Until the introduction of targeted therapy (discussed in more detail in the later section on targeted therapy), metastatic resection and cytokine therapy remained the only viable treatment options in mRCC. Interferon-α and IL-2 have been extensively evaluated over the past three decades. In a randomized phase II study from MDACC, treatment with low-dose IFN-α-2b compared to intermediate-dose IFN-α-2b resulted in no significant differences in progression-free survival (PFS) or OS, but patients had an improved quality of life while on low-dose therapy (38). Sustained complete remissions with IFN-α are rare (1%-2%), and with the relatively low response rate of approximately 7%, IFN-α monotherapy never received US Food and Drug Administration (FDA) approval for treatment of mRCC and is no longer considered as a single agent for mRCC at MDACC.
High-dose IL-2 (HD IL-2) received FDA approval in the treatment of mRCC in 1992 based on the results of several phase II trials that found an overall response rate of 15% to 20% and a durable response in the majority of patients who achieved a complete response. A phase III trial comparing HD IL-2 with an outpatient low-dose IL-2 plus IFN-α regimen yielded a higher response rate to HD IL-2 of 23% versus 10% but no statistically significant differences in PFS and OS. However, durable responses of greater than 3 years were seen in 7% of those treated with HD IL-2 versus 0% of patients in the other arm, supporting HD IL-2 as a viable standard-of-care option for patients who are candidates for this therapy (39). Although the management of toxicity related to the delivery of HD IL-2 is challenging, high-volume centers have published a toxic death rate of less than 1%, with response rates of roughly 15% to 20% and durable remissions in the range of 5% to 7% (40,41). Given the ability to produce a sustained remission with likely cure in a small subset of patients, at MDACC, we offer frontline HD IL-2 therapy to patients with excellent performance status, previous nephrectomy, limited or no comorbidities, and low-volume metastatic disease burden, especially lung-only disease.
Over the last decade, seven agents have been FDA approved for the treatment of mRCC. Of these agents, five are vascular endothelial growth factor (VEGF) pathway–blocking agents, with four being within the small-molecule tyrosine kinase inhibitor family and one, bevacizumab, being a monoclonal antibody directed against VEGF on the cell surface. The remaining two agents are mammalian target of rapamycin (mTOR) inhibitors. These agents target both the tumor cells and the tumor microenvironment.
Vascular Endothelial Growth Factor, or Vascular Endothelial Growth Factor Receptor–Targeted Agents
The presence of a VHL mutation in up to 80% of patients with ccRCC and the resultant increased production of angiogenic factors has made this axis the most exploited treatment target. A number of agents that target either VEGF or its receptors (VEGFR) were FDA approved in the past 10 years (Table 35-3).
Table 35-3Phase III Studies Leading to Approval of Molecularly Targeted Agents in Renal Cell Carcinoma ||Download (.pdf) Table 35-3 Phase III Studies Leading to Approval of Molecularly Targeted Agents in Renal Cell Carcinoma
|Agent ||Year FDA Approved ||Trial Design ||Setting ||No. of Patients ||MSKCC Risk (%) ||Median PFS (months) ||Median OS (months) |
|Sorafenib ||2005 ||Sorafenib vs placebo || |
|903 || |
|5.5 vs 2.8 ||19.3 vs 15.9 (NS) |
|Sunitinib ||2006 ||Sunitinib vs IFN || |
|750 || |
|11.0 vs 5.0 ||26.4 vs 21.8 (P = .051) |
|Temsirolimus ||2007 ||Temsirolimus vs temsirolimus plus IFN vs IFN ||Frontline Any histology ||626 || |
|5.5 vs 4.7 vs 3.1 ||10.9 vs 8.4 vs 7.3 |
|Everolimus ||2009 ||Everolimus vs placebo || |
Sorafenib or sunitinib failures
|416 || |
|4.9 vs 1.9 ||14.8 vs 14.4 |
|Bevacizumab plus IFN-α ||2009 ||Bevacizumab plus IFN vs IFN plus placebo || |
|649 || |
|10.2 vs 5.4 ||23.3 vs 21.8 |
| || ||Bevacizumab plus IFN vs IFN || |
|732 || |
|8.5 vs 5.2 ||18.3 vs 17.4 |
|Pazopanib ||2009 ||Pazopanib vs placebo || |
Frontline and cytokine failures
|435 || |
|11.1 vs 2.8 ||22.9 vs 20.5 |
|Axitinib ||2012 ||Axitinib vs sorafenib || |
|723 || |
|6.7 vs 4.7 ||20.1 vs 19.2 |
Bevacizumab is a humanized recombinant anti-VEGF antibody. Two large randomized phase III studies demonstrated an improved PFS in patients who received a combination of bevacizumab plus IFN-α, when compared to IFN-α alone in patients with mRCC who had not received prior systemic therapy (42,43). The AVOREN study compared patients treated with the combination of bevacizumab plus IFN versus placebo plus IFN and found that the bevacizumab combination resulted in a superior median PFS of 10.2 months compared to 5.4 months. The Cancer and Leukemia Group B (CALGB) 90206 study yielded a median PFS of 8.5 months for the combination arm versus 5.2 months for IFN monotherapy, a difference that was statistically significant. Of note, the OS for both studies was numerically superior in the bevacizumab-containing arm but did not reach statistical significance. Bevacizumab plus IFN was FDA approved for advanced RCC in 2009.
Sorafenib is an orally bioavailable small-molecule inhibitor of VEGFR, platelet-derived growth factor receptor (PDGFR), and Raf and was FDA approved in 2005 for the treatment of advanced RCC. In a randomized phase III trial, sorafenib yielded a significant improvement in PFS compared to placebo (median, 5.5 vs 2.8 months) in patients who had failed one prior therapy, with the majority having received prior cytokines (44). A phase II study compared sorafenib monotherapy to sorafenib plus IFN-α and found similar overall response rates, toxicity, and median PFS, leading further exploration of this combination to be abandoned (45).
Sunitinib is an oral inhibitor of VEGFR and PDGFR. When it was first tested in the cytokine-refractory population, a time to progression of 8.7 months was achieved (46), earning it provisional FDA approval in early 2006. A follow-up first-line phase III trial randomizing patients between sunitinib and IFN showed a median PFS of 11.0 months for sunitinib versus 5.0 months for IFN (47). Median OS of sunitinib-treated patients was 26.4 months versus 21.8 months for the IFN-treated group (P = .051), which although not statistically significant was likely due to crossover from IFN to sunitinib and salvage therapy after protocol (48). When a subgroup analysis of the individuals who did not receive any subsequent therapy was performed, it was found that those who received sunitinib had a median OS of 28 months versus 14 months for the IFN group.
Pazopanib is an oral small molecule with a lower half-maximal inhibitory concentration (IC50) for VEGFR when compared to sorafenib and sunitinib (49). A randomized, phase III trial compared pazopanib to placebo in patients treated with a cytokine and previously untreated patients and demonstrated an overall PFS of 9.2 versus 4.2 months (hazard ratio, 0.46; 95% confidence interval, 0.34-0.62; P < .0000001 (50). Pazopanib was FDA approved in 2009 for the first-line treatment of advanced RCC. Pazopanib has not been evaluated prospectively after first-line targeted therapy. At MDACC, we retrospectively studied 93 patients who received targeted therapy preceding pazopanib and observed an overall response rate of 15%, a median PFS of 6.5 months, and a median OS of 18.1 months (51). Adverse events were similar to those described in the large prospective trials with the agent.
Axitinib is a selective small-molecular inhibitor of the VEGFR-1, VEGFR-2, and VEGFR-3 signaling pathways (52). In a randomized phase III trial, axitinib was compared to sorafenib as second-line therapy after sunitinib, cytokines, bevacizumab plus IFN, or temsirolimus. The overall median PFS time was 6.7 versus 4.7 months in favor of axitinib (53). Median OS was not statistically different between the two groups (20.1 months for axitinib and 19.2 months for sorafenib) (54). The largest difference between the two arms was in patients previously treated with cytokines. Patients who developed hypertension with a diastolic blood pressure of greater than 90 mm Hg on trial had a significantly improved survival in both treatment arms as compared to patients who remained normotensive. When axitinib was compared with sorafenib in the first-line setting, the median PFS was 10.1 months with axitinib and 6.5 months with sorafenib with overlapping confidence intervals. Despite the numerically longer PFS with axitinib, the difference did not reach the trial’s prespecified threshold of statistical significance (55).
Mammalian Target of Rapamycin Inhibitors
Temsirolimus is an intravenous sirolimus ester that was tested in intermediate- and poor-risk patients after phase II data had suggested that this was the subgroup of patients most likely to benefit from temsirolimus (56). This first-line phase III trial randomized patients to temsirolimus, temsirolimus plus IFN, or IFN monotherapy. The median OS in the temsirolimus arm was 10.9 months versus 8.4 months for the combination arm and 7.3 months for IFN monotherapy (57). An elevated pretreatment serum lactate dehydrogenase was found to be both a predictive and prognostic biomarker in patients treated with temsirolimus compared to IFN (OS, 6.9 vs 4.2 months, P < .002) (58).
Everolimus is an orally bioavailable sirolimus ester that was evaluated in patients who had progressed on sorafenib, sunitinib, or both. This phase III trial (RECORD-1) randomized patients between everolimus 10 mg by mouth daily versus placebo in a 2:1 fashion. Median PFS was 4.0 months with everolimus versus 1.9 months with placebo (59).
Because everolimus and temsirolimus are mTORC1 inhibitors, agents capable of blocking both the mTORC1 and mTORC2 pathways have been developed. In a recent study comparing everolimus with GDC-0980, a pan PI3K and TORC1/2 inhibitor, the median PFS was 6.1 months with everolimus versus 3.7 months with the investigational agent, with a higher rate of adverse events in the investigational arm (60). The reasons for this surprising result are unclear at this time.
The major side effects of the targeted agents are summarized in Table 35-4.
Table 35-4Summary of Side Effects of Targeted Agents Approved in Renal Cell Carcinoma ||Download (.pdf) Table 35-4 Summary of Side Effects of Targeted Agents Approved in Renal Cell Carcinoma
|Agent ||Sorafenib ||Sunitinib ||Bevacizumab ||Pazopanib ||Temsirolimus ||Everolimus ||Axitinib |
|Hypertension ||X/X ||XX/– ||XX/X ||XX/X || || ||XX/X |
|Fatigue ||XX/X ||XXX/X ||XX/X ||X/X ||XX/X ||X/X ||XX/X |
|Hand-foot skin reaction ||XX/X ||XX/X || ||XX/X || || ||XX/X |
|Diarrhea ||XX/X ||XX || ||XXX/X ||XX/X ||X/X ||XXX/X |
|Dysgeusia ||X /– ||XX/X || ||X/ || || || |
|Stomatitis ||X/X ||X/X || || ||X/X ||XX/X ||X/X |
|Cardiac toxicity ||X/X ||X/X ||X/X ||X/X || || || |
|Nausea ||X/X ||XX/X || || || ||X/0 ||XX/X |
|Asthenia ||XX/X ||X/X ||XX/XX || ||XX/X ||X/X ||X/X |
|Pulmonary toxicity ||X/X || || || ||X/X ||X/X || |
|Hepatotoxicity || ||XX/X || ||XXX/XX || ||XX/X || |
|Hypertriglyceridemia || || || || ||XX/X ||XXX/X || |
|Rash ||XX/X ||X/X || || ||XX/X ||XX/X ||X/X |
|Hyperglycemia || || || ||XX/X ||XX/X ||XX/X || |
|Hypothyroidism ||X/– ||X/0 ||? ||X/– || || ||X/X |
|Proteinuria ||X/X ||X/X ||X/X ||X/X || || || |
|Cytopenias ||X/X ||XXX/X ||X/X ||XX/X ||XX/X ||XXX/X ||XX/X |
|Increased creatinine ||X/X ||XXX/X ||X/X ||XX/X ||X/X ||X/X ||X/0 |
Blockade of VEGFRs or depletion of the VEGF ligand causes class effects, which include hypertension, fatigue, proteinuria, and a slightly increased risk of bleeding and thromboembolic events. All of the anti-VEGF agents will cause these side effects to varying degrees. Sorafenib, sunitinib, and pazopanib are also inhibitors of PDGF, Flt3, and a number of other receptor tyrosine kinases and thus will induce hand-foot syndrome, diarrhea, and dysgeusia. Sunitinib appears to be particularly prone to inducing hypothyroidism (61,62) and, in some cases, cardiomyopathy with decreased ejection fraction (63). The frequency of cardiac toxicity may be underappreciated. A single-institution experience from Stanford found that 33% of patients had evidence of cardiac toxicity even when excluding hypertension (64). The rate of heart failure induced by sunitinib at MDACC in the treatment of a variety of tumor types including mRCC was 2.7% (65). Emerging data suggest that scrupulous control of blood pressure in patients on sunitinib will decrease cardiac stress and resultant cardiac failure.
Other side effects include wound dehiscence and increased thromboembolic events. Our group reported perioperative complications in patients with mRCC and primary in situ who received antiangiogenic agents in the presurgical setting prior to cytoreductive nephrectomy. In a single-arm phase II trial (35), perioperative wound healing complications in patients who received 8 weeks of bevacizumab therapy were increased when compared to a set of matched controls. The retrospective study, which looked at 44 individuals who received sorafenib, sunitinib, or bevacizumab preoperatively, did not detect a significant elevation of any perioperative events (66).
The mTOR inhibitors demonstrate several unique side effects, including hyperglycemia, hypertriglyceridemia, and noninfectious pneumonitis. However, these agents are not as likely to induce hypertension or hand-foot skin reaction.
Agent Selection and Side Effect Management
A number of different factors are important when choosing the best initial agent for patients with metastatic ccRCC. Clearly, evidence-based criteria for selection are vital, but as seen in Fig. 35-3, there are several agents available for a particular treatment stage.
The University of Texas MD Anderson Cancer Center approach to initial systemic treatment lines for patients with metastatic clear cell renal cell carcinoma. HD IL-2, high-dose interleukin-2; mTOR, mammalian target of rapamycin VEGF, vascular endothelial growth factor.
For example, if we are dealing with a patient who has undergone nephrectomy, has good-risk characteristics, and is younger than age 70 years, HD IL-2, sunitinib, bevacizumab plus IFN, and pazopanib are all reasonable options. In the COMPARZ trial, a noninferiority phase III trial with PFS as the primary end point, sunitinib and pazopanib were directly compared (67). The trial showed noninferiority of pazopanib. Importantly, the side effect profile and quality-of-life assessment favored pazopanib. Consequently, we prefer pazopanib over the standard dosing schedule of sunitinib and over bevacizumab plus IFN given the relative ease of patient administration. Although HD IL-2 is often offered, many patients are not interested to receive it because of the low likelihood of success and the formidable toxicity.
Table 35-4 provides a summary of some of the most common side effects seen with these agents. A review of these side effects may aid in treatment selection for specific patients. Some may have occupational considerations that make hand-foot skin reaction a particular problem. Others may have cardiac comorbidities that make an agent like sunitinib, with a known effect on cardiac output in a subset of patients, less favorable. Table 35-5 summarizes the standard dose-reduction algorithms used in clinical trials of these agents.
Table 35-5Dose Reduction Algorithm Used in Pivotal Trials of Approved Targeted Agentsa ||Download (.pdf) Table 35-5 Dose Reduction Algorithm Used in Pivotal Trials of Approved Targeted Agentsa
|Agent ||Standard Dose ||Dose Reduction Schema |
|Sorafenib ||400 mg PO bid ||Dose level 1: 400 mg PO daily |
| || ||Dose level 2: 400 mg PO every other day |
| || ||Alternateb: Dose reduction to 600 mg PO daily |
|Sunitinib ||50 mg PO daily 4 weeks on, followed by 2 weeks off ||Dose level 1: 37.5 mg PO daily, 4 weeks on, 2 weeks off |
| || ||Dose level 2: 25 mg PO daily, 4 weeks on, 2 weeks off |
| || ||Alternateb: Schedule change to 50 mg PO 14 days on and 7 days off |
|Temsirolimus ||25 mg IV weekly ||Dose level 1: 20 mg IV weekly |
| || ||Dose level 2: 15 mg IV weekly |
|Everolimus ||10 mg PO daily || |
Dose level 1: 5 mg PO daily
Dose level 2: 5 mg PO every other day
|Bevacizumab plus IFN ||Bevacizumab 10 mg/kg IV every 14 days; IFN 9 MU SC TIW || |
IFN: Dose level 1: 6 MU SC TIW
Dose level 2: 3 MU SC TIW
| || ||Bevacizumab: for proteinuria: If greater than 2 g/dL hold until below 500 mg/dL |
|Pazopanib ||800 mg PO daily ||600 mg/d (dose level 1); 400 mg/d (dose level 2) |
|Axitinib ||5 mg PO bid ||3 mg PO bid (dose level 1); 2 mg PO bid (dose level 2) |
In addition to dose interruptions and dose reductions, a change in schedule may be beneficial for some patients. Our group and others have retrospectively compared cohorts of patients treated on the standard sunitinib schedule of 4 weeks on, 2 weeks off with a schedule of 2 weeks on and 1 week off (68). The 2-week-on, 1-week-off schedule has a better toxicity profile and retrospectively has similar treatment efficacy compared with the standard approach (69). However, prospective comparison of the two treatment schedules has not been reported.
Symptom control is essential for patients receiving molecularly targeted agents. Table 35-6 outlines supportive care measures that can mitigate or prevent specific side effects. It is essential that the patient and health-care team maintain an ongoing dialogue during each cycle of therapy to ensure that patients proactively and appropriately manage these adverse events. Successful adverse event management will translate into higher drug compliance and a greater probability of achieving a successful outcome.
Table 35-6Management Recommendations for Commonly Experienced Toxicities ||Download (.pdf) Table 35-6 Management Recommendations for Commonly Experienced Toxicities
|Side Effect ||Preventative Measures ||Supportive Care Measures |
|Diarrhea ||In patients with prior history of diarrhea on agent, consider loperamide once daily in morning ||Loperamide 1-2 tabs after diarrhea ||Diphenoxylate plus atropine ||1 scoop psyllium with 1 oz water daily |
|Hand-foot syndrome ||Heavy emollients applied to hands and feet bid and prn ||As in preventive measures, plus urea-based callus creams || || |
|Fatigue ||Regular physical activity ||Consider modafenil or methylphenidate ||Check thyroid function || |
|Hypertension || || |
Maintain BP below 140/90 using:
Calcium channel blockers (amlodipine okay but not diltiazem)
Angiotensin-converting enzyme inhibitors
| || |
|Hypothyroidism || ||Levothyroxine || || |
|Dysgeusia ||Salt and soda mouthwash 4 times a day || |
Avoidance of hot and spicy foods
Salt and soda mouthwash
|Carafate || |
|Mouth sores ||Salt and soda mouthwash 4 times a day ||Xylocaine-based mouthwash || || |
|Hyperglycemia ||Scrupulous glycemic control ||Scrupulous glycemic control || || |
|Rash (sorafenib) || || |
| || |
|Rash (temsirolimus and everolimus) || ||Topical steroids || || |
|Noninfectious pneumonitis (temsirolimus and everolimus) || ||Corticosteroids || || |
A retrospective review of patients treated with temsirolimus or everolimus at MDACC found a rate of noninfectious pneumonitis (NIP) of 6% with temsirolimus and 23% with everolimus (70). We observed that patients who developed NIP had longer treatment duration and longer OS. Recent guidelines have been established to diagnose and treat NIP with the important caveats that patients with radiographic findings but lacking symptoms can continue therapy and patients with radiographic findings with mild to moderate cough can continue therapy with close monitoring (71). More severe symptoms require corticosteroids with a consideration of break or permanent discontinuation of mTOR inhibitor therapy depending on the severity of the event.
The decision for second-line and later therapy has become increasingly complex. Sequencing of VEGF-VEGF–directed therapy or VEGF-mTOR–directed therapy has been compared prospectively. In a randomized phase III trial of second-line therapy in patients who received first-line sunitinib, temsirolimus was compared to sorafenib. The trial’s primary end point of detecting a superior PFS with temsirolimus was not met, with a median PFS of 4.1 months with temsirolimus and 3.7 months with sorafenib. Interestingly, the secondary end point of median OS favored the sorafenib arm (16.6 vs 12.3 months, P = .01). Although median OS was not the primary end point of the trial, the authors hypothesized that VEGF-VEGF sequencing may be more beneficial compared with the so-called “sandwich approach” of VEGF-mTOR-VEGF sequence (72). In the community, VEGF-mTOR-VEGF sequencing is the most common current treatment approach (73). In the AXIS trial, axitinib was compared to sorafenib in the second-line setting (although first-line treatment could be cytokine-based treatment) and led to an improved PFS (53). A phase II, single-arm, single-institution study found that after failure of frontline sunitinib or bevacizumab, pazopanib had activity, with a median PFS of 7.5 months (74). As such, a reasonable treatment approach for patients with good- or intermediate-risk disease by Heng criteria who are deemed good candidates for targeted therapy and do not elect to pursue HD IL-2 therapy can receive pazopanib as first-line therapy and receive axitinib or everolimus as second-line therapy. Depending on performance status and comorbidities, the decision can be made to continue with an alternative VEGF-directed therapy with sorafenib or sunitinib or change to an mTOR-directed therapy at progression. Certainly, consideration of a clinical trial should be entertained in the frontline and later line settings.
Patients who fall into the poor prognostic group remain a considerable unmet need in the care of patients with mRCC. At this time, temsirolimus remains the only agent with category 1 evidence to support its use. Ongoing trials in this setting include the FLIPPER trial (NCT01521715), which is a phase IV trial evaluating pazopanib in poor-risk mRCC, and a randomized phase II trial at MDACC comparing temsirolimus to pazopanib in the frontline setting (NCT01392183).
Combinations of Targeted Therapy
In an attempt to improve on the success of single-agent targeted therapy, combinations of VEGF and mTOR pathway blockade have been pursued. To date, combinations are associated with significant toxicity without a positive impact on response rate, PFS, or OS, as compared with sequential single-agent targeted therapy. A phase III trial compared the standard of bevacizumab plus IFN-α versus bevacizumab plus temsirolimus (75). The response rate, median PFS, and median OS were not found to be statistically different between the two treatment arms. As a result of early phase and later phase clinical trials to date, combinations of VEGF and mTOR inhibitors are unlikely to yield significant clinical benefit.