity. Conclusions: In this retrospective study of patients with mccRCC receiving 2L TKI monotherapy following 1L ICI, we observed 2L antitumor activity and tolerance comparable to historical data for 1L TKI. gene, which has led to the development of VEGF-receptor tyrosine kinase Fenoprofen calcium inhibitors (VEGFR-TKI) as anti-cancer therapies in ccRCC [3C6]. From 2006 to 2017, the standard of care in metastatic ccRCC (mccRCC) shifted in the front-line setting to VEGF targeted therapies [7C9]. In second and subsequent lines of therapy, VEGFR-TKIs, mTOR inhibitors, and immune checkpoint inhibitors (ICI) have been frequently utilized [10C12]. Nivolumab, a monoclonal antibody targeting programmed death-1 (PD-1) was the first ICI to be approved in advanced RCC, showing OS benefit over everolimus . More recently, in CheckMate 214, a pivotal randomized phase 3 trial, nivolumab and ipilimumab demonstrated statistically superior median OS and higher objective response rate (ORR), in patients with IMDC intermediate- and poor-risk disease compared with sunitinib [14, 15]. These results led to the FDA approval of combination nivolumab and ipilimumab in the front-line setting for treatment of mccRCC. The mccRCC treatment landscape is further Fenoprofen calcium rapidly changing with the exploration of combinations of ICI and anti-VEGF therapies. The results of the IMmotion-151 were recently reported and the combination of atezolizumab, an anti-PD-L1 antibody, with bevacizumab, an anti-VEGF therapy, was superior to sunitinib in terms of PFS (11.2 vs. 7.7 months, HR 0.74, p = 0.02) and ORR (43% vs. 35%) in PD-L1 positive patients, per investigator assessment Fenoprofen calcium , opening the possibility of another non-TKI containing ICI-based regimen in the frontline. The JAVELIN Renal 101 Phase 3 trial has now been reported as a TKI/ICI registration trial meeting (one of) its primary endpoints, demonstrating superior PFS for the combination of axitinib and avelumab over sunitinib in PD-L1 positive patients (13.8 vs. 7.2 months, HR 0.61) . In addition, the KEYNOTE-426 trial has demonstrated both PFS and OS advantage of axitinib plus pembrolizumab over sunitinib (mPFS 15.1 months vs. 11.1 months, HR 0.69), which may lead to further approvals in the first-line landscape . With front-line approval of the combination of nivolumab and ipilimumab and upcoming data on anti-VEGF/ICI combination therapy, understanding responses of subsequent therapies is needed. This retrospective study of patients with mccRCC reports on ORR, progression-free survival (PFS), safety of Fenoprofen calcium second line (2L) VEGFR-TKI, and OS after progressive disease with front-line (1L) ICI-based, non-TKI containing therapy. Patients and Methods: We conducted this retrospective, multicenter Opn5 study after IRB approval was obtained at the two participating centers. A combined de-identified secure database was constructed of 70 patients with mccRCC treated from December 2015 to February 2018 at MD Anderson Cancer Center and Memorial Sloan Kettering Cancer Center with a 2L VEGFR-TKI after progressive disease with 1L ICI. All patients had previously received 1L ICI in the setting of clinical trials (nivolumab vs. nivolumab-ipilimumab vs. nivolumab-bevacizumab in “type”:”clinical-trial”,”attrs”:”text”:”NCT02210117″,”term_id”:”NCT02210117″NCT02210117, nivolumab-ipilimumab in “type”:”clinical-trial”,”attrs”:”text”:”NCT02231749″,”term_id”:”NCT02231749″NCT02231749, atezolizumab-bevacizumab in “type”:”clinical-trial”,”attrs”:”text”:”NCT02420821″,”term_id”:”NCT02420821″NCT02420821, atezolizumab in “type”:”clinical-trial”,”attrs”:”text”:”NCT01984242″,”term_id”:”NCT01984242″NCT01984242, and nivolumab-ipilimumab in “type”:”clinical-trial”,”attrs”:”text”:”NCT01472081″,”term_id”:”NCT01472081″NCT01472081). Baseline demographic and clinical data were collected by individual chart review and included gender, age, IMDC risk score at time of 2L therapy start, nephrectomy status, presence of sarcomatoid dedifferentiation, metastatic sites, previously received ICI regimen, and choice of 2L TKI. Histologic diagnosis of ccRCC was made or confirmed in each case via review of tumor specimens by dedicated genitourinary pathologists at either of the two participating sites. During 2L TKI therapy, patients were managed per best practice established at the participating centers sites. Charts were reviewed for individual treatment courses with dedicated attention to treatment dose adjustments and reasons for treatment discontinuations. Radiographic response assessment was provided by two blinded radiologists, who assessed all cross-sectional scans obtained to evaluate extent of disease per RECIST v1.1 . Continuous variables were summarized using descriptive statistics, and categorical data were tabulated with frequency and percentage. The Kaplan-Meier method was applied to estimate time-to-event outcomes. OS and PFS times were calculated from the start of 2L.