Moreover, we critically analyze the impact of recently approved therapeutic antiangiogenic agents and checkpoint inhibitors after progression to first-generation tyrosine kinase inhibitors and their mode of action

Moreover, we critically analyze the impact of recently approved therapeutic antiangiogenic agents and checkpoint inhibitors after progression to first-generation tyrosine kinase inhibitors and their mode of action. we provide an overview on ongoing phase?III trials combining antiangiogenic therapies with checkpoint inhibitors in the first-line setting. Moreover, we critically analyze the impact of recently approved therapeutic antiangiogenic agents and checkpoint inhibitors after progression to first-generation CTNND1 tyrosine kinase inhibitors and their mode of action. In addition, response and resistance hypotheses and biomarkers to antiangiogenic therapy in clinical CUDC-305 (DEBIO-0932 ) practice are critically discussed. placental growth factor, progression-free survival, vascular endothelial growth factor, mammalian target of rapamycin. (Adapted from [22]) Cabozantinib This is an oral multi-TKI blocking VEGFR-1, 2, 3, RET, KIT, TRKB, FLT-3, AXL, TIE-2, with the additional potential to inhibit c?MET. The c?MET expression was noticed to be an independent prognostic marker and a?potential therapeutic target especially in ccRCC, associated with worse disease-specific survival [23] due to aggressive tumor behavior [24] and increased PD-L1 expression [21]. The open-label, randomized phase?III METEOR trial included 658 mRCC patients with previous treatment with one or more VEGF-targeted TKIs, receiving cabozantinib 60?mg or everolimus 10?mg once per?day consecutively. Interestingly, the median progression-free survival (PFS) (cab vs. eve: 7.4 vs. 3.9?months; hazard ratio HR?= 0.51; em p /em ? 0.0001) as well as the overall survival (OS) (cab vs. eve: 21.4 vs.16.5?months; HR?= 0.66; em p /em ?= 0.00026) was significantly increased in the cabozantinib group compared to everolimus, thus becoming one of the new efficient second-line TKIs in the recent European Society of Medical Oncology (ESMO) and EAU guidelines. Nevertheless, a?dose reduction during treatment occurred in 60% of all patients undergoing cabozantinib therapy, with serious adverse events grades 3/4 in 39% [25]. Lenvatinib This is a?multi-target TKI of VEGFR-1, -2, -3 also inhibiting FGFR-1, -2, -3 and -4, PDGFRalpha, KIT and RET. Antiangiogenesis activity and antitumor cell growth of lenvatinib was previously confirmed by inhibiting VEGF and FGF-driven proliferation and tube formation of human umbilical vein endothelial cells in vitro. In addition, in vivo angiogenesis induced by overexpressed VEGF or FGF was significantly suppressed with oral lenvatinib treatment [26]. The enhanced antitumor activity by combining lenvatinib plus everolimus may be explained by the simultaneous targeting of tumor cell growth and angiogenesis in human RCC xenograft models [27]. This combination confirmed an additive activity in VEGF-activated, and synergistic activity against FGF-activated endothelial cells, with suppression of mTOR-S6K-S6 signaling [27]. In the clinical setting, the phase?1b study confirmed lenvatinib 18?mg and everolimus 5?mg once a?day as the maximum tolerated dose in patients with mRCC, with manageable toxicity and the best therapeutic response (stable disease in 45.5% and partial remission in 36.4%) [28]. The following phase?II trial with 153 patients who progressed after first-line VEGF-targeted therapy received either lenvatinib 18?mg combined with everolimus 5?mg, single-agent lenvatinib 24?mg, or single-agent everolimus 10?mg. Compared to lenvatinib and everolimus monotherapy, the combination of lenvatinib and everolimus showed the best median PFS (14.6?months) and median OS (25.5?months), with diarrhea as the most common grade 3/4 adverse event in 20% [29]. Based on the limited size of approximately 150 patients in this phase?II study, CUDC-305 (DEBIO-0932 ) the combination of lenvatinib and everolimus was not, at this stage, recommended either by current ESMO 2016 [30] or by EAU 2017 guidelines [22] on RCC as a?novel second-line therapeutic regimen. Nivolumab This is the first approved CUDC-305 (DEBIO-0932 ) PD-1 checkpoint inhibitor in the second-line treatment of mRCC. The randomized phase?II trial evaluated three doses of nivolumab (0.3, 2 and 10?mg/kg intravenously once every 3?weeks) to identify a?potential dose-response relationship and assess the activity and safety of nivolumab in patients with mRCC. Interestingly, no dose-dependent relationship was confirmed by PFS (2.7 vs. 4.0 vs. 4.2?months, respectively) and ORR (20% vs. 22% vs. 20%, respectively) with manageable safety profiles across the three doses (grade?3C4 adverse events AE: 5% vs. 17% vs. 13%, respectively) [31]. The following phase?III Checkmate?025 trial compared nivolumab (3?mg/kg intravenously every 2?weeks) with everolimus (10?mg orally once a?day) in patients who received previous treatment with one or two regimens of antiangiogenic therapy. Nivolumab confirmed significantly better.