Lancet. and OS of double-TT using TKI-mTORi (5.4 and 30 months, respectively) were significantly better compared with TKI-TKI (0.3 and 2 months) or mTORi-TKI (2 and 6 months) (p 0.001). For triple-TT, the tPFS and OS of TKI-mTORi-TKI (22.8 and 25 months, respectively) were significantly superior compared with those for TKI-TKI-mTORi (4 and 9 months) (p 0.05). For patients with intermediate-risk according to the Heng or Memorial Sloan-Kettering Cancer Center risk models, TKI-mTORi was associated with a significantly longer tPFS and OS compared with TKI-TKI [expect for OS in the Heng group (p = 0.086)]. For the triple TT group, TKI-mTORi-TKI JAK3-IN-2 resulted in improved tPFS and OS compared with TKI-TKI-TKI or TKI-TKI-mTORi (p 0.05). Conclusion In patients with mRCC, sequential administration of TKI-mTORi led to a significantly superior tPFS compared with any other TT sequence. By contrast, OS did not differ significantly according to TT sequence. strong class=”kwd-title” Keywords: renal cell carcinoma, metastasis, sequential, targeted therapy, survival INTRODUCTION The advent of multiple targeted therapies (TT) for the treatment of metastatic renal cell carcinoma (mRCC) has renewed hope for increasing the therapeutic response rate, slowing disease progression and improving survival outcomes. Complete responses to treatment are rare, and patients eventually progress, requiring subsequent lines of therapy for disease control [1-3]. Following first-line tumor progression, individualized sequential therapy has become the standard treatment [4-6]. As the number of TTs used for second-, third-, and fourth-line therapies increase, so too do the potential sequential combinations in which they can be administered. For patients with mRCC, the optimal sequence to obtain maximum clinical benefit and improve progression-free JAK3-IN-2 survival (PFS) and overall survival (OS) is unknown. Tyrosine kinase inhibitors (TKI) of the vascular epithelial growth factor (VEGF)-receptor and mammalian target of rapamycin inhibitors (mTORi) are the major drug classes used for mRCC treatment. For their anticancer activity, these classes utilize distinct pathways with minimal cross-resistance. Therefore, alternating TT sequentially can improve therapeutic efficacy. The most commonly employed TT sequences are TKI-TKI-mTORi and TKI-mTORi-TKI [2, 5-9], but there is limited evidence for the optimal sequential TT use for mRCC, especially in Asian individuals [5, 6, 9]. This study targeted to compare the survival results of individuals who underwent sequential treatment using double- or triple-TT, with or without immunotherapy (ITx). Results were reported as total PFS (tPFS) and OS, relating to drug treatment sequence and risk, as classified using the initial prognostic criteria of the Memorial Sloan-Kettering Malignancy Center (MSKCC)  and the International Metastatic Renal Cell Carcinoma Database Consortium (Heng criteria) risk models . RESULTS Baseline patient characteristics Between 2005 and 2015, the records for 292 individuals with mRCC were included. Eighty-one individuals were included in the final analysis. Baseline individual characteristics are demonstrated in Table ?Table1.1. The median age was 55 years, and individuals were mainly male. Second-, third-, and fourth-line TT were given to 81 (27.7%), 30 (10.3%), and 9 (3.1%) individuals, respectively. Nephrectomy and metastasectomy rates were 28.4% and 34.6%, respectively. The overall median treatment durations for double- and triple-TT were 30.2 (5.3C66.7) weeks and 37.8 (8.0C83.8) weeks, respectively. Table 1 Baseline patient characteristics (N=81) thead th align=”remaining” valign=”middle” rowspan=”1″ colspan=”1″ /th CBLC th align=”center” valign=”middle” rowspan=”1″ colspan=”1″ N(%) or Median (min-max) /th /thead Age (years)55 (30-76)gender (Male/ Woman)64/ 17 (79/ 21)Nephrectomy/metastasectomy22/ 28 (28.4/ 34.6)Heng beneficial risk15 (18.5)?Intermediate risk60 (74.1)?Poor risk6 (7.4)MSKCC beneficial risk18 (22.2)?Intermediate risk56 (69.1)?Poor risk7 (8.6)Pathologic/medical T, T2, T3, T423/12/35/11 (13.5/28.4/14.8/43.2)?N0, N, Nx20/19/42 (24.7/23.5/51.8)?M54 (66.7)Fuhrman nuclear grade 1/2/3/4/unfamiliar8/23/24/3/23 (9.9/28.4/29.6/3.7/28.4)Histology Clear cell/ Non-clear cell/unknown68/7/6 (84/8.6/7.4)Second line ITx/TKI/mTORi (N=81)10/35/36 (12.3/43.2/44.5)Third line ITx/TKI/mTORi (N=30)5/16/9 (16.7/53.3/30)Forth line TT9 (11.1)Two times Sequential TT?TKI-mTORi39 (48.1)?TKI-TKI30 (37.1)?TKI-ITx10 (12.3)?mTORi-TKI2 (2.5)Double sequence response-RECIST?CR/PR/SD/PD0/6/48/27 (0/7.4/59.3/33.3)Triple sequential TT?TKI-TKI-TKI1 JAK3-IN-2 (3.3)?TT-TT-ITx9 (30.0)?ITx-TT-TT8 (26.7)?TKI-mTORi-TKI6 (20.0)?TKI-TKI-mTORi6 (20.0)Triple sequence response-RECIST?CR/PR/SD/PD0/5/17/8 (0/16.6/56.7/26.7)Treatment duration of Second/Third-line TT(Month)3.1 (1-66.7)/5.0 (1-47.1)Overall median duration of double/triple sequential TT (months)30.2 (5.3-66.7)/37.8 (8-83.8)Total PFS of Two times/Triple sequential TT (Month)10.2 (1-74.4)/17.8 (3.5-83.8)OS of Two times/Triple sequential TT (Weeks)30.0 (21.1-38.8)/40.0 (18.4-61.6)Survival/death14/ 67 (17.3/82.7) Open in a separate windowpane TT, targeted therapy; ITx, immunotherapy; TKI, tyrosine kinase inhibitor; mTORi, mammalian target of rapamycin inhibitor; CR, total remission; PR, partial response; SD, stable disease; PD, progressive disease; PFS, progression-free survival; OS, overall survival Survival durations relating to double- or triple-TT The tPFS durations were 10.2 and 17.8 months for individuals who underwent double-TT or triple-TT, respectively. The OS durations were 30.0 and 40.0 months for those who underwent double-TT or triple-TT, respectively. Fourteen (17.3%) individuals remained alive at study completion. Survival durations relating to sequential double-TT TKI-mTORi use (n =.