Sequential Therapy for Renal Cell Carcinoma

With several agents now approved and broadly available for the treatment of patients with advanced renal cell carcinoma (RCC), a great deal of attention has been focused on determining the most appropriate sequence of therapies. The concept of sequential therapy has developed for several reasons, including: (1) the availability of molecularly targeted agents with distinct toxicities and mechanisms of action; (2) the fact that responses to molecularly targeted agents in RCC are typically not complete or durable; therefore, treatment with these agents must be thought of as noncurative except in rare circumstances; and (3) the fact that combinational regimens of available agents have not yet demonstrated substantially improved efficacy. Therefore, accepting that the majority of advanced RCC is incurable, efforts have been focused on identifying sequences of therapies that might maximize both duration of disease control and quality of life for individual patients. In this review, we will summarize these efforts so far and discuss how these efforts might expand in the future.

Sequential Therapy Starting With Immunotherapy

Although the premise of a prospective, defined, sequential regimen depends on the assumption that advanced RCC is incurable, it should be remembered that a subset of patients can experience durable remissions from immunotherapy. Although single-agent interferon (IFN)-? has largely been removed from the RCC treatment algorithm by recent phase 3 trials, high-dose 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 current era, response to high-dose IL-2 exceeds 25%, with at least 10% of patients exhibiting complete responses that last in excess of 2 years.¹ Therefore, high-dose IL-2 remains a viable therapeutic option for patients with advanced RCC.

With respect to sequence of therapy, 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.^2-5 At the same time, a small retrospective study has suggested that the efficacy of high-dose IL-2 following VEGF-targeted therapies may be limited.6 Although the later point must be validated independently, the data available thus far suggest that patients deemed appropriate for IL-2 should be treated with IL-2 as a primary therapy before molecularly targeted agents.

The determination of which patients might be best suited for consideration for high-dose IL-2 is dependent upon many factors. Clinical factors that should favor IL-2 include younger age, good performance status, few medical comorbidities, and disease that is not rapidly growing. Although many efforts have focused on identifying pathologic or molecular factors that might predict for the likelihood of benefit from IL-2, so far only the presence of clear cell histology is regularly adhered to. Finally, the consideration of IL-2 may also depend on more practical factors such as proximity to an IL-2 specialty center and patient motivation.

While existing data suggest that IL-2 should be considered as a primary therapy for appropriately selected patients with advanced RCC, more novel immunotherapies may have broader activity across treatment scenarios. More will be discussed regarding these novel agents in the following sections.

Sequential Therapy Starting With Molecularly Targeted Agents

For most patients with advanced RCC, molecularly targeted agents will be selected as the primary therapy of choice. A subset of these patients will first be treated with temsirolimus, an allosteric inhibitor of mTOR that is recommended by the National Comprehensive Cancer Network (NCCN) for the treatment of patients who have poor prognostic features (?3 of 6 of the following: Karnofsky performance status <80, time from diagnosis to randomization <12 months, serum lactose dehydrogenase >1.5 the upper limit of normal, hemoglobin less than the lower limit of normal, corrected serum calcium >10 mg/dL, and >1 metastatic site).7 The majority of patients, however, will begin therapy with a VEGF-targeted treatment. The NCCN currently gives category 1 recommendations for 3 such therapies (sunitinib, pazopanib, and bevacizumab plus IFN). In the United States, most patients will likely be treated with sunitinib or pazopanib, which are both tyrosine kinase inhibitors (TKIs) with activity against VEGF receptor 2 and platelet-derived growth factor receptor. With respect to second-line therapy, the NCCN currently gives category 1 recommendations for 2 agents, everolimus and axitinib, for patients who have previously been treated with VEGF-targeted TKIs. This is further complicated by that fact that retrospective analysis has suggested that there is no definitive cross-resistance between agents such as sorafenib, sunitinib, and bevacizumab/IFN, and these agents also remain therapeutic options following initial TKI failure.8 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 3 trial of everolimus versus placebo (RECORD-1) suggests that everolimus has similar activity following the failure of 2 VEGF TKIs as after 1.⁹ 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.^10-13 Finally, the only comparative trial between VEGF TKIs and mTOR inhibitors was the recently reported INTORSECT trial in which 512 patients with advanced RCC in whom prior sunitinib therapy had failed were randomized to receive either temsirolimus or sorafenib. This phase 3 trial failed to show that temsirolimus was superior to sorafenib in median progression-free survival (PFS) (4.28 vs 3.91 months; hazard ratio [HR] 0.87; P=.1933) and was actually inferior in overall survival (12.27 vs 16.64 months; HR 1.31; P=.0144).¹⁴ 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 supporting a certain sequence of therapies are drawn from the analysis of the outcomes in a large group of patients, the decision with respect to individual patients must of course 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) might benefit from changing to an mTOR inhibitor given the largely nonoverlapping toxicities of these classes of agents.¹⁵ A patient’s clinical response to initial VEGF-targeted therapy might also be taken into account. For a patient who is primarily refractory to a VEGF TKI, it would seem logical to try a therapy with a different mechanism of action such as an mTOR inhibitor. Likewise, a patient who had a prolonged benefit from the first VEGF-targeted TKI might be more likely to benefit from a different VEGF-targeted agent. In a recently reported secondary end-point analysis of the phase 3 AXIS trial, it was shown that the median PFS for patients whose duration of prior sunitinib therapy was ?9 months was significantly longer than for those whose prior sunitinib duration was <9 months whether they were treated with sorafenib (4.6 vs 2.9 months) or axitinib (6.3 vs 4.5 months).¹⁶ All of these findings must be validated prospectively and independently, however, before it is appropriate to incorporate them formally in selection algorithms.

Ultimately, the field must be guided by prospective clinical trials investigating sequential therapy. Impor­tant trials assessing sequential therapies are shown in the Table. Hopefully completion of these studies will provide more information on the most appropriate sequence of agents for patients with RCC. Unfortunately, the arena of molecularly targeted agents in RCC also remains quite fluid. It is possible that the more potent, next-generation VEGF-targeted TKI tivozanib will soon be approved by the FDA following its positive phase 3 trial.¹⁷ The broad availability of such an agent across treatment scenarios (axitinib is currently only approved after failure of at least 1 systemic agent) will engender even more questions with respect to sequential therapy. For example, does it make the most sense to use a less potent VEGF TKI first and then follow with the more potent agents (eg, axitinib)? Conversely, would it make more sense to use the most potent VEGF TKI first? If that is the case, will a less potent VEGF TKI have efficacy following failure on the more potent VEGF TKI? Or would the more appropriate sequence become a highly potent VEGF TKI followed by an mTOR inhibitor, followed by rechallenge with the same highly potent VEGF TKI? Regardless, it is clear that any current understanding regarding sequential therapy of molecularly targeted agents in RCC is at risk of changing quite rapidly.



Novel Therapeutic Agents in RCC

Many novel therapeutic agents are planned for assessment in RCC. As if sequential therapy was not already complicated enough with just 2 primary therapeutic 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 TKIs (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. In particular, the PD-1 antibodies are likely the closest to possibly gaining broad approval. Recently, the PD-1 antibody nivolumab (MDX-1106, BMS-936558) demonstrated preliminary activity in patients with advanced RCC, many of whom had been heavily pretreated.¹⁸ Interestingly, at the time of data analysis and publication, 5 of 8 patients with objective responses who had started treatment more than 1 year before had responses lasting at least 1 year. Thus, although these results are quite preliminary, there is a suggestion that responses to these novel immunotherapies may be durable in some cases. In addition to several combination studies (including with VEGF TKIs and ipilimumab), nivolumab is scheduled to be assessed in a phase 3 clinical trial versus everolimus in patients with advanced RCC in whom prior antiangiogenic therapy has failed. 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 likely be a push to move these agents into the first-line setting. 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 high-dose IL-2) followed by sequential molecularly targeted therapy.

Novel Technologies

In step with continued investigation of novel therapies is the development and broader availability of novel technologies. Perhaps the most directly applicable to personalizing sequential therapy are next-generation sequencing technologies for whole genome or whole exome sequencing. Preliminary work with such platforms has already proven fruitful. Voss and colleagues recently reported the finding of mutations in tuberous sclerosis complex 2 and mTOR in tumor specimens from patients with RCC who had prolonged responses to rapalogues.¹⁹ More information on the frequency of these and other mutations will likely be available in the anticipated publication of the results of The Cancer Genome Atlas project. While the large-scale utilization of whole genome or whole exome sequencing for the analysis of other clinically annotated groups of tumor specimens may currently be somewhat cost prohibitive, such work is progressively becoming more feasible. It is hoped that the subsequent interrogation of such genetic information will allow the identification of markers to direct individual patients to specific therapies. At the same time, it is becoming clear that there is both intratumoral and intermetastases genetic heterogeneity within an individual patient’s RCC tumor burden.²⁰ Inasmuch as this heterogeneity may also emerge temporally following treatment with various systemic therapies, in the future the sequence of therapies for an individual patient may ultimately be determined by serial genetic analysis rather than depending on codified treatment algorithms.

Conclusion

Until a therapeutic strategy emerges that can result in durable remissions for the majority of patients with advanced RCC, sequential therapy remains a reality for most patients. Efforts thus far have focused on identifying sequences among currently available therapies that may maximize control of tumor growth and maintenance of patient quality of life; however, with the increasing complexity of the therapeutic landscape of RCC, many critical questions remain unanswered. 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. With the rapid emergence of novel technologies, however, the sequence of agents may soon be largely dictated by the genetic characterization of an individual’s tumor specimens prior to initiating therapy.

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