With 8 therapies approved by the US Food and Drug Administration (FDA) for the treatment of patients with advanced renal cell carcinoma (RCC), practitioners are faced with the challenge of selecting the most appropriate therapies for their patients within this crowded therapeutic landscape.

When selecting a treatment plan for a previously untreated patient with advanced RCC, practitioners must frequently think beyond the first line of therapy and approach the patient with a possible sequence of therapies already in mind. Sequential therapy with various single agents is a practical reality for most patients with advanced RCC for numerous reasons, including: (1) the availability of multiple molecularly targeted agents with distinct toxicities or mechanisms of action; (2) the fact that responses to molecularly targeted agents in RCC are typically neither complete nor durable; therefore treatment with these agents must be thought of as noncurative except in rare circumstances; and (3) the fact that combination regimens of available therapies have not demonstrated substantially improved efficacy. Therefore, the goal for the practitioner treating patients with advanced RCC must be to administer these agents sequentially so as to maximize duration of disease control and quality of life for individual patients.

Perhaps the first question a practitioner should address when faced with an untreated patient with advanced clear cell RCC is whether or not the patient is a candidate for immune therapy. Although the idea of sequential therapy is based upon the assumption that advanced RCC is incurable, it should be remembered that a subset of patients can experience durable remissions from immune therapy. In the current era, immune therapy with high-dose (HD) interleukin-2 (IL-2) is still frequently given to patients with RCC at specialized centers. While IL-2 has historically been felt to benefit only a small subset of patients, recent studies suggest that in the modern era response to HD IL-2 exceeds 25%, with approximately 8% to 10% of patients exhibiting complete responses that last for more than 2 years, although efforts to identify predictive biomarkers have not yet been successful.

These improved results are most likely the result of limiting consideration of HD IL-2 to patients with certain characteristics, such as younger age, good performance status, few medical comorbidities, clear cell tumor histology, and disease that is not rapidly growing.

With respect to sequence, several clinical trials have shown that molecularly targeted therapies, both those targeting vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR), have substantial activity in cytokine-refractory patients.

 At the same time, a small retrospective study has suggested that the efficacy of HD IL-2 following VEGF—targeted therapies may be limited.

 While the latter point must be proven prospectively, these data support the premise that HD IL-2 should be considered a primary therapy for appropriately selected patients with advanced RCC.

While first-line treatment with immune therapy outside of a clinical trial is currently limited to HD IL-2, the early clinical activity reported with PD-1 and PD-L1 antibodies suggests that this might change in the near future.

 These novel immunotherapies have shown activity in multiple clinical scenarios, however, so their eventual place in sequential therapy regimens remains unclear at present. Moreover, the durability of responses to these novel agents has yet to be fully characterized. Nonetheless, the fact that treatment with VEGF- or mTOR-targeted agents so infrequently results in durable or complete remissions supports the approach that a regimen containing an immune therapy should at least be considered first line in all patients with clear cell RCC.

Once it is determined that a patient is not a candidate for immune therapy, the practitioner must select from several different FDA-approved agents characterized by 2 broad classes: (1) VEGF-targeted agents (sunitinib, sorafenib, pazopanib, bevacizumab [plus interferon-alfa (IFN)]); and (2) mTOR inhibitors (temsirolimus) (Figure 1). Two other agents, the VEGF-targeted tyrosine kinase inhibitor (TKI) axitinib and the mTOR inhibitor everolimus, are approved only following failure of at least 1 prior therapy. The practitioner’s next decision point is affected by the assessment of the patient’s prognosis. Currently, the National Comprehensive Cancer Network (NCCN) gives a category 1 recommendation to sunitinib, pazopanib, and bevacizumab/interferon, along with a category 2A recommendation to sorafenib, for the first-line treatment of patients with predominantly clear cell advanced RCC.

Temsirolimus is also given a category 1 recommendation for the treatment with poor prognosis (defined as 3 or more of 6 poor prognostic risk factors) patients with predominantly clear cell RCC. The risk factors used by the phase III trial of temsirolimus in RCC were largely based on the Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Those criteria used 6 poor-risk prognostic factors (less than 1 year from diagnosis to the start of systemic therapy, Karnofsky performance status score of 60-70, hemoglobin level less than the lower limit of normal [LLN], corrected calcium greater than 10mg/dL, LDH >1.5 times the upper limit of normal [ULN], and metastasis to greater than 1 organ site) to define patients with poor prognosis.

 Thus, temsirolimus should be considered as a first-line agent in patients with poor- risk RCC.

At the same time, while VEGF-targeted agents have not been assessed exclusively in patients with poor prognostic features, it is clear that they have activity in this group of patients. Data supporting the efficacy of sunitib in this group of patients come from the phase III trial of sunitinib versus IFN in treatment-naïve RCC patients, the sunitinib expanded access program, and retrospective analysis.

 The largest analysis arises from the expanded access program (n = 373) in which patients in the MSKCC poor-risk group had a median progression-free survival (PFS) of 4.1 months (95% CI, 3.1-5.0) and median overall survival of 5.4 months (95% CI, 4.6-6.4).

 While similar data do not yet exist for pazopanib, a randomized phase II trial of pazopanib versus temsirolimus in patients with poor-risk RCC (NCT01392183) may provide some prospective and comparative data for this subset of patients. For now, VEGFR-targeted TKIs such as sunitinib should be considered alternative first-line therapies for patients with poor-risk RCC. For most remaining patients with clear cell RCC who do not meet poor-risk criteria, the data support the use of VEGF-targeted therapy in the first line.

The most compelling data likely come from the recently reported RECORD-3 trial, a randomized phase II trial comparing the sequence of sunitinib followed by everolimus to the sequence of everolimus followed by sunitinib with the primary objective of noninferiority of everolimus compared with sunitinib in the first line. The trial failed to meet its primary endpoint with the first-line PFS of patients treated with everolimus (n = 238) of 7.9 months versus 10.7 months for patients treated with sunitinib (HR 1.4; 95% CI, 1.2-1.8).16 In the US, most patients will likely be treated with sunitinib or pazopanib, which are both TKIs with activity against VEGF receptor 2 (VEGFR2) and platelet-derived growth factor receptor (PDGFR). While both agents carry level 1 recommendations from the NCCN, comparative data have recently been made available by the COMPARZ trial.17 In this randomized, phase III, noninferiority trial, 1110 patients with clear cell RCC were randomized in a 1:1 ratio to receive either pazopanib or sunitinib at standard dose and schedule with a primary endpoint of PFS. The median PFS of patients treated with pazopanib was 8.4 months versus 9.5 months in patients treated with sunitinib.

Pazopanib was determined to be non-inferior to sunitinib with a point estimate for the hazard ratio of disease progression or death from any cause of 1.05 (95% CI, 0.90-1.22). Patients treated with sunitinib experienced a higher incidence of fatigue (63% vs 55%), hand-foot syndrome (50% vs 23%), and thrombocytopenia (78% vs 41%) compared with patients treated with pazopanib. Patients treated with pazopanib experienced a higher incidence of alanine aminotransferase elevations (60% vs 43%) compared with patients treated with sunitinib. The appended quality of life analysis revealed that patients treated with pazopanib reported less fatigue, fewer side effects, and greater satisfaction with treatment compared with patients with sunitinib. These data are supported by the results of the PISCES study, in which 169 patients with advanced RCC were randomized to receive either sunitinib followed by pazopanib or the reverse sequence with the primary endpoint of patient preference for sunitinib or pazopanib. The final analysis revealed that significantly more patients preferred pazopanib as compared with sunitinib (71% vs 22%; P <.001) with similar results for physicians (61% vs 21%).18

While this comparative data are helpful, the most reasonable approach for practitioners is to base their treatment choice on their own prior experience and on patient characteristics. For example, practitioners might favor sunitinib for patients with underlying liver dysfunction and good baseline performance status and favor pazopanib for patients with baseline fatigue or cytopenias. Ultimately, the decision for first-line molecularly targeted agents will likely be based as much on individual practitioner preference (eg, comfort and familiarity with drug dosing and side effect management, mode of administration) as on any treatment algorithms.

The NCCN guidelines also give a category 1 recommendation to the combination of bevacizumab and interferon-a based on the results of 2 independent, randomized, phase III trials comparing the combination to interferon-a alone.

 The approval of bevacizumab in combination of interferon-a has likely limited the popularity and use of this regimen in the US. However, the available data support this combination as a viable alternative to either VEGF-targeted TKI (sunitinib or pazopanib) in the first-line space.

While clear cell RCC remains by far the most common histologic subtype of RCC, accounting for 75% to 80% of renal tumors, the treatment for the other histologic subtypes, including papillary (10% to 15%), chromophobe (4% to 5%), collecting duct, medullary, Xp11.2 translocation, and unclassified (4% to 5%), remains a challenge for the field.21 Retrospective data suggest that responses to HD IL-2 in patients with non—clear RCC are extremely rare and this therapy is typically not considered in patients with non–clear cell RCC

 Most clinical trials with novel immunotherapy agents have generally excluded patients with non—clear cell histology, so the efficacy of these agents in other histologic subtypes remains largely unexplored. There also is little data on the molecularly targeted agents, although retrospective analysis suggests that in general patients with non–clear cell RCC treated with these agents experience significantly lower response rates and poorer median PF and overall survival.

Of the molecularly targeted agents, only temsirolimus has been studied in a randomized, phase III trial that accepted patients with non—clear cell histology. Upon subanalysis of this trial, among the 73 patients with non–clear cell histology (75% of which had the papillary subtype) randomized to receive either temsirolimus (n = 36) or IFN (n = 37), the median overall survival of patients was 11.6 months in the temsirolimus group versus 4.3 months in the IFN group.

For this reason, the NCCN gives temsirolimus a category 1 recommendation for the treatment of patients with non—clear cell RCC who are poor risk and a category 2A recommendation for all others.

Similarly, scant data are available for the other molecularly targeted agents. Sorafenib and sunitinib have both demonstrated modest efficacy and safety in patients with non—clear cell histology in their respective expanded-access programs and based on these data are given category 2A recommendations by the NCCN.14,26 In particular, in its expanded-access program, sunitinib showed an objective response rate of 11% and median PFS of 7.8 months (95% CI, 6.3-8.3) in 588 evaluable patients with non–clear cell histology. Sorafenib demonstrated an objective response rate of 3.1% in 127 patients with either chromophobe or papillary histology. Several clinical trials are ongoing in the patients with non–clear cell RCC.

Potentially the most informative data may be from several randomized, phase II trials comparing mTOR inhibitors with VEGF antagonists. The most recently reported of these is the ESPN study, a randomized, phase II trial in which 108 patients with non—clear cell RCC were planned to be randomized to receive either everolimus to sunitinib with planned crossover at first progression.27 At the first interim analysis, 35 patients had received everolimus and 33 patients had received sunitinib. The median first-line PFS of sunitinib was 6.1 months (95% CI 4.7-10.8) versus 4.1 months (95% CI, 2.7-7.4) with everolimus (P = .25). The median overall survival of patients treated with everolimus was 10.5 months (95% CI, 7.4-NA) while the median overall survival of patients treated with sunitinib was not reached (P = .01). Based on a futility analysis, the trial was halted and concluded that everolimus could not be recommended for the first-line therapy of patients with non–clear cell RCC.

Thus, the ideal first-line therapy for patients with non—clear RCC remains murky. Several ongoing clinical trials may add some clarity or potentially add additional therapeutic options (NCT01399918, NCT01767636). In the meantime, it appears reasonable for practitioners to treat patients with metastatic non–clear cell RCC in the first-line with either a VEGF antagonist such as sunitinib or temsirolimus.

Because only a minor subset of patients with metastatic RCC experiences durable long-term remissions from any therapy, the vast majority of patients will require a second-line therapy. Not surprisingly, the selection of a second-line therapy is greatly influenced by the identity of the first-line therapy. Patients who were treated first-line with HD IL-2 can be treated much like first-line patients, with the remaining molecularly targeted agents have shown significant activity in cytokine-refractory patients. In addition, axitinib has been given a category 1 recommendation by the NCCN following the failure of 1 prior therapy and is an option for these patients. For those patients who were treated first line with temsirolimus, a VEGF-targeted therapy such as sunitinib, pazopanib, and axitinib would be a reasonable second-line agent.

The decision is perhaps less clear cut for patients who have failed a VEGF-targeted treatment in the first line. The NCCN gives category 1 recommendations for 2 agents, everolimus and axitinib, for patients who have previously been treated with VEGF-targeted TKI. This is made even more complicated by the fact that retrospective analysis has suggested that there is no definitive cross-resistance between agents such as sorafenib, sunitinib, and bevacizumab/interferon and these agents also remain therapeutic options following initial TKI failure.28 Regardless, in principle the decision facing physicians with respect to a second-line therapy following failure of a first-line TKI is whether to prescribe another VEGF-targeted agent (axitinib or similar agent) or change to an mTOR inhibitor (everolimus). Some guidance on this decision is available from current data. First, the final analysis of the pivotal phase III trial of everolimus versus placebo (RECORD-1) suggests that everolimus has similar activity following the failure of 2 VEGF-targeted TKIs as after 1.29 At the same time, both retrospective analysis and prospective clinical trials suggest that VEGF-targeted agents may have activity following disease progression on other VEGF (or even the same) pathway inhibitors.

Finally, the only comparative trial between VEGF-targeted TKI and mTOR inhibitors was the recently reported INTORSECT trial in which 512 patients with advanced RCC who had failed prior sunitinib therapy were randomized to receive either temsirolimus or sorafenib. This phase III trial showed that there was no significant difference between temsirolimus and sorafenib in median PFS (4.3 vs 3.9 months; HR, 0.87; P = .19) or overall response rate (ORR).

However, patients treated with sorafenib experienced significantly longer overall survival compared with those treated with temsirolimus (16.6 vs 12.3 months; HR, 1.31, P = .01). Taken together, these data appear to favor the sequence of VEGF-VEGF-mTOR over VEGF-mTOR-VEGF (where VEGF indicates VEGF-targeted therapy and mTOR indicates mTOR inhibitors).

While the existing data support a certain sequence of therapies in general, the choice of second-line therapy for individual patients should take into account patient-specific factors. For example, a patient who experienced severe mechanism-specific toxicities from a VEGF-targeted agent (eg, hypertension, proteinuria, cardiac complications, etc) might benefit from changing to an mTOR inhibitor given the largely non-overlapping toxicities of these 2 classes of agents.

A patient’s clinical response to an initial VEGF-targeted therapy may also be taken into account. In a patient who is primarily refractory to a VEGF-targeted TKI, it would seem logical to try an agent with a different mechanism of action such as an mTOR inhibitor. Likewise, a patient who had a prolonged benefit from a first VEGF-targeted TKI might be more likely to benefit from a different VEGF-targeted agent. In a recently reported secondary endpoint analysis of the phase III AXIS trial, it was suggested that patients who experienced a longer PFS on first-line sunitinib tended to have a longer PFS on either axitinib or sorafenib.

 While these findings may simply reflect the underlying aggressiveness of disease, and in fact similar analysis has shown conflicting findings

 it nonetheless may be predictive of expected clinical benefit of second-line VEGF-targeted treatment.

Much like with first-line therapy, there are even less data for the sequential therapy of non—clear cell RCC. Most patients with non–clear cell RCC will be treated in the first-line setting with either a VEGF-targeted agent or an mTOR inhibitor. Given the lack of data regarding cross-resistance to the various classes of agents in patients with non–clear cell RCC, it is logical in the second-line to switch to an alternate mechanism of action. Therefore, it would be reasonable in patients who had been treated in the first-line with a VEGF-targeted therapy to proceed with an mTOR inhibitor in the second line, and vice versa. Finally, given the poor clinical outcomes observed with either available class of agent in non–clear cell RCC, it is also reasonable to seek out clinical trial options for these patients. One trial of interest is a phase II trial of axitinib in patients who have failed temsirolimus (NCT01798446).

Many novel therapeutic agents are being actively assessed in patients with advanced RCC. Although current therapy in RCC is largely limited to 2 classes of agents (VEGF-targeted agents and mTOR inhibitors), clinicians may soon be faced with the challenge of integrating agents with completely novel mechanisms of action into their therapeutic algorithms. While some agents may be combined with VEGF-targeted TKI (eg, ALK inhibitors, MET inhibitors) and others used in place of current therapies (novel PI3-kinase/mTOR inhibitors in place of the rapalogues), perhaps the most relevant class of agents with respect to sequential therapy is the novel immunotherapies given their distinct mechanism of action and efficacy in multiple clinical settings. In particular, the PD-1 antibodies are likely the closest to possibly gaining broad approval, although it should be stressed that most available data remain preliminary thus far. In addition to several combination studies (including with VEGF-targeted TKI and ipilimumab), the PD-1 antibody nivolumab is being assessed in a phase III clinical trial versus everolimus in patients with advanced RCC who have failed prior anti-angiogenic therapy (NCT01668784). A positive trial and possible approval of this agent in the second-line setting would be anticipated to have a major effect on sequential algorithms. Should PD-1 (or PD-L1) antibodies demonstrate the ability to induce durable remissions in even a subset of patients, there will be compelling rationale to move these agents into the first-line setting, either as single agents or in combination with other agents. In that case, the most appropriate sequence in most patients with clear cell RCC might become immune therapy (with PD-1/PD-L1 antibodies or HD IL-2) followed by sequential molecularly targeted therapy.

Until a therapeutic strategy emerges that can result in durable remissions for most patients with advanced RCC, sequential therapy remains a reality for most patients. For now, in the absence of data from large randomized trials, the decision on sequence of therapies must be individualized mostly based on clinical factors. These decisions will likely become increasingly complicated in the near future by the availability of novel classes of agents with distinct toxicities and mechanisms of action. However, practitioners may also soon be aided by the development of selection algorithms that are based more on genetic characterization than on clinical factors.

Affiliations: Daniel C. Cho, MD, is an assistant professor, department of medicine, Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center, New York, NY.

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By Daniel C. Cho, MD

Articles

Sequencing VEGFR-Targeted and mTOR-Targeted Therapy in Advanced Renal Cell Carcinoma