**5. Combination therapy in metastatic RCC**

With the increasing use of VEGF and mTOR inhibitors, it has been noted that patients eventually develop resistance / relapse after 6 months to 3 years of therapy. [25] This has been the driving force for the development of more novel anti-angiogenic agents or treat‐ ment strategies such as combination of the various targeted agents (combination of antiangiogenic agents or with mTOR inhibitors, chemotherapy or immunotherapy). [74] Combination therapies may lead to a more complete blockade of aberrant signaling and potentially delay / prevent the development of resistance observed with single-agent treatment. [74] Unfortunately, this invariably leads to increased toxicities as experienced in some of the phase I trials. [75]

### **5.1. VEGF-ligands or receptor inhibitors / mTOR plus immunotherapy combination**

Two single arm phase II studies using sorafenib in combination with standard dose IFN-α showed higher ORR (approximately 30%) and longer PFS (7 – 12 months) when compared with phase III data of sorafenib monotherapy. [76, 77] However, in a randomized phase II trial of sorafenib vs. sorafenib and low-dose IFN-α in patients with advanced RCC, no statistically significant difference in ORR and PFS was noted in the two arms. [78] These results should be interpreted cautiously given the small number of patients in these studies. [78]

reduction of both agents and resulted in a considerably lower maximum tolerated dose in contrast to the maximal tolerated dose of the single agent. Bevacizumab potentiated the sideeffects of sorafenib such as hypertension and hand-foot syndrome; hematological, vascular toxicities (including microangiopathic hemolytic anaemia) and hypertension in the sunitinib combination. [75] Finally, a phase II study assessing the tolerability and efficacy of multiple combinations of currently available therapies, is being processed in the Eastern Cooperative Oncology BeST trial. The four arms are bevacizumab (10mg/kg), bevacizumab (5mg/kg) / temsirolimus (25 mg), bevacizumab (5mg/kg) and sorafenib (200mg twice daily)/ temsirolimus

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Sequential use of targeted agents has several potential benefits. Firstly, this approach could lead to a treatment continuum, secondly, it provides patients the opportunity to receive full doses of the targeted agents without affecting tolerability and finally, sequential targeting of different molecular pathways could potentially overcome any resistance that would arise from

Few phase II trials using anti-angiogenic agents after progression on immunotherapy lead to promising results. [32, 59, 87] In a phase III trial (TARGET) patient who had progressed on cytokine therapy after receiving sorafenib, there was a notable doubling of PFS from 2.8 to 5.6 months. [41] Likewise, the utilization of axitinib post progression on cytokine in a phase II trial, lead to a TTP of 15.7 months. [77] There are no head-to-head data present to guide which agent is best utilized post cytokine therapy and a properly conducted phase III trial are

In this strategy, the RECORD-1 trial investigated the efficacy of everolimus vs. placebo with best supportive care post progression on sunitinib, sorafenib or both. Seventy one per cent of patients included in the trial had received prior sunitinib treatment and 55% sorafenib therapy. Patient on everolimus achieved addition of 3-month in terms of PFS regardless of prior treatment. No overall survival benefit was observed due to large numbers of cross over from

RECORD-3, a phase III clinical trial recently closed to patient recruitment, randomly assigned patients to either everolimus or sunitinib. Upon first sign of progression, patients would cross over to sunitinib if they were on everolimus and to everolimus if previously on sunitinib. The primary end point of this trial was to evaluate whether PFS post first-line treatment for patients

who received everolimus will be non-inferior to patients who receive sunitinib. [52]

(25mg). [85]. The results are currently pending.

**6. Sequencing therapy in metastatic RCC**

**6.1. Anti-angiogenic therapy after immunotherapy**

required to share further insight into this treatment strategy.

**6.2. mTOR blockade after anti-angiogenic therapy**

placebo to everolimus arm (80%). [67]

single target inhibition. [86]

Both AVOREN (n = 649) [79] and CALGB 90206 (n = 732) [80] compared bevacizumab / IFNα combination with IFN-α demonstrated that the PFS interval was significantly longer with bevacizumab plus IFN-α than with the IFN-α alone (AVOREN: 10.2 months versus 5.4 months, respectively; p = 0.0001; CALGB 90206: 8.5 months versus 5.2 months, respectively; p < 0.0001). The ORRs were 31% with bevacizumab plus IFN-α and 13% with placebo plus IFN-α (p = 0.0001) in the AVOREN study. In the CALGB 90206 trial, the ORRs were 25.5% with bevaci‐ zumab plus IFN-α and 13.1% with IFN-α (p < 0.0001). [74, 79, 80] The design of these trials however did not have a bevacizumab monotherapy arm and therefore the clinical efficacy of bevacizumab monotherapy remained unanswered. In an open-label phase 2 study (TORAVA), 171 patients with metastatic RCC were randomly assigned (2:1:1) to receive the combination of bevacizumab (10 mg/kg every 2 weeks) and temsirolimus (25 mg weekly) or sunitinib (50 mg/day for 4 weeks followed by 2 weeks off) or the combination of IFN-α (9 x 106 IU three times per week) and bevacizumab (10 mg/kg every 2 weeks). PFS at 48 weeks was 29.5% (26 of 88 patients, 95% CI 20.0-39.1) in group A, 35.7% (15 of 42, 21.2-50.2) in group B, and 61.0% (25 of 41, 46.0-75.9) in group C. Median PFS was 8.2 months (95% CI 7.0-9.6) in group A, 8.2 months (5.5-11.7) in group B, and 16.8 months (6.0-26.0) in group C. The toxicity of the experimental regimen was high with over 50% of patients not able to tolerate the combination of bevacizumab and temsirolimus over several months. This combination failed to show any beneficial activity and was more toxic than the treatments used in the other arms, and therefore was not recommended as first line treatment in these patients. [81]

The combination of temsirolimus and IFN-α was studied in a phase III trial. Six hundred and twenty six patients were randomized to receive of IFN-α alone, temsirolimus alone, or a combination of the two drugs. Median OS times in the IFN-α arm, the temsirolimus arm, and the combination-therapy arm were 7.3, 10.9, and 8.4 months, respectively. Unlike temsirolimus alone, the combination of temsirolimus plus IFN-α did not improve OS. Therefore the temsirolimus / IFN-α combination is not recommended as standard practice for treatment of advanced RCC. [65]

Lastly, in a global, open-labelled multi-centre phase IIIb trial (INTORACT), temsirolimus and bevacizumab was compared with interferon and bevacizumab as first-line treatment in 791 patients with predominantly clear-cell metastatic RCC. [82] At the interim analysis, 489 patients were assessed PFS events. Median PFS with temsirolimus / bevacizumab combination was 9.1 month compared to 9.3 months in the interferon / bevacizumab group. The median OS was 25.8 months in the temsirolimus and 25.5 months for the interferon group. [82]

### **5.2. VEGF-ligands or receptor inhibitors / mTOR combination**

Bevacizumab in combination with sorafenib and sunitinib has been evaluated in two phase I trials. In these trials although there were some promising results regarding the median time to progression and partial response rates in the combination arms, the adverse effects observed in the latter were prominent. [83, 84] The combination arm in both trials required dose reduction of both agents and resulted in a considerably lower maximum tolerated dose in contrast to the maximal tolerated dose of the single agent. Bevacizumab potentiated the sideeffects of sorafenib such as hypertension and hand-foot syndrome; hematological, vascular toxicities (including microangiopathic hemolytic anaemia) and hypertension in the sunitinib combination. [75] Finally, a phase II study assessing the tolerability and efficacy of multiple combinations of currently available therapies, is being processed in the Eastern Cooperative Oncology BeST trial. The four arms are bevacizumab (10mg/kg), bevacizumab (5mg/kg) / temsirolimus (25 mg), bevacizumab (5mg/kg) and sorafenib (200mg twice daily)/ temsirolimus (25mg). [85]. The results are currently pending.
