A Review of Data on Optimal Sequencing and Combinations of Current Therapies in Renal Cell

The past 2 to 3 decades saw a palpable therapeutic nihilism associated with the management of patients with advanced renal cell carcinoma (RCC), interrupted briefly by the initial excitement regarding high-dose interleukin-2.¹ Over the past several years, phase I/II clinical trials of tyrosine kinase inhibitors (TKIs), vascular endothelial growth factor (VEGF) inhibitors, and mammalian target of rapamycin (mTOR) inhibitors in advanced RCC (primarily of clear cell histology) demonstrated intriguing, paradigm-shifting activity. This led to a series of phase III trials that culminated with the FDA’s approval of 6 new drugs in a 5-year span for the management of advanced RCC.

As we reach the midway point of the first decade of targeted therapeutics in RCC, some high-level observations can be made. Despite unequivocal progress, none of the currently available agents cure patients with metastatic RCC and few complete responses are seen with any of them. Although clinical studies with the mTOR inhibitor temsirolimus (Torisel) provided evidence of an improvement in overall survival (OS) in patients with poor risk (per Memorial Sloan-Kettering criteria) disease, demonstrating improvement in survival with other agents has been problematic. This is likely because studies for most of these drugs allowed crossover by large numbers of patients.² From a patient management perspective, these agents are generally associated with significant toxicity, negatively affecting the quality of life for many patients. Although published data on sequential therapy are limited, it has become a de facto standard of care. Using these agents in combination is more than a little challenging, pending results from additional studies.

PROPOSED MECHANISMS OF RESISTANCE IN SEQUENTIAL THERAPY

It was the significant progress in our understanding of the molecular pathogenesis of RCC during the past decade that led to the development of therapies targeting the VEGF and mTOR pathways.³ Results from a series of phase III studies provide compelling evidence that sunitinib (Sutent), pazopanib (Votrient), temsirolimus, and the combination of bevacizumab (Avastin) and interferon-alpha are clinically active in patients with metastatic RCC as initial therapies or following initial cytokine therapy. The objective response rate (ORR) ranged from 7% to 31% with these agents, and progression-free survival (PFS) ranged from 4 to 11 months.^4-8

In chronic myeloid leukemia, another malignant disease commonly treated with targeted agents (eg, imatinib [Gleevec] and nilotinib [Tasigna]), the mechanism of drug resistance is presumed to be mutation of a gene that encodes a key tyrosine kinase receptor targeted by the drug. In contrast, investigators exploring resistance mechanisms in RCC note that because the main target for VEGF receptor (VEGFR) inhibitors resides on the surface of endothelial cells,⁹ a mutation conferring treatment resistance would most likely have to occur in the tumor endothelium, but it is highly improbable that such a mutation would occur simultaneously in the endothelium of each individual tumor metastasis.¹⁰ Other proposed mechanisms for acquired resistance include reemergence of VEGF-driven vasculature, upregulation of alternative proteins in the setting of persistent VEGF or mTOR blockade, and novel mechanisms that are not antiangiogenic in nature.^10-13

STATUS OF SEQUENTIAL THERAPY

Following FDA approval of sunitinib, many clinicians managing RCC patients with disease progression on sorafenib (Nexavar) empirically used sunitinib as a salvage option. Retrospective series soon appeared in the literature documenting responses to both agents when used in sequence and reporting clinical activity in patients with disease progression following other VEGFtargeting agents, such as bevacizumab.^14-17

More recently, prospectively designed phase II trials have addressed the issue of cross-resistance when using VEGFtargeted therapeutics in sequence. Rini and associates conducted a prospective multicenter phase II trial of sunitinib in 61 patients with metastatic clear cell RCC that had evidence of progression following a bevacizumab-based therapy regimen. Patients received 50 mg of sunitinib daily in 6-week cycles, comprising 4 weeks on therapy followed by 2 weeks off therapy. The researchers observed an ORR of 23% with a median PFS of 30 weeks and a median OS of 47 weeks. Observed treatment-related toxicity was typical of sunitinib in other settings.¹⁶

The investigational drug axitinib is an oral, potent, selective inhibitor of VEGFRs 1, 2, and 3 that demonstrated substantial activity in a phase II trial of patients with cytokine-refractory metastatic RCC.¹⁸ In this multicenter trial, Rini and associates administered 5 mg of axitinib twice daily to patients with metastatic RCC (all histologic subtypes) whose disease progressed following therapy with sorafenib. The prior number of therapies a patient had received was not a limiting factor in enrollment. All 62 patients enrolled had received prior sorafenib and 74.2% had received ≥2 prior systemic treatments. The ORR, which was the study’s primary endpoint, was 23%. The median duration of response was 17.5 months and median OS was 7.4 months.¹⁹ Although these studies have limitations, including their design and small size, they provide compelling clinical evidence that cross-resistance is not inevitable when patients who fail on one VEGF-targeting drug switch to another.

Motzer and colleagues recently reported the results of an international phase III trial testing the role of mTOR inhibition following disease progression on agents that target VEGF.²⁰ Patients who received prior therapy with bevacizumab, interleukin-2, or interferon-alfa were also permitted to participate. Researchers randomly assigned patients at a 2:1 ratio to 10 mg of the mTOR inhibitor everolimus (Afinitor; n = 272) or placebo (n = 138) daily. The primary endpoint was median PFS, which was documented using Response Evaluation Criteria in Solid Tumors and assessed via a blinded, independent central review. At the time of disease progression, treatment was unblinded and patients receiving placebo were offered open-label everolimus. Objective antitumor activity was observed, with 60% of patients treated with everolimus experiencing tumor shrinkage compared with 10% given placebo. Based on independent review, median PFS in the everolimus arm was 4 months versus 1.9 months in the placebo group, representing significant improvement (hazard ratio [HR], 0.30; 95% confidence interval [CI], 0.22-0.40; P <.001). When stratifying patients according to prior VEGF TKI therapy, the PFS advantage for everolimus persisted across all groups (Table 1).

COMBINATION THERAPY IN ADVANCED RCC

The current clinical paradigm for the management of advanced RCC is rapidly evolving. Following the FDA approval of sorafenib and sunitinib, and given the scarcity of effective therapies, patients treated with 1 of these agents were typically treated with the alternative agent following progression. Clinical evidence indicating a lack of cross-resistance between these TKIs validated this empiric approach. Subsequent studies provided additional data on sequencing approaches, such as evidence from a phase III study supporting the utility of everolimus following therapy with a VEGF TKI.

Investigators exploring the role of combination therapy have applied the concepts of vertical blockade and horizontal blockade.²¹ A vertical blockade uses at least 2 agents to target 1 pathway at ≥2 levels; a horizontal blockade uses ≥2 agents to target separate pathways with different functions in parallel.²¹

Bevacizumab Plus Erlotinib

The initial attempt to test the concept of horizontal blockade was a phase II trial of bevacizumab in combination with the epidermal growth factor receptor inhibitor erlotinib (Tarceva). Patients were treated with 10 mg/kg of bevacizumab every 2 weeks and an oral, 150-mg dose of erlotinib daily. Of 58 evaluable patients, 12 (21%) had objective partial remissions. At a median follow-up of 15 months, median PFS was 11 months; 43% of patients were progression-free at 12 months and 26% were progression-free at 18 months.²² The subsequent addition of the platelet-derived growth factor receptor inhibitor imatinib to the combination was not tolerable.²³

Bukowski and colleagues attempted to define the role of combination therapy further by conducting a randomized, placebo-controlled phase II trial.²⁴ Eligible patients had metastatic RCC, predominantly of clear cell histology, and they were randomized to receive 10 mg/kg of bevacizumab every 2 weeks combined with 150 mg daily of erlotinib or placebo. For patients treated with bevacizumab plus erlotinib, the ORR was 13% and median PFS was 8.5 months compared with an ORR of 14% and median PFS of 9.9 months for patients treated with bevacizumab alone. The study provided additional data supporting the single-agent activity of bevacizumab.

Bevacizumab Plus Sunitinib

Recent reports describe attempts to achieve vertical blockade by blocking the VEGF-VEGFR axis and/or hypoxiainducible factor. Feldman and associates conducted a phase I trial evaluating bevacizumab plus sunitinib in patients with metastatic RCC.²⁵ Patients who received ≤2 prior therapy regimens, excluding bevacizumab or sunitinib, were eligible. Bevacizumab was administered at a fixed dose of 10 mg/kg every 2 weeks, combined with an escalating dose of sunitinib.

The study determined that the maximum tolerated dose (MTD) for the regimen consisted of 50 mg of sunitinib and 10 mg/kg of bevacizumab. The authors noted, however, that chronic therapy with the MTD dose frequently resulted in grades 3/4 levels of hypertension and hematologic and vascular toxicities, with approximately half the patients stopping therapy secondary to adverse events.

Although activity was seen, with 1 complete and 12 partial responses, the authors said that they did not recommend pursuing this regimen at the MTD because of the significant therapy-related toxicity.²⁵ While this trial documented the constellation of thrombocytopenia, hemolytic anemia, hypertension, proteinuria, and renal insufficiency with microangiopathy in 5 patients, a similar phase I trial that enrolled patients with RCC and other solid tumors did not observe this constellation of events in any participants.²⁶

Everolimus Plus Bevacizumab

A phase II study recently reported positive data on the efficacy of everolimus in combination with bevacizumab following VEGFtargeted TKI therapy. Investigators gave this doublet to 59 patients, 29 of whom had been previously treated with sunitinib or sorafenib.²⁷ The median PFS in this patient population was 10 months, suggesting that these agents might act synergistically in patients with TKI—refractory disease.

Temsirolimus Plus Sunitinib

Fischer and colleagues conducted a phase I study of temsirolimus in combination with sunitinib in patients with advanced RCC.²⁸ Patients were eligible if they had received ≤2 prior systemic regimens for metastatic disease. Investigators administered 15 mg of temsirolimus once weekly by intravenous infusion, and 25 mg of sunitinib was administered orally once daily for 4 weeks; this was followed by a 2-week rest period. In the first cohort of 3 patients, 2 patients experienced dose-limiting toxicities. The study was terminated because of the substantial toxicity observed with even the low starting doses of both agents.²⁸

Bevacizumab Plus Sorafenib

Sosman and colleagues conducted a phase I trial investigating the combination of sorafenib and bevacizumab in patients with advanced RCC who had not received prior VEGF TKI therapy.²⁹ Initial doses consisted of 200 mg of sorafenib twice daily with a 5 mg/kg dose of bevacizumab once every 2 weeks in 28-day cycles, with dose modification based on observed toxicities. Therapy was relatively well tolerated, with only 4 of 48 patients discontinuing because of toxicity. The investigators established the MTD at 200 mg daily of sorafenib plus 15 mg/kg of bevacizumab once every 2 weeks. Of the 46 evaluable patients, 21 (46%) achieved a partial response. The median time to progression was 11 months, and 10 patients (21%) were progression-free at 18 months.²⁹

Ongoing Trials

Several ongoing prospective trials are testing the role of combination therapy. The Eastern Cooperative Oncology Group is conducting the randomized phase II BEST (Bevacizumab, Sorafenib, and Temsirolimus) trial, which randomizes patients to bevacizumab monotherapy, bevacizumab combined with temsirolimus or sorafenib, or a doublet of sorafenib and temsirolimus.

Ongoing industry randomized trials include a phase III study comparing the combination of bevacizumab and interferon-alpha versus the combination of bevacizumab and temsirolimus, and a randomized phase II trial comparing the combination of everolimus and bevacizumab with interferon-alpha and bevacizumab (Table 2).

CONCLUSION

Following a protracted period in which interleukin-2 was the only FDA-approved drug available for the management of advanced RCC, the last several years have seen the approval of sorafenib, sunitinib, temsirolimus, everolimus, bevacizumab (in combination with interferon), and, most recently, pazopanib. The trials that led to the regulatory approval of these agents support their role as initial therapy, but they offer little guidance regarding the optimal means of selecting therapy for patients with clear cell RCC and essentially no guidance for RCC patients with non-clear cell histologies.

Current evidence supports the role of temsirolimus as initial therapy for patients with advanced RCC who are classified as “poor risk,” based on a trial design that used a modified version of the Memorial Sloan-Kettering Cancer Center definition for poor risk. Clinical trial evidence also supports the use of everolimus in patients with disease progression following therapy with sorafenib, sunitinib, or both.^20,30-31

Following disease progression on a front-line agent, data guiding subsequent therapy selection are limited. None of the available data support 1 sequence of agents over another. Currently, therapy decisions are frequently informed by a patient’s disease status, issues regarding therapy logistics (ie, oral vs parenteral therapy), and an agent’s potential toxicity.³

The role of combination therapy in advanced RCC remains the subject of ongoing investigation. Experience to date suggests that many combinations present challenges, secondary to significant toxicity. Prospective, randomized trials are needed to determine whether sequential therapy or combination therapy is the optimal approach.