Vitale

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Review

Clinical management of metastatic kidney cancer: the role of new molecular drugs

Maria Giuseppa Vitale*,1 & Giacomo Cartenì1

1UOSC Oncologia Medica, Azienda Ospedaliera di Rilievo Nazionale ‘Antonio Cardarelli’, 80131 Naples, Italy

*Author for correspondence: [email protected]

Over the last few years, the most recent advances of the molecular mechanisms involved in renal cell carcinoma have led to the use of new drugs targeting VEGF, such as bevacizumab plus interferon, sorafenib, sunitinib, pazopanib, and axitinib, or the mTOR, such as temsirolimus and everolimus. The purpose of this review is to analyze the results of Phase III trial with these targeted agents, and on the management of the treatment and, in particular, when to start and to stop therapy and the use of alternative schedule of sunitinib. Recent developments in immunotherapy are also discussed.

First draft submitted: 13 July 2015; Accepted for publication: 14 October 2015; Published online: 30 November 2015

Keywords • axitinib • everolimus • immunotherapy • metastatic • pazopanib • renal cancer • sorafenib • sunitinib • target therapy • treatment

Renal cell carcinoma (RCC) accounts for 2–3% of all adult malignancies. The number of patients who present with advanced disease at diagnosis has decreased over the last years due to increased use of imaging techniques while about a third of patients undergoing surgery develops distant metas-tases: the choice of the best medical treatment possible is very important. An understanding of the pathogenesis of RCC led to the development of targeted therapy utilizing tyrosine kinase inhibitors (TKIs), anti-VEGF antibodies and mTOR inhibitors [1–3].

Seven drugs have been approved by the US FDA for the treatment of advanced RCC: sunitinib, sorafenib, pazopanib, axitinib, temsirolimus, everolimus and bevacizumab in combination with interferon (IFN). Actually, the role of IL-2 is very limited because of modest clinical benefit and significant toxicity. It should be an option in first-line treatment or in subsequent therapy in patients with good performance status and normal organ function.

The aim of this review is to focus on the first-, second- and third-line treatment, and on the management of the treatment and, in particular, when to start and to stop therapy and the use of alternative schedule of sunitinib.

First-line treatmentThree drugs have shown efficacy (in terms of the progression-free survival [PFS] over either IFN-α or placebo) in the first-line treatment of patients with good or intermediate prognosis: bevacizumab (combined with IFN-α), sunitinib and pazopanib [4–7].

Temsirolimus has shown an improvement of overall survival (OS) compared with IFN-α or combination of temsirolimus and IFN-α in the first-line treatment of patients with poor progno-sis [8]. Sunitinib is also an option in these patients as demonstrated by the subgroup analysis from the pivotal trial and expanded access programs. Sorafenib is another option (Table 1).

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Sunitinib is a multikinase inhibitor target-ing several receptor tyrosine kinases, including VEGFr-2, PDGFR, FLT-3 and stem cell factor receptor (c-KIT) [9].

Sunitinib has shown effectiveness in a Phase III trial of sunitinib (50 mg/day given orally for 4 weeks followed by 2 weeks without treat-ment) versus interferon (9 MIU subcutaneously three-times a week) demonstrating a significant advantage with sunitinib in 750 metastatic RCC (mRCC) patients [5]. In this trial, 90% of patients had a favorable or intermediate prognosis risk. The primary end point was PFS and secondary end points included patient-related outcome, OS, response rate. The median PFS was 11 months for sunitinib arm and 5 months for IFN-α arm. The objective response rate was 31% for suni-tinib arm and 6% for IFN-α arm. Patients in the sunitinib group had a not statistically signifi-cant OS advantage compared with IFN-α arm (median OS was 26.4 months for sunitinib arm and 21.8 months for IFN-α arm; p = 0.051). The

OS in mRCC patients in treatment with suni-tinib became 26.4 months and for IFN-α arm 20 months (p = 0.036), without c onsidering 25 cases of crossover with sunitinib [10].

Results from an EAP (expanded access trial) demonstrated that sunitinib is also active in patients with brain metastases, poor perfor-mance status and nonclear cell histology with a good profile of toxicity [11].

EAP revealed the activity and efficacy of sutinitib in 373 patients with poor risk mRCC, with a median PFS of 4.1 months and a median OS of 5.3 months (in all mRCC patients the EAP demonstrated ORR 17%, median PFS of 10.9 months and median OS 18.4 months).

The main toxicities of sunitinib were hema-tologic, endocrine (thyroid dysfunction), gas-trointestinal (stomatitis, diarrhea) and skin (hand–foot skin syndrome), asthenia/fatigue and hypertension [10,11].

Treatment of mRCC with sunitinib is often associated with toxicity necessitating dose

Table 1. Phase iii trials of targeted therapy in first-line treatment in metastatic renal cell carcinoma patients.

Study Targeted therapy

Patients (n) ORR (%) Median PFS (months)

Median OS (months)

More frequent grade 3/4 toxicities (%)

Motzer et al. S vs I 375 (S) 375 (I)

31(S) 6 (I)

11 (S) 5 (I)

26.4 (S) 21.8 (I)

Fatigue 7 (S), 12 (I) Neutropenia 12 (S), 7 (I) Lymphopenia 12 (S), 22 (I) Hyperlipasemia 16 (S), 6 (I) Hyperuricemia 12 (S), 8 (I)

AVOREN I+B vs I+P 325 (I+B) 316 (I+P)

31 (I+B) 13 (I+P)

10.2 (I+B) 5.4 (I+B)

23.3 (I+B) 21.3 (I+P)

Fatigue 12 (I+B), 8 (I+P) Asthenia 10 (I+B), 7 (I+P) Proteinuria 7 (I+B), 0 (I+P) Anemia 3 (I+B), 6 (I+P)

CALGB 90206 I+B vs I 363 (I+B) 369 (I)

25.5 (I+B) 13.1 (I)

8.5 (I+B) 5.2 (I)

18.3 (I+B) 17.4 (I)

Hypertension 9 (I+B), 0 (I) Anorexia 17 (I+B), 8 (I) Fatigue 35 (I+B), 28 (I) Proteinuria 13 (I+B), 0 (I)

ARCC I T I+T

207 (I) 209 (T) 210 (I+T)

4.8 (I) 8.6 (T) 8.1 (I+T)

1.9 (I) 3.8 (T) 3.7 (I+T)

7.3 (I) 10.9 (T) 8.4 (I+T)

Asthenia 26 (I), 11 (T), 38 (I+T) Anemia 22 (I), 20 (T), 38 (I+T) Neutropenia 7 (I), 3 (T), 15 (I+T) Hyperglycemia 2 (I),11 (T), 6 (I+T) Infection 4 (I), 5 (T), 11 (I+T)

Sternberg et al. Paz vs P 290 (Paz) 145 (P)

30 (Paz) 3 (P)

9.2 (Paz) 4.2 (P)

22.9 (Paz) 20.5 (P)

Hypertension 4 (Paz) Diarrhea 4 (Paz) ALT elevation 30 (Paz) AST elevation 21 (Paz)

COMPARZ Paz vs S 557 (Paz) 553 (S)

31 (Paz) 25 (S)

8.4 (Paz) 9.5 (S)

28.3 (Paz) 29.3 (S)

Fatigue 11 (Paz), 18 (S) HF syndrome 6 (Paz), 12 (S) Thrombocytopenia 4 (Paz), 22 (S) Neutropenia 5 (P), 20 (S) ALT elevation 17 (Paz), 5 (S) AST elevation 12 (Paz), 3 (S)

B: Bevacizumab; HF: Hand–foot; I: IFN-α; ORR: Objective response rate; OS: Overall survival; P: Placebo; Paz: Pazopanib; PFS: Progression-free survival; S: Sunitinib; T: Temsilorimus.

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Clinical management of metastatic kidney cancer: the role of new molecular drugs review

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reduction. Maintaining adequate dosing and drug levels are important to optimize clinical efficacy. Standard sunitinib schedule is 4 weeks of treatment and 2 weeks of rest (schedule 4/2).

Alternative regimens to the standard 4/2 schedule include schedule of 50 mg/day 2 weeks on/1 week off, continuous schedule of 37.5 mg daily and the ‘Stop and Go strategy’. Many trials (observational and Phase II) have evaluated the alternative schedules of sunitinib [12].

Some randomized Phase II and retrospective trials showed that the alternative schedule of sunitinib (50 mg/day 2 weeks on/1 week off) was better tolerated than standard schedule and was similar in efficacy.

In particular, at 2014 ASCO Genitourinary Cancer Symposium, Bracarda et al. have pre-sented the final results of a multicenter retrospec-tive analysis, the RAINBOW study. This trial has demonstrated that the use of schedule 2/1 of sunitinib shows an improved safety profile and increased efficacy compared with schedule 4/2. The study included three groups: group A, 208 patients with schedule 2/1 for toxicities during initial therapy using schedule 4/2; group B, 41 patients with schedule 2/1, because of poorer clinical conditions; group C, 27 patients with schedule 4/2. Toxicities such as fatigue were inferior with schedule 2/1 [13].

Patients have often different ability to metabo-lize the drug that is highly dependent by hepatic cytochromes. This could explain both the differ-ent toxicity and effectiveness. Therefore, the use of schedule should not be defined from the start of treatment but evaluated only on the toxicity reported with the classical schedule. The use of schedule could reduce the emergence of resist-ance by maintaining the full dose and using of the schedule.

●● Bevacizumab plus iFNBevacizumab is a humanized monoclonal anti-body directed against VEGF [14,15].

A multicenter Phase III trial (AVOREN) ran-domized 649 patients to receive IFN (9 MU sub-cutaneously three-times/week) combined with either bevacizumab (10 mg/kg every 2 weeks) or placebo.

Median PFS was 10.2 months in patients treated with bevacizumab plus IFN versus 5.4 months of control arm; bevacizumab plus IFN has shown a higher response rate in the combination arm (31% vs 13%). Fatigue was the most common grade 3 toxicity. A trend toward improved OS was

also observed (IFN + bevacizumab 23.3 months vs 21.3 months IFN + placebo; p = 0.129) but was not statistically significant [4,16].

The efficacy and safety of Bevacizumab was also demonstrated in a multicenter Phase III trial, conducted in the USA and Canada by the Cancer and Leukemia Group B [17]. Median PFS and objective response rate were better in patients receiving bevacizumab plus IFN (PFS: 8.5 vs 5.2 months; objective response rate: 25.5 vs 13.1%). Toxicity was most frequent in the bevacizumab and IFN group: grade 3 hyper-tension (9 vs 0%), anorexia (17 vs 8%), fatigue (35 vs 28%) and proteinuria (13 vs 0%). There were no significant difference between the two groups in term of OS (18.3 months in bevaci-zumab plus IFN arm and 17.4 in those receiving IFN alone) [18].

No difference in terms of OS was evident in both studies, probably because patients receive second-line treatments after progression (62% of patients CALGB 90206 in the IFN-α arm and 54% of patients in the bevacizumab–IFN-α arm, respectively, received anti VEGF-targeted agents such as sunitinib and sorafenib). Despite primary end point of these studies – OS – was not reached, the bevacizumab and Interferon has been considered a valid option of treatment on the basis of the PFS results.

●● TemsilorimusTemsirolimus is an inhibitor of mTOR (a serine–threonine kinase implicated in the processes of transduction and regulation of protein degrada-tion and angiogenesis) for intravenous use [19,20].

The ARCC trial evaluated temsilorimus, IFN, or their combination for the first-line treatment of patients with poor-risk disease.

Two-thirds of patients had received prior nephrectomy and 80% had clear cell histology. Patients had a Karnofsky performance status (KPS) <80 and three or more of the following characteristics: the time from diagnosis to first treatment <1 year, corrected serum calcium >10 mg/dl, LDH >1.5-times the upper limit of nor-mal, hemoglobin <lower limit of normal, and multiple sites of metastases. Temsirolimus was less toxic than IFN or and combination.

The median OS was longer in the single-agent temsirolimus arm (10.9 months for temsiroli-mus, 7.3 months for IFN and 8.4 months for the combination).

Fatigue was the most common grade 3–4 tox-icities observed in 12% of patients treated with

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temsirolimus, 27 and 30% of IFN in combination while anemia of grade 3–4 toxicity was observed in 21% of patients treated with temsirolimus, 24 and 39% of IFN in combination. Response rates were similar in all three arms. Overall, temsirolimus significantly improved OS of poor-risk mRCC patients with a good profile of toxicity. Therefore, it should be considered as standard first-line th erapy for patients with poor-risk features [8].

●● PazopanibPazopanib has a broad spectrum of kinase inhi-bition including VEGFR 1–3, PDGFR A–B and c-Kit [21]. The safety and effectiveness of pazopanib was evaluated in a Phase III trial in which patients (naive and cytokine-pretreated) with metastatic or locally advanced RCC with no prior were randomized to oral pazopanib or placebo (randomization 2:1 for pazopanib). The primary end point was PFS [6]. PFS was longer in patients who received pazopanib (median PFS 9.2 vs 4.2 months) and becomes even longer in naive subpopulation (11.1 vs 2.8 months). The objective response rate was 30% with pazopanib, compared with 3% with placebo. The analysis of QoL showed a no significant trend in favor of pazopanib (vs placebo) of the scores of the q uestionnaires (validated) [22].

Main toxicities (any grade) were diarrhea (52%), hypertension 940%), hair color changes, nausea (26%) and anorexia (22%).

Hepatotoxicity with elevated levels of ala-nine (30%) and aspartate (21%) transaminase was significant grade 3 toxicity. There was no statistically significant difference in terms of OS between pazopanib- and placebo-treated patients (22.9 vs 20.5 months, respectively; hazard ratio [HR]: 0.91; 95% CI: 0.71–1.16; one-sided p = 0.224), probably because of crosso-ver from placebo to pazopanib and prolonged duration of crossover treatment [23].

Results of a large noninferiority Phase III, randomized trial (COMPARZ) of sunitinib versus pazopanib showed that they have a simi-lar profile of efficacy with a different profile of tolerability [7,24]. A total of 1110 patients with clear-cell, mRCC, were randomized to receive a continuous dose of pazopanib or sunitinib in 6-week cycles. The primary end point was PFS, and the study had as objective to demonstrate the noninferiority of pazopanib versus suni-tinib. Secondary end points were OS, safety and quality of life. OS was similar between the two drugs and pazopanib is noninferior to sunitinib

in terms of PFS. Fatigue (63% sunitinib vs 55% pazopanib), hand–foot syndrome (50 vs 29%) and thrombocytopenia (78 vs 41%) was higher for sunitinib while hepatotoxicity was more fre-quent with pazopanib (60 vs 43% with suni-tinib). About quality of life, pazopanib seems to be better than sunitinib.

Health-related quality-of-life (HRQoL) assessments were administered at baseline, on day 28 of cycles one through nine, and on day 42 of subsequent cycles; this could explain the obtained result because of the worst toxicity of sunitinib on day 28 of cycle.

PISCES trial was a double-blind crossover trial that has evaluated patient preference for pazopanib or sunitinib and HRQoL with the two different treatments [25]. A total of 169 patients received pazopanib 800 mg per day for 10 weeks, a 2-week washout, and then sunitinib 50 mg per day (4 weeks on, 2 weeks off, 4 weeks on) for 10 weeks, or the reverse sequence for the first-line treatment. Patient preference by questionnaire was obtained at the end of the two treatment periods. Other objectives were reasons for prefer-ence, physician preference, safety and HRQoL.

A total of 70% of patients preferred pazopanib over sunitinib (22%) because of less fatigue and better overall quality of life for pazopanib, with less diarrhea for sunitinib. Pazopanib (61%) was also preferred by physicians over sunitinib (22%). Pazopanib was superior to sunitinib in terms of HRQoL.

The study showed a clear preference in favor of pazopanib, however the patient preference ques-tionnaire had not received external validation, and over 30% of the randomized patients could not be evaluated for the primary end point of the study. The parameters of QoL were gener-ally favorable to pazopanib, but improvements of pazopanib over sunitinib have always been less than the minimum difference of clinical i nterest (MID).

Second-line treatmentAfter first-line treatment with VEGF-targeted therapy both axitinib and everolimus are valid treatment options [26,27]. They have shown signifi-cantly improved PFS over placebo (everolimus) or sorafenib (axitinib), but not OS. Sorafenib can be used as another option of treatment (Table 2) [28].

●● everolimusEverolimus is a derivative of rapamycin that acts as an inhibitor of mTOR. Everolimus was




evaluated in a Phase III, international, mul-ticenter randomized, double-blind, placebo-controlled study in patients with mRCC whose disease had progressed despite prior treatment with VEGFR-TKI. PFS was the primary end point. Secondary end points included safety, objective tumor response rate, OS, disease-related symptoms and QoL. Median PFS was 1.9 months in patients receiving placebo and 4.9 months in patients treated with everoli-mus. Patients randomized to placebo were allowed to cross over to everolimus treatment after disease progression. No statistically sig-nificant treatment-related difference in OS was revealed, although there was a trend in favor of everolimus. Median OS was 14.8 months for everolimus and a trend in OS favoring everolimus was observed (HR: 0.87, 95% CI: 0.65–1.15). Crossover to everolimus after dis-ease progression confounded the OS analy-sis. QoL was better for patients treated with everolimus [29].

The REACT study has provided everolimus in patients with mRCC after failure with VEGF inhibitor. Everolimus was well tolerated and sta-ble disease was the best tumor response in the majority of patients (51.6%) [30].

In the prospective, noninterventional CHANGE study between August 2009 and January 2012, patients with mRCC (median age: 68 years; 75% male; median KPS, 80%; 88% clear cell histology) received everolimus 10 mg/d until disease progression or unaccepta-ble toxicity after treatment with VEGF inhibitor or cytokines. Study end points were the treat-ment duration, time to progression (TTP), PFS, KPS and safety.

At the start of first-line therapy, MSKCC risk status was favorable in 35%, intermedi-ate in 56% and poor in 9%. Median treat-ment duration was 6.6 months, median TTP 7.4 months, PFS 7 months. In the safety popu-lation (n = 318), median time to ≥10% dete-rioration in KPS was 8.4 months (95% CI: 6.1–10.1 months); the most common adverse effects (AEs; any grade) were dyspnea (17%), anemia (14%) and fatigue (12%). Treatment adherence was high. The CHANGE study dem-onstrates favorable effectiveness and tolerability for everolimus [31].

The effectiveness and safety of everolimus in the second-line treatment after failure of VEGF receptor-targeted TKI, was evaluated in an observational, retrospective study conducted in

Table 2. Phase iii trials of targeted therapy in second-line treatment in metastatic renal cell carcinoma patients.

Trial Targeted therapy Patients (n) ORR (%) Median PFS (months)

Median OS (months)

More frequent grade 3/4 toxicities (%)

RECORD-1 E vs P 227 (E) 139 (P)

1.8 (E) 0 (P)

4.9 (E) 2 (P)

14.8 (E) 14.4 (P)

Stomatitis 5 (E) Infections 10 (E) Fatigue 5 (E) Dyspnea (E) Lymphocytes decreased 18 (E) Glucose increased 16 (E)

AXIS A vs S 361 (A) 362 (S)

19 (A) 9 (S)

6.7 (A) 4.7 (S)

20.1 (A) 19.2 (S)

Diarrhea 11 (A), 7 (S) Hypertension 16 (A), 11 (S) Fatigue 11 (A), 5 (S) HF syndrome 5 (A), 16 (S) Hypophosphatemia 2 (A), 16 (S) Lipase elevation 5 (A), 15 (S)

TARGET S vs P 451 (S) 452 (P)

10 (S) 2 (P)

5.5 (S) 2.8 (P)

17.8 (S) 15.2 (P)

Hypertension 4 (S) Decreased hemoglobin 3 (S) Fatigue 5 (S) Dyspnea 4 (S) HF skin reaction (S)

INTORSECT T vs S 259 (T) 253 (S)

8 (T) 8 (S)

4.28 (T) 3.91 (S)

12.27 (T) 16.64 (S)

HF syndrome 0 (T) 15 (S) Fatigue 6 (T) 7 (S) Anemia 9 (T) 3 (S) Hypophosphatemia 5 (T) 7 (S) Hyperglycemia 8 (T) 2 (S) Diarrhea 2 (T) 6 (S)

A: Axitinib; E: Everolimus; HF: Hand-foot; ORR: Objective response rate; OS: Overall survival; P: Placebo; PFS: Progression-free survival; S: Sorafenb; T: Temsilorimus.

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2 years (2011–2013) at ten oncological centers in the Campania region of Italy. Study objec-tives were PFS, response rate and safety. PFS was 8 months, 19% of patients had a partial response and 62% a stable disease. No grade 4 toxicity was reported [32].

The Phase II RECORD-1 trial evaluated the role of first-line mTOR inhibitor in mRCC. Primary end point was to assess noninferior-ity of first line with everolimus compared with first line with sunitinib in terms of PFS. After progression to first-line treatment, patients were crossed to alternative treatment. This trial has showed that the best sequence is the use of sunitinib in first line and everolimus in second line: median PFS after first line with sunitinib and everolimus was 10.71 and 7.85 months, respectively; median PFS for the sequence sunitinib-everolimus was 25.79 months and 21.13 months for the reverse sequence. Median OS was 22.41 months for the sequence everoli-mus-sunitinib and 32.03 months for the reverse sequence [33].

●● AxitinibAxitinib is a potent and selective inhibitor of the tyrosine kinase that acts on receptors of VEGFR-1, VEGFR-2 and VEGFR-3 [34].

The Phase III randomized, prospective, open-label ‘AXIS’ trial compared axitinib (5 mg twice daily) with sorafenib (400 mg twice daily) in patients after failure with cytokines (35% of enrolled patients), sunitinib (54%), bevaci-zumab (8%) or temsirolimus (3%). The pri-mary end point of the study was PFS; secondary end points included OS, the objective response rate, duration of response and QoL and safety. The median PFS was 6.7 months for axitinib arm and 4.7 months for sorafenib arm (HR: 0.665, 95% CI: 0.544–0.812). The median survival was 20.1 months for axitinib and 19.2 months for sorafenib (HR: 0.969; 95% CI: 0.800–1.174). In patients pretreated with cytokines, the median PFS was 12.1 months for axitinib versus 6.5 months for sorafenib (HR: 0:46; 95% CI: 0.32–0.68). Axitinib also caused a relative reduction in risk of death (HR: 0.81; 95% CI: 0.56–1.19) [26,35].

The most frequent adverse events during treatment with axitinib were diarrhea (51.3 vs 50.4% for axitinib to sorafenib), hypertension (39.3 vs 29.0%), fatigue (34.8 vs 26.2%), nau-sea (28.7 vs 18.3%), decreased appetite (28.4 vs 24.8%), dysphonia (28.1 vs 11.8%) and

palmar-plantar (27.3 vs 51.0%). The param-eters of QoL were similar between the two arms [36]. Axitinib dose increases to 7 mg and then to 10 mg, twice daily, were allowed for those patients without hypertension or adverse reactions above grade 2. Diastolic blood pres-sure of 90 mm Hg or higher appears to be a pre-dictive biomarker of axitinib efficacy in patients with RCC [37].

●● SorafenibSorafenib is a small molecule inhibing the RTKs VEGFR2, VEGFR3, Flt-3, c-KIT and PDGFR and the nonreceptor serine threonine kinases BRAF and CRAF [38]. The BRAF and CRAF kinases are involved in survival and proliferation of tumor cells [39,40].

In the Phase III TARGET trial 905 patients, after failure with cytokine-based treatment, were randomized to receive either sorafenib 400 mg orally twice daily or placebo. PFS was 5.5 months for sorafenib arm versus 2.8 months for placebo arm (p < 0.000001). No signifi-cant difference in terms of OS was revealed (17.8 months for sorafenib vs 15.2 months for placebo) because of the crossover of placebo group to sorafenib [41].

There are no randomized studies on the use of sorafenib (as experimental treatment) after VEGF inhibitor progression. There are two studies in which sorafenib was the control arm: Axis (axitinib vs sorafenib) [26] and Intorsect (temsilorimus vs sorafenib) trials [27].

The median PFS was 4.4–3.9 months, and the median OS was 16.5–16.6 months in Axis and Intorsect trials, respectively. About the adverse reactions, diarrhea grade 3–4 were found in 7.6–5.6% of cases, fatigue grade 3–4 in the 3.9–7.1%, hand–foot syndrome reac-tion grade 3–4 in 17.2–15.1%, hypertension in grade 3–4 12.1%, in Axis and Intorsect trials, respectively.

Third-line treatmentThe pivotal trial of everolimus has demonstrated the effectiveness of using this drug even in third-line treatment of mRCC. Another treatment option is represented by sorafenib as demon-strated by GOLD trial, a multicenter Phase III of sorafenib versus dovitinib. In GOLD trial, patients in progression after a first-line treatment with VEGF-inhibitor and a second-line treat-ment with mTOR inhibitor were randomized to receive dovitinib (500 mg orally according to a




5 days on and 2 days off schedule) or sorafenib (400 mg orally twice daily). Primary end point was PFS. A total of 284 patients received dovi-tinib while 286 patients sorafenib. Median PFS was 3.7 months for dovitinib and 3.6 months for sorafenib. Common grade 3 or 4 toxicities were hypertriglyceridemia (38 [14%]), fatigue (28 [10%]), hypertension (22 [8%]) and diarrhea (20 [7%]) in the dovitinib group, and hyperten-sion (47 [17%]), fatigue (24 [8%]), dyspnea (21 [7%]) and palmar–plantar erythrodysesthesia (18 [6%]) in the sorafenib group. Dovitinib showed to be no better than sorafenib in third line of treatment of RCC [42].

Algorithm of therapy of mRCC is showed in Table 3.

when to start?The biology of mRCC includes a subpopula-tion of patients with indolent disease and can sometimes allow the possibility to delay the start of treatment. Because of the toxicity and noncurative nature of current systemic therapy, initial surveillance may be an option in selected patients. The TARGET trial (sorafenib vs pla-cebo), RECORD-1 trial (everolimus vs placebo) and the Phase III trial of pazopanib versus pla-cebo show that there is no statistically significant difference in terms of OS between the two arms of these studies.

A prospective Phase II observation conducted in patients with mRCC prior to initial systemic treatment has demonstrated that a subset of patients can be safely observed for a period of time before starting systemic therapy.

Radiographic assessment was performed at baseline, every 3 months for year 1, every 4 months for year 2, then every 6 months. The primary objective was to characterize time to initiation of systemic treatment. Secondary end points included assessment of depression/anxiety using standardized questionnaires (FKSI-DRS and HADS) and peripheral blood immune repertoire (TH1/TH2, MDSC, Tregs). A total of 52 patients were accrued; median age 67 years (range: 47–88); 75% male; 94%; Eastern Cooperative Oncology Group per-formance status: 0; 96% clear cell; 8% prior metastasectomy and Heng risk group favorable/intermediate 26%/74%. Baseline tumor burden (per RECIST 1.0) was 3.2 cm (0.8–19.6 cm). Median time on observation until systemic therapy was started was 14.1 months (95% CI: 10.6–19.3), with estimated 12-month and

24-month rates of continued surveillance of 58 and 33%, respectively. Median change in tumor burden on study was 0.8 cm (0–6.5 cm); relative change +34% (0–311%) and median growth rate 0.14 cm/month (0–1.75). In total, 31 patients have come off observation (61% for PD), and 25 patients have received systemic therapy. Patients with baseline tumor burden ≤1.5 cm versus >1.5 cm had a median observa-tion period of 31.6 months versus 13.8 months (p = 0.06). Anxiety/depression were not prev-alent at baseline, and scores did not worsen over time. There were no significant changes in immunologic parameters [43]. Therefore, in patients with mRCC with small metastasis, asymptomatic, for example, lung metastasis, initial surveillance could be an option.

when to stop?Prolonged treatment in mRCC patients may cause significant AEs that sometimes requires a treatment break. A treatment break is feasible in selected patients. Mittal et co-workers have analyzed retrospectively mRCC patients on tar-geted therapy who discontinued treatment for ≥3 months for reasons other than progressive disease. Pts could receive treatment breaks with multiple lines of therapy (defined sequentially as treatment A, B, C, among others). A number of patients continue on treatment/observation, hence durations were estimated using the Kaplan–Meier method. One hundred and twelve patients were observed: 75% male; median age at diagnosis 56; 95% clear cell. A total of 19% of patients had received prior systemic therapy. In total, 48% patients were favorable, 48% intermediate and 4% poor risk by Heng criteria. Overall, patients received a median of two treatments. Treatment A primar-ily included sunitinib (55%), sorafenib (13%), or bevacizumab in combination with tem-sirolimus (10%)/IFN (9%). Common reasons

Table 3. Algorithm of therapy of metastatic renal cell carcinoma.

Line of therapy Therapy Other options

First-line therapy Sunitinib ObservationGood or intermediate-risk group Pazopanib

Bevacizumab + IFN-αHigh-dose IL–2 Sorafenib

First-line therapy Temsirolimus Clinical trialPoor-risk group Sunitinib After tyrosine kinase inhibitor therapy Everolimus

AxitinibSorafenib

After cytokine therapy Axitinib Pazopanib

Sorafenib Sunitinib

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for breaks in treatment A were toxicity/AEs (57%) and physician choice (26%). A total of 40 (36%) patients remain on treatment break from the first treatment (A). A total of 25 (22%) patients have undergone two treatment breaks. A total of 68 (61%) patients restarted treatment (B); 33 (49%) of these were rechallenged with previously used therapy and 35 (51%) received alternative TKIs. Overall, 30 patients have died; median survival is 71.7 months (range: 1.3–93+ months). Achievement of CR prior to the initial treatment break (n = 15) was associated with a longer surveillance period (p = 0.0004) [44]. This strategy may be associ-ated with acceptable overall disease control and reduced toxicity.

The Phase II/III STAR trial is comparing two ways of taking sunitinib or pazopanib continu-ously with having planned treatment breaks in patients with locally advanced and/or metastatic advanced kidney cancer. This trial is ongoing and its primary outcomes are 2-year OS and averaged QoL-adjusted years (QALYs).

Other targetsCabozantinib is an oral, small-molecule kinase inhibitor that targets the MET receptor and VEGFR-2 and other potentially relevant recep-tor tyrosine kinases including RET, KIT, AXL and FLT3. METEOR trial, a randomized, open-label, Phase III trial evaluated the effi-cacy of cabozantinib at a dose of 60 mg daily, as compared with everolimus at a dose of 10 mg daily, in 658 patients with RCC after VEGFR-targeted therapy. PFS was longer with cabozan-tinib than with everolimus: 7.4 months with cabozantinib and 3.8 months with everolimus. The objective response rate was 21% with cabo-zantinib and 5% with everolimus. A planned interim analysis showed that OS was longer with cabozantinib than with everolimus but did not reach the st atistical significance [45].

The role of immunotherapyAlthough the treatment with VEGF and mTOR inhibitor have demonstrated PFS benefit, most patients with mRCC inevitably relapsed due to acquired resistance [46] and, therefore, there is the notable need for treatment options with mechanisms of action that could potentially result in improved efficacy and a survival advan-tage. Multiple resistance mechanisms, such as dysfunction of immune checkpoints help tumors to evade specific immune responses.

Cancer cells have a protein called PD-L1 on their surface that helps them evade the immune system. Novel antibodies directed against immune checkpoint regulators that block the PD-L1 protein, or the corresponding PD-1 pro-tein on immune cells called T cells, can help the immune system r ecognize the cancer cells and attack them.

Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, dem-onstrated antitumor activity with a manageable safety profile in a randomized, dose-ranging Phase II trial [47].

Choueiri demonstrated that the clinical response to treatment with nivolumab was evident not only in mRCC patients with have an expression pretreatment of PD-L1 but also patients PD-L1-negative obtained responses to treatment with nivolumab [48]. The rational combination of the two drugs (ipilimumab and nivolumab) is based on their inhibitory activity on the immune system (CTLA-4 and PD-1), to obtain efficacy of the antitumor activity of the immune system greater than what can be obtained by the inhibition of one of the two checkpoints. In a Phase I study of nivolumab in combination with ipilimumab in mRCC, the combination of the two drugs showed accept-able safety and encouraging antitumor activ-ity (favorable/intermediate MSKCC score; KPS ≥80%; untreated or any number of prior therapies) [49].

A Phase III, randomized, open-label study of nivolumab combined with ipilimumab versus sunitinib monotherapy in subjects with previ-ously untreated, advanced or mRCC (CA209-214 trial) is on going. The purpose of this study is to compare the PFS and the OS of nivolumab combined with ipilimumab to sunitinib mono-therapy in patients with previously untreated renal cell cancer [50].

Another target under investigation is atezoli-zumab (anti-PD-L1 antibody) in combination with bevacizumab versus sunitinib in a rand-omized, open-label study in patients with inop-erable, locally advanced, or mRCC in first-line treatment [51].

A randomized, open-label, Phase III study compared nivolumab with everolimus in 821 patients with renal-cell carcinoma who had received previous treatment with one or two regimens of antiangiogenic therapy. The pri-mary end point was OS. The secondary end points included the objective response rate




and safety. The median OS was 25.0 months with nivolumab and 19.6 months with everoli-mus. The objective response rate was greater with nivolumab than with everolimus (25 vs 5%). The median PFS was 4.6 months with nivolumab and 4.4 months with everolimus. Grade 3 or 4 treatment-related AEs occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%) [52].

With the advent of immunotherapy drugs, the treatment algorithm for kidney cancer should be enriched. Soon the oncologists will be able to use immunotherapy drugs in both first-line and sub-sequent-line treatment. In the near-term future, we will have the possibility of use nivolumab or cabozantinib after progression with first-line treatment.

ConclusionThe development of many drugs for the treat-ment of RCC has certainly changed the progno-sis of this disease. About the first-line treatment with sunitinib, the choice of an ideal schedule for single individual patient may guide the decision-making process. The use of a schedule should be also evaluated with the other VEGF and m-TOR inhibitor to optimize efficacy with reduction of toxicity. It is not yet defined what is the correct sequence of treatment (TKI–mTOR vs TKI–TKI) and, therefore, further studies are needed to better understand this choice. It is important to define the role of immunotherapy in the treatment of mRCC with the hope to get good results from Phase III clinical trials on going.

Future perspectiveThe VEGF inhibitors and mTOR inhibitors have dramatically improved the treatment options and outcome for patients with advanced RCC. Novel treatment approaches are still nec-essary because of the appearance of resistance. Areas of promising investigation are the identifi-cation of the development of novel immunother-apies, particularly those involving checkpoint inhibitors used alone or in combination with VEGF inhibitor. We speculate that, in the next 5 years, immunotherapeutic agents will be more and new targets will be explored.

Specific targets or agents of interest include angiopoietins such as trebaninib, a protein that prevents the interaction of ligands, Ang1 and Ang2, with the Tie2 receptor involved in vas-cular growth, remodeling, and stabilization; dalantercept, a protein that inhibits angiogen-esis by blocking the interation of BMP9 and BMP10, proteins in the TGF-β superfamily with ALK1 on proliferating endothelial cells and the development of mature, functional vas-culature, and HDM2 for acquired resistance to VEGF pathway inhibition.

Together, these developments could lead to a new era of rational and more effective therapy for patients with advanced RCC.

Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a finan-cial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or p ending, or royalties.

No writing assistance was utilized in the production of this manuscript.

executive summary ● Seven drugs have been approved for the treatment of renal cell carcinoma: sunitinib, sorafenib, pazopanib, axitinib,

temsirolimus, everolimus and bevacizumab + interferon.

● It is important the correct management of treatment: the use of schedule of sunitinib (2:1) should not be defined from the start of treatment but evaluated only on the toxicity reported with the classical schedule (4:2).

● After first-line treatment with VEGF-targeted therapy both axitinib and everolimus are valid treatment options. Sorafenib can be used as another option of treatment.

● In patients with metastatic renal cell carcinoma with small metastasis, asymptomatic, for example, lung metastasis, initial surveillance could be an option. On the other hand, a treatment break is feasible in selected patients.

● In a near future, a new immunotherapic agent (nivolumab) and a dual inhibitor (MET and VEGFR-2) cabozantinib will change the algorithm of treatment of metastic renal cell cancer.

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•• ThisPhaseIIItrialevaluatedtheefficacyofcabozantinibcomparedwitheverolimusin658patientswithRCCafterVEGFR-targetedtherapy.Progression-freesurvivalwaslongerwithcabozantinibthanwitheverolimus.

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50 Clinical trials database: NCT02231749. https://clinicaltrials.gov

51 Clinical trials database: NCT02420821. https://clinicaltrials.gov

52 Motzer RJ, Escudier B, McDermott DF et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N. Engl. J. Med. (2015) (Epub ahead of print).

•• ThisPhaseIIIstudycomparednivolumabwitheverolimusafterprevioustreatmentwithoneortworegimensofantiangiogenictherapy.Overallsurvivalwaslongerwithnivolumabthanwitheverolimusandtheobjectiveresponseratewasgreaterwithnivolumabthanwitheverolimus.

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