**6. Third line and beyond**

Small prospective and retrospective trials suggest that changing the mechanism of action in the third line may restore the sensitivity to the initial treatment [3,9,27,32,39,40]. In the ASCO meeting in 2010 Ferrari presented the results of a prospective trial that compared the admin‐ istration of everolimus or temsirolimus as third line therapy to good performance status patients resistant to TKI-s. Median PFS was 6 months and disease control was achieved in 39% of patients. These results suggest that treatment with mTOR inhibitor in the third line and further than, could be a potential promising treatment option [40].

Another trial conducted by Di Lorenzo et.al. evaluated sorafenib treatment in the third line after treatment with sunitinib and mTor inhibitor. Of the 34 patients eligible, 23.5% responded to third line sorafenib. Desease control was 44%, median PFS was 4 and median OS was 6 months. 47% of patients that responded to first line therapy, responded to third-line sorafenib while of patients who did not respond to first-line, did not respond also to third-line sorafenib. The most common 3/4 grade side effects of third line sorafenib were hand-foot syndrome, anemia, fatigue, diarrhea and neutropenia. These results show that sorafenib could be considered in the third line treatment in mRCC patients after the failure on sunitinib and mTOR inhibitor [41]. Blesious retrospectively evaluated 105 patients in the RECORD-1 trial of whom 36 received a VEGF-TKI after receiving everolimus. Patients that received sunitinib, sorafenib and dovitinib had median PFS of 8 months, 5.3 months and 12.0 months. A partial response was reported in 8.6% of patients and 68.8% of patients had stable disease. Median OS was 29.1 months [42].

**7. Future directions**

**7.1. New targeted agents**

in 8.5% of patients [46].

**7.2. Biomarkers**

goals [25].

The current practice of delivery of sequential monotherapy targeted agents is empirical and mainly based on non-comparative clinical trials. In treatment refractory patients often practical issues like route of delivery or physician familiarity with the drug prevail over the scientific evidence in selecting treatment. Deeper understanding of the biology of response and resistance to targeted agents will elucidate future way in treatment of mRCC patients. New multi-targeted inhibitors are being rapidly developed and their role in overcoming resistance will become clear in the next few years. Together with the developments of these new drugs, finding predictive biomarkers of these new and "old" therapies is one of the major research

Changing Mechanisms of Action as a Strategy for Sequential Targeted Therapy of Metastatic Renal-Cell Carcinoma

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Dovitinib is an investigational multi-target inhibitor of FGF receptors 1-3, PDGF receptor, VEGFrs 1-3 and c-KIT. One of the mechanisms of resistance to VEGF-TKI seems to be hypoxiamediated induction of FGF signaling. Dovitinib was tested in a phase II trial in which patients with mRCC who failed prior treatment with VEGF-TKI or mTOR inhibitor or cytokines. Median PFS and OS were 5.5 months and 11.8 months in all patients and 6.1 months and 10.2 months in patients treated with previous VEGF-TKI or mTOR inhibitor. The main grade 3 toxicities of dovitinib were nausea/vomiting in 15%, fatigue in 13.6%, asthenia in 13.5%, diarrhoea in 10.2% and hypertension in 10.2% of patients. Grade 4 hypertriglicemia occurred

Tivozanib is a potent selective long half-life tyrosine kinase inhibitor targeting VEGFR 1-3. 517 patients were included in a phase III trial published by Motzer et.al at ASCO 2012. Patients were randomized to receive either tivozanib or sorafenib. Median PFS was 11.9 months for tivozanib and 9.1 months for sorafenib (p=0.042). Overall response rate was 33% in tivozanib and 23% in sorafwnib group (p=0.014). Adverse events grade 3 for tivozanib were hyperten‐

Predictive biomarkers could help clinicians to determine the best treatment approach [48,49]. Multiple candidate biomarkers of biological tumor activity as well as treatment response and patient prognosis are being evaluated [49]. However up to date, none of them showed potential in clinical use. VHL gene status did not correlate with PFS or OS. The reason for this may be that almost all RCC cancers have VHL silencing and so this marker cannot be selective enough. Biomarkers in the peripheral blood have also been tested. Results of some trials showed that patients with mRCC and elevated expression of angiogenic factors have greater benefit from VEGF-targeted therapies, although other trials yielded inconsistent results. Other types of predictive markers, like changes in the tumor blood flow measured by MRI during treatment

sion, diarrhea, fatigue, neutropenia and hand-foot syndrome [47].

with targeted agents are being explored [25,48,49].

In a trial of Grunwald efficacy of VEGF-targeted therapies in patients after everolimusresistant patients who had progressed on a previous TKI was explored. Patients received sunitinib, sorafenib, dovitinib or bevacisumab/ IFN therapy after failure of everolimus. Of the 40 patients included 10% had partial response and 55% had stable disease. Median PFS was 5.5 months. Authors conclude that VEGF targeted therapy show promising activity in everolimus resistant metastatic RCC [43].

Porta et. al. evaluated retrospectively the overall PFS benefit of the sequence VEGF-TKI, mTor inhibitor, VEGF-TKI sequence. The sequence of sorafenib-mTOR-sunitinib (14 patients) was compared to the sequence sunitinib-mTOR-sorafenib (26 patients). No significant difference in PFS was found between the two groups (21.9 months vs 22.8 months). The median PFS for the threelinesoftreatmentwere11.7months-5.1months-9.1monthsforthegroupsorafenib-mTORsunitinib and 14.4 months-4.3 months-3.9 months for sunitinib-mTOR-sorafenib group [44].

The results of these trials suggest that re-challenging strategy of VEGF-TKI in the third line of treatment after progression on VEGF-TKI in the first and mTOR inhibitors in the second may be a successful treatment approach. The other observation of these trials is that some patients have minor benefit from the VEGF-TKI inhibitors in the third compared to the benefit in the first line. The explanation for this is that probably partial cross-resistance to the VEGF-TKIs accounts at least to some extent for this. One possible strategy to overcome this resistance is to use the third-line agent with the ability to broadly inhibit multiple angiogenic pathways in addition to VEGF signaling [9].

Even if no clinical guidelines exist for the fourth-line targeted therapy, some reports suggest that patients may gain clinical benefit from the sequences of targeted agents with different mechanisms of action. 48 months of PFS was achieved in an mRCC patient treated with four lines of targeted therapies (sunitinib, everolimus, sorafenib, temsirolimus). Despite intensity, treatment was well tolerated and no cumulative toxicity was present. This case study advocates that sequential use of sunitinib, everolimus, sorafenib and temsirolimus and show that this could be effective treatment approach with good toxicity profile [45].

Metastatic RCC patients can get benefit from multiple lines of targeted therapy. Resistance to VEGF-TKIs and mTOR inhibitors seem to be at least partially reversible and re-challenging with the inhibitors from the same group in subsequent lines of therapy may be a therapeutic option if toxicity does not limit it. Tailoring treatment to the particular patient is of utmost importance [3,9,27,32].
