Every time I see patients with advanced RCC, I start the patient assessment by applying International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk criteria, also known as the Heng score.1,2 These six predictors of overall survival (OS) in advanced RCC include performance status (<80%), time since diagnosis (<12 months), hemoglobin (<LLN), neutrophil count (>ULN), platelet count (>ULN), and corrected serum calcium (>ULN).
Favorable-risk patients that lack these IMDC criteria and can live for a number of years on systemic therapy. In a study of more than 500 patients with metastatic RCC (mRCC), 75% of favorable-risk individuals remained alive after 2 years of treatment targeting vascular endothelial growth factor (VEGF) or VEGF receptors.1 Median OS time was not reached among favorable-risk patients, was 23 months among intermediate-risk patients (those with 1-2 risk factors), and was 8 months among poor-risk patients (those with 3-6 risk factors).1 A large multicenter cohort study validated these findings, with respective median OS times of 43.2 months (0 IMDC criteria), 22.5 months (1-2 IMDC criteria), and 7.8 months (3-6 IMDC criteria)(P < .0001).2
After applying IMDC risk criteria, I follow the decision-making algorithm recently described by Drs. Toni Choueiri and Robert Motzer.3 If the kidney is in place and the patient has 0-2 IMDC risk criteria, I consider upfront cytoreductive nephrectomy.1 Recent data has suggested those patients with more than 3 IMDC criteria may not benefit from cytoreductive nephrectomy. For poorer-risk patients (3-6 IMDC risk criteria) and those who are post-nephrectomy, I offer a tyrosine kinase inhibitor (TKI), usually sunitinib or pazopanib. These are equally effective in the first line, although pazopanib may confer better quality of life due to reduced risk of severe fatigue, diarrhea, and hand and foot syndrome.
Because rates of complete response (CR) are usually only about 2-3% for TKI therapies and 9% with high-dose interleukin-2 therapy, 5-7 there’s been an aggressive return to the use of metastasectomy in managing mRCC.3 Whether we urologists administer systemic therapy or not, we should see our patients with mRCC every 3-6 months to evaluate their potential need for surgical resection of isolated lung nodules, liver lesions, and/or bone lesions.
Also, keep in mind that observation alone can be appropriate for the minority of favorable-risk patients who have indolent, low-volume mRCC.34 This approach prevents unnecessary toxicity without compromising treatment response when patients do start anti-angiogenic therapy.4 Active surveillance for these patients should include regular CT scans every 3-6 months.
First-Line Targeted Therapies
New trials and approvals have enriched our options for first-line targeted therapy of advanced and metastatic RCC but they’ve also created challenges in treatment sequencing.
Within this context, I find guidelines from the European Society for Medical Oncology (ESMO) especially helpful.12 The authors summarize standard first-line treatments for favorable and intermediate-risk RCC, including sunitinib, pazopanib, and bevacizumab plus interferon.8,10-12 The mTOR inhibitor temsirolimus was often used for poor-risk patients but is being supplanted by sunitinib, which has shown good efficacy in poor-risk patients.9 and for that reason I rarely use temsirolimus anymore.
Another useful resource is the Canadian Consensus Guidelines 2017, which reiterates the current standard of first-line therapy with a TKI (sunitinb or pazopanib) or bevacizumab-interferon therapy.13
Sunitinib or pazopanib?
Sunitinib and pazopanib have shown particular efficacy against advanced and mRCC.10,11 In a large randomized phase III trial, treatment with sunitinib typically at least doubled progression-free survival (PFS) time compared with interferon-alfa therapy (median PFS, 11 months vs. 5.1 months; hazard ratio [HR] for progression or death, 0.42; 95% confidence interval [CI], 0.32 to 0.54; P < .001).11 In a separate large phase III trial, median PFS was 9.2 months with pazopanib versus 4.2 months with placebo (HR, 0.46; 95% CI, 0.34 to 0.62; P < .0001).10
So how do we choose between sunitinib and pazopanib? The COMPARZ study (NCT00720941) randomly assigned 1,110 patients with treatment-naive clear-cell mRCC to receive pazo- panib (800 mg/day) or sunitinib (50 mg/day for four weeks on and two weeks off; a 4:2 schedule), typically for 8 months.14 The primary endpoint, PFS, was similar between arms (median PFS, 8.4 months [95% CI, 8.3 to 10.9 months] for pazopanib vs. 9.5 months [8.2 to 11.1 months] for sunitinib (HR, 1.05; 0.90 to 1.22), as was a key secondary endpoint, OS (median, 28.4 and 29.3 months, respectively).
While COMPARZ found pazopanib was non-inferior to sunitinib, the safety analysis revealed important differences.14 The sunitinib arm had significantly higher rates of grade 3-4 fatigue, hand-foot syndrome, mucosal inflammation, leukopenia, thrombocytopenia, lymphocytopenia, neutropenia, anemia, hypophosphatemia, hypomagnesemia, and hypermagnesemia, while the pazopanib arm was at significantly greater risk of liver toxicity. Elevations in ALT were especially common (all-grade: 60% with pazopanib vs. 43% for sunitinib; grade 3-4: 15% vs. less than 5%), but patients also developed AST and alkaline phosphatase increases.
Real-world or community studies shed more light on pazopanib’s hepatotoxic potential. In an observational study of outpatients who received pazopanib for mRCC, about 21 to 51 patients developed ALT increases of at least twice the upper limit of normal for every 100 person-years of exposure. Importantly, the treatment caused no cases of hepatocellular injury sufficient to cause new-onset hyperbilirubinemia, which is a marker of a drug’s potential to induce life-threatening hepatic injury.16
My take-home point is to monitor liver function every 2 weeks for the first 8 weeks when patients are starting pazopanib. If patients develop elevated ALT or AST levels, stop treatment and then re-start after their values normalize. In my experience, about 70% of patients will not develop recurrent liver toxicity after re-starting pazopanib at half strength (400mg).
When choosing between pazopanib and sunitinib, it’s also useful study to consider PISCES, a double-blind crossover trial of 114 mRCC patients who were randomized to either pazopanib (800 mg/day for 10 weeks), followed by a 2-week washout period, followed by sunitinib (50 mg per day on a 4:2 schedule for 10 weeks) or to the opposite sequence of therapy.8 The primary endpoint was treatment preference. Fully 70% of patients preferred pazopanib, and most said it was because they had less fatigue and diarrhea and better quality of life. 22% of patients preferred sunitinib and only 8% had no preference (P < .001). Notably, the intention-to-treat analysis and all preplanned subgroup analyses all favored pazopanib.
The alternative 2:1 sunitinib schedule
The adverse effects of sunitinib tend to be worst during the third and fourth week of treatment,18,19 which can force dose reductions that potentially reduce efficacy. To address this problem, several studies have explored a 2:1 (2 weeks on, 1 week off) dosing schedule as an alternative to the FDA-approved 4:2 schedule.19-21, 23 The results support 2:1 dosing as a worthwhile alternative that may reduce toxicity.
For example, in a study of 208 mRCC patients, switching from a 4:2 to a 2:1 schedule reduced the rate of grade 3 or worse toxicities from 46% to 8% (P < .001).20 (In an external control group of patients who stayed on a 4:2 schedule, 29% developed grade 3 or worse adverse events.)20
In a second study, only 27% of patients required dose interruptions for toxicity on a 2:1 sunitinib schedule versus 53% of patients on a 4:2 schedule (P = .04).23 The 2:1 group had significantly lower rates of hand-foot syndrome and diarrhea but resembled the 4:2 group in terms of efficacy outcomes, including dose intensity, median PFS time, and objective response. Comparing data from five of these observational studies19-23 with the COMPARZ trial14 and the sunitinib registrational trial6 also shows that a 2:1 schedule consistently reduces adverse events without compromising efficacy.
Manage to toxicity
Studies of alternative sunitinib schedules have not been FDA-reviewed, but they’re compelling enough that Pfizer, the maker of sunitinib, recommends considering switching to a 2:1 schedule when needed instead of dose-reducing.44
This approach makes sense because sunitinib dose determines efficacy. For example, in a pharmacokinetic study of more than 400 patients, an above-median sunitinib area under the curve (AUC) was associated with significantly lower rates of tumor progression (risk ratio [RR], 0.52; P = .001) and death (RR, 0.49; P = .014).17
In other words, patients who can tolerate 50 mg daily sunitinib tend to have better outcomes, and those who can tolerate higher doses may do even better. I recommend dosing to toxicity to maximize patient’s chances of tolerating and doing well on sunitinib. Some of my patients on 62.5 mg or 75 mg/day because they can tolerate those doses, while others are on 37.5 mg or 25 mg/day because they could not tolerate 50 mg/day on a 2:1 schedule. We have no biomarker yet to help us individualize TKI dose. For now, toxicity is the biomarker.
Additional tips on TKI toxicities
Guidelines describe many other useful strategies for managing TKI toxicities.24,25 Here are a few brief tips. For fatigue, be sure to rule out anemia. For hand-foot-syndrome, urea-based creams can be very helpful. A dose of loperamide after each bowel movement is usually adequate to manage diarrhea, but if not, consider dose reduction.
For patients who develop hypertension, I usually prescribe a calcium channel blocker such as amlodipine (5 to 10 mg once daily). Internal medicine or cardiology consults can be very useful if blood pressure remains uncontrolled on single-agent antihypertensive therapy. Also, many cancer centers now have cardio-oncologists who are helpful in co-managing these patients.
A seamless and responsive call schedule is essential for safely managing systemic cancer therapy. In my clinic, two physicians regularly treat advanced RCC but several more are trained to provide on-call support.
The multikinase inhibitor cabozantinib has been approved for the second-line treatment of advanced RCC since 2012.26 However, more recent data suggest it might be an appropriate first-line treatment for intermediate-risk or poor-risk disease.1,3,27,28
In the open-label, randomized, phase II CABOSUN trial, 157 intermediate-risk and poor-risk RCC patients received either first-line cabozantinib (60 mg orally daily) or sunitinib (50 mg; 4:2 schedule).27,28 Median PFS time was 8.6 months (95% CI, 6.8 to 14 months) for cabozantinib, versus 5.3 months (3.0 to 8.2 months) for sunitinib (HR, 0.48; 95% CI, 0.31 to 0.74; P = .0008).28 However, cabozantinib did not significantly outperform sunitinib in terms of median OS (26.6 months and 21.2 months, respectively; HR, 0.79, 0.53 to 1.2; P = 0.27). Cabozantinib and sunitinib had similar rates of treatment discontinuation and grade 3-4 adverse events.28 Hypertension was more common with cabozantinib (all-grade: 67%; grade 3-4: 28%) than sunitinib (44%; 21%, respectively).32
Based on these data, the FDA approved cabozantinib for the first-line treatment of advanced RCC in December 2017.29 However, keep in mind that CABOSUN was a small phase II trial with fewer than 80 patients per arm. Although the data were independently reviewed and the statistical methods were sound, sunitinib appeared to underperform in CABOSUN compared to other trials of similar populations. Patients received a 4:2 treatment schedule, raising questions about whether toxicities led to under-dosing of sunitinib. The findings of CABOSUN merit phase III validation, but this Phase II CABOSUN gives us compelling data on the efficacy of cabozantinib in the intermediate and poor-risk mRCC patient.
First-Line Immunotherapy for RCC
Immunotherapy for RCC is not new; high-dose interleukin-2 therapy predates anti-angiogenic treatments.30,31 Responses to IL-2 can be highly durable – in a study of 255 mRCC patients who received high-dose IL-2 (600,000 or 720,000 IU/kg every 8 hours for up to 14 consecutive doses), only 7% had a CR, but objective responses lasted a median of 54 months and up to 11 years.33
Based on such data, I consider high-dose IL-2 for particular patients, such as those who are younger and have low-volume RCC with pulmonary metastases. However, the advent of newer immuno-oncologic (IO) drugs is shifting immunotherapy toward the forefront of treatment for a broader range of patients.39
Of particular importance is the phase III CheckMate-214 trial, which compared frontline combination nivolumab (a PD-1 checkpoint inhibitor previously approved for the second-line treatment of advanced RCC) plus ipilimumab therapy with sunitinib in 1,096 patients with mRCC.35 Patients were randomly assigned to nivolumab (3 mg/kg IV) plus ipilimumab (1 mg/kg IV) every 3 weeks for four doses, followed by long-term nivolumab monotherapy (3 mg/IV every 2 weeks), or to sunitinib 50 mg orally once daily. Minimum follow-up time was 17.5-months.
The topline trial readout sparked substantial attention at the most recent ESMO meeting and the results have been recently published in NEJM. Among 847 intermediate or poor-risk patients, median OS was not reached with nivolumab-ipilimumab (95% CI, 28.2 months to not estimable) and was 26 months (22.1 months to not estimable) with sunitinib (HR, 0.63; 99.8% CI, 0.44 to 0.89; P < .0001).35 CheckMate-214 was the first study to meet its co-primary OS endpoint in this treatment setting. Importantly, however, sunitinib outperformed nivolumab-ip- ipilimumab among favorable-risk patients. In this subgroup, rates of overall response were 52% and 29%, respectively (P = .0002) and median PFS was 25.1 months versus 15.3 months (HR, 2.2; P < .0001).35 Exploratory analyses indicated that nivolumab-ipilimumab was superior to sunitinib when patients had more than 1% of tumor cells expressing PD-L1 (HR, 0.48 (0.28 to 0.82; P = .0003), but was comparable to sunitinib when patients had less than 1% PD-L1 expression (median PFS, 11.0 vs. 10.4 months, respectively; P = .97).35 Intermediate-risk and poor-risk patients usually had higher levels of PD-1 expression than did favorable-risk patients, which seemed to explain why these subgroups had such different IO treatment outcomes.35
The results of CheckMate-214 may change the RCC treatment paradigm and already have triggered updated guidelines from the European Association of Urology.36 However, we need longer follow-up data and OS data to determine if PD-L1 expression is a reliable biomarker for treatment response. Based on what we know now, nivolumab-ipilimumab may become a new standard first-line option for intermediate and poor-risk RCC. For favorable-risk disease, first-line TKI therapy (e.g. sunitinib or pazopanib) may be a better option.
Managing IO toxicities
CheckMate-214 data showed acceptable toxicity for nivolumab-ipilimumab in the first-line RCC treatment setting.35 Grade 3 or higher adverse events affected 46% of patients versus 63% of those who received sunitinib. The most common grade 3 or higher adverse events in the IO arm were immune-related hepatitis (6%), colitis (5%), fatigue (4%), adrenal insufficiency (3%), and hypophysitis (3%), and 60% of patients required systemic corticosteroids to help control these symptoms. Sunitinib therapy was most likely to cause grade 3 hypertension (16%), hand-foot syndrome (9%), and fatigue (9%), reflecting its known safety profile.35
It’s also important to keep in mind that not all patients are candidates for IO therapy. Autoimmune disease, poor performance status, and comorbidities all are potentially exclusionary. For such patients, individualized TKI therapy has been a reasonable treatment option with potentially good outcomes. It also remains unclear whether combination or individually sequenced checkpoint-TKI therapy might produce better OS results than standard sunitinib therapy. Various trials are examining these combinations39 and we await final results.
A number of publications offer helpful guidance on managing immuno-oncologic toxicities.37,38 Keep in mind that these are manageable if the entire treatment team commits to thorough, timely patient/caregiver education, surveillance, intervention, and referrals when needed. Patients who receive IOs need to understand that immune-related adverse events can occur at any time during treatment and to promptly report symptoms of hepatitis, adrenal crisis, pneumonitis, colitis, or rash. Toxicities worse than grade 1 merit treatment interruption and corticosteroids; patients should resume IO therapy only after they are off corticosteroids and their symptoms have resolved or have improved to grade 1.38 For grade 3 toxicities, permanently discontinue IO therapy if symptoms don’t improve within 4-6 weeks. For grade 4 toxicities, stop treatment permanently regardless of how fast patients improve with immunosuppressive therapy.38 Consult promptly with medical oncology colleagues and other specialists when needed.
Adjuvant Therapy for High-Risk Resected RCC
Adjuvant systemic therapy is an important consideration for patients with high-risk resected RCC. In the ideal scenario, such a patient is at very high risk of recurrence and receives an adjuvant drug with substantial activity against microscopic cancer, clinically meaningful outcomes, and low toxicity and cost. The reality is, of course, more complicated.
Trials with readouts
Several clinical trials have evaluated TKI agents for the adjuvant treatment of renal RCC post-nephrectomy. The ASSURE study, which compared adjuvant sunitinib, sorafenib, and placebo, suffered from high drop-out rates because of toxicities and found no significant differences in terms of OS or disease-free survival (DFS).40 The trial design may have contributed to its negative readout; only half of patients were classified as high-risk (pT3-pT4, grade 3-4) for recurrence (a proxy for adherence to therapy) with a substantial number of intermediate risk patients, not all patients had clear-cell histology, the starting dose changed mid-trial, and dose reductions were permitted.40
In contrast, the phase III S-TRAC trial of adjuvant sunitinib only enrolled patients with high-risk locoregional clear-cell RCC, consistently started patients at 50 mg, and only permitted dose reductions to 37.5 mg.41 The dropout rate was much lower than in the ASSURE trial and, after a median follow-up period of 5.4 years, adjuvant sunitinib prolonged DFS by a median of 1.2 years compared with placebo (HR, 0.76; 95% CI, 0.59 to 0.98; P = .03).41 These findings led the FDA to approve sunitinib for the adjuvant treatment of high-risk RCC after nephrectomy.42 Although OS data from S-TRAC are pending, it appears that the regimen can delay the onset of metastasis in disease-free patients, an important consideration given the rapid pace of clinical research. I myself have a number of post-surgical high-risk for recurrence (pT3 and greater) RCC patients on adjuvant sunitinib therapy outside of clinical trials.
We also have data on adjuvant pazopanib. In the PROTECT trial, 1 year of treatment (600 mg pazopanib) did not improve DFS compared with placebo among intermediate-risk patients (HR: 0.86; 95% CI, 0.70 to 1.01).43 This result once again backs the hypothesis that adjuvant therapy is less beneficial when patients are less concerned about imminent disease progression, and likely most beneficial in the highest-risk for recurrence patient.
Adjuvant pazopanib did show a more pronounced 31% risk reduction among PROTECT participants who received 800 mg pazopanib, which was the initial starting dose before toxicities led to a trial-wide dose reduction.43 However, there is no indication that pazopanib’s maker will pursue an FDA approval for RCC in the adjuvant setting at this time.
Ongoing and recruiting trials
We also await results from trials of adjuvant sorafenib (SORCE; NCT00492258), axitinib (ATLAS; NCT01599754), and everolimus (EVEREST or S0931; NCT01120249). Finally, five trials of adjuvant therapy in RCC are currently recruiting: IMmotion010 (NCT03024996) compares adjuvant atezolizumab (1200 mg
IV every 3 weeks for 1 year) with placebo in post-metastasectomy patients with clear-cell or sarcomatoid RCC; PROSPER (NCT03055013) compares nephrectomy with or without nivolumab in patients with all histologies of RCC; KEYNOTE-564 (NCT03142334) compares adjuvant pembrolizumab with placebo in patients with clear-cell RCC; and CheckMate-914 (NCT03138512) is comparing nivolumab-ipilimumab with placebo in patients with clear-cell or sarcomatoid RCC.
In summary, patients whose RCC is at high risk of recurrence should talk with an educated urologist and/or oncologist about the potential benefits of adjuvant therapy. Motivated patients who are interested to pursue this option need to understand the available data and potential DFS benefits of adjuvant sunitinib.
Written by: Anil Kapoor, MD, Professor of Surgery (Urology & Oncology) at McMaster University/ St. Joseph’s Hospital in Hamilton, Ontario, Canada.
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- Klapper JA, Downey SG, Smith FO, et al. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma: a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer 2008;113(2):293-301.
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- Shantakumar S, Nordstrom BL, Djousse L, et al. Occurrence of hepatotoxicity with pazopanib and other anti-VEGF treatments for renal cell carcinoma: an observational study utilizing a distributed database network. Cancer Chemother Pharmacol 2016;78(3):559-566.
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