BERKELEY, CA (UroToday.com) -
Research strides within the past decade have paved the way to enhanced understanding of the underlying pathogenesis of renal cell carcinoma (RCC) and the subsequent introduction of 7 agents targeting the vascular endothelial growth factor (VEGF) or mammalian target of rapamycin (mTOR) signaling pathways. These include the VEGF receptor tyrosine kinase inhibitors (VEGFr-TKIs) sunitinib, sorafenib, pazopanib, axitinib; the anti-VEGF monoclonal antibody bevacizumab (in combination with the cytokine interferon [IFN]-α); and the mTOR inhibitors temsirolimus and everolimus. Sequential monotherapy with targeted agents is the current standard of care. Uniformly recommended first-line treatment options include temsirolimus for patients with poor prognosis, and bevacizumab (plus IFN-α), sunitinib, or pazopanib for patients with low or intermediate risk.[1, 2, 3, 4] Unfortunately, resistance develops in most patients within a median of 5 to 11 months, requiring second-line and successive therapy. The search for optimal sequencing of targeted agents continues, with the goal of achieving prolonged survival and acceptable tolerability.
In patients who have failed first-line VEGF-based therapy, second-line options with grade A (level 1 recommendations) include everolimus[1, 2, 3, 4] and axitinib,[1, 2] based on data from the pivotal phase 3, randomized RECORD-1[6, 7] and AXIS8 studies, respectively. To date, these studies represent the largest set of prospective data on efficacy and safety profiles in the second-line treatment of patients with mRCC. Though direct comparisons of these trials cannot be made, select distinctions provide insight with regard to VEGF→VEGF compared with VEGF→mTOR sequencing.
The RECORD-1 trial enrolled patients with mRCC who had progressed on treatment with sunitinib and/or sorafenib; previous use of bevacizumab, interleukin, or IFN-α was also permitted. In the AXIS trial, all patients received axitinib or sorafenib as purely second-line therapy (post failure on sunitinib, cytokines, bevacizumab plus IFN-α, or temsirolimus). In the RECORD-1 study, median PFS with everolimus was significantly greater than placebo in the overall (heavily pretreated) population (4.9 mo vs 1.9 mo, respectively, p < 0.001). Impact of everolimus vs placebo on median PFS was greater in patients who received only one previous VEGFr-TKI (5.4 mo vs 1.9 months, respectively; p < 0.001)9 compared with 2 previous VEGFr-TKIs (4.0 mo vs 1.8 mo, respectively; p < 0.001). In patients who received sunitinib as the only previous therapy, median PFS with everolimus vs placebo was 4.6 mo vs 1.8 mo, respectively (p < 0.001). In the AXIS trial, median PFS with axitinib vs sorafenib was longer in the overall population (6.7 mo vs 4.7 mo, respectively; p < 0.0001) compared with patients who had failed previous therapy with sunitinib (4.8 mo vs 3.4 mo, respectively; p = 0.0107). Notably, this result is similar to the median PFS achieved with everolimus in the RECORD-1 trial (for the overall and subpopulations studied)[7, 9] and is lower than the PFS benefit achieved with axitinib and sorafenib in the subgroup of patients previously treated with cytokines (12.1 mo and 6.5 mo, respectively, p < 0.0001 ). Similarly, median OS benefit for axitinib and sorafenib was lower in patients previously treated with sunitinib (15.2 mo and 16.5 mo, respectively, p = 0.4902) compared with patients previously treated with cytokines (29.4 mo and 27.8 mo, respectively, p = 0.1435), suggesting the potential presence of cross resistance between VEGFr-TKIs, at least to some degree.
Cumulative toxicity is an important concern with sequential therapy. Though tolerability profiles of everolimus and axitinib are distinct and cannot be directly compared, safety data from the AXIS8 and RECORD-1 trials suggests better tolerability with VEGF→mTOR sequencing compared with VEGF→VEGF sequencing. In the RECORD-1 study, dose interruptions or dose reductions were required in 38% and 7% of everolimus-treated patients, respectively, compared with 77% and 31% of axitinib-treated patients, respectively, and 80% and 52% of sorafenib-treated patients, respectively, in the AXIS trial. These rates are higher compared with results from the phase 3 TARGET study, in which the large majority of patients with mRCC (83%) receiving sorafenib as second-line therapy had progressed on initial therapy with cytokines; dose reductions and dose interruptions with sorafenib in the TARGET trial occurred in 13% and 3% of patients, respectively. In a retrospective subanalysis of the RECORD-1 study in patients who had previously discontinued VEGFr-TKI therapy due to intolerance, the overall tolerability profile was similar to that shown in the total population; rates of grade 3 and 4 AEs were low. Similarly, in the REACT, open-label, expanded access study, incidence of the most common grade 3 or 4 AEs across all prior treatment subgroups was similar to those reported for the overall population, including patients previously intolerant to VEGF-TKIs. In the AXIS trial, incidence of AEs in patients receiving axitinib or sorafenib were higher in patients receiving first-line therapy with sunitinib compared with those receiving first-line therapy with cytokines. Presence of cumulative toxicity has also been suggested in prospective phase 2 studies of sequential treatment with sorafenib in patients with sunitinib-refractory or bevacizumab-refractory mRCC.[15, 16]
The randomized, open-label phase 3 INTORSECT trial is the first head-to-head prospective comparison evaluating second-line therapy of temsirolimus vs sorafenib post failure on sunitinib. This study is also the first to prospectively evaluate temsirolimus as a second-line treatment. Temsirolimus was numerically but not significantly superior to sorafenib in prolonging median PFS (4.28 mo vs 3.91 mo, respectively; p = 0.1933 (by independent assessment)). Median OS statistically favored sorafenib vs temsirolimus (16.64 mo vs 12.27 mo, respectively; p = 0.014). It should be noted that these outcomes are unlikely to reflect efficacy of everolimus versus a VEGFr-TKI in a purely second-line setting. Real-world data[18, 19, 20] and an indirect comparison of clinical studies suggest improved outcomes with everolimus compared with temsirolimus and/or sorafenib in VEGFr-TKI-refractory patients. It is hoped that results from the ongoing phase 2, open label RECORD-4 study (NCT01491672) evaluating everolimus in the true second line mRCC setting (in patients who progressed on first-line treatment with a cytokine, bevacizumab, or a VEGFr-TKI) will shed further light on this question.
In summary, optimal second-line sequencing after failure on VEGF-based therapy in patients with mRCC continues to be the focus of intense research efforts. A growing body of evidence suggests that switching mechanism of action (e.g., to an mTOR inhibitor) may extend clinical benefit and lessen the likelihood of cumulative toxicity.
- National Comprehensive Cancer Network, Inc. The NCCN Clinical Practice Guidelines in Oncology™ for Kidney Cancer V.2.2012.
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- Ljungberg B, Cowan NC, Hanbury DC, et al. EAU guidelines on renal cell carcinoma: the 2010 update. Eur Urol. 2010;58:398-406.
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- Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449-456.
- Motzer RJ, Escudier B, Oudard S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer. 2010;116:4256-4265.
- Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378:1931-1939.
- Calvo E, Escudier B, Motzer RJ, et al. Everolimus in metastatic renal cell carcinoma: subgroup analysis of patients with 1 or 2 previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies enrolled in the phase III RECORD-1 study. Eur J Cancer. 2012;48:333-339.
- Motzer RJ, Escudier B, Tomczak P, et al. Axitinib vs sorafenib for advanced renal cell carcinoma: phase III overall survival results and analysis of prognostic factors. Poster presented at:37th Congress of the European Society for Medical Oncology; September 28 - October 2, 2012; Vienna, Austria
- Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125-134.
- Bracarda S, Hutson TE, Porta C, et al. Everolimus in metastatic renal cell carcinoma patients intolerant to previous VEGFr-TKI therapy: a RECORD-1 subgroup analysis. Br J Cancer. 2012;106:1475-1480.
- Larkin J, Blank C, Bono P, Kim D, Panneerselvam A, Grunwald V. The REACT expanded-access program of everolimus in patients with metastatic renal cell carcinoma refractory to VEGF-targeted therapy: subgroup analyses by prior therapy. Presented at: European Multidisciplinary Cancer Congress; September 23-27, 2011; Stockholm, Sweden. Poster 7147.
- FDA Oncologic Drugs Advisory Committee. AXITINIB (AG-013736) For the Treatment of Patients With Advanced Renal Cell Carcinoma. 2011:1-107. (NDA 202324). Report.
- Di Lorenzo G., Carteni G, Autorino R, et al. Phase II study of sorafenib in patients with sunitinib-refractory metastatic renal cell cancer. J Clin Oncol. 2009;27:4469-4474.
- Garcia JA, Hutson TE, Elson P, et al. Sorafenib in patients with metastatic renal cell carcinoma refractory to either sunitinib or bevacizumab. Cancer. 2010;116:5383-5390.
- Hutson TE, Escudier B, Esteban E, et al. Temsirolimus vs sorafenib as second line therapy in metastatic renal cell carcinoma: phase 3 results from the INTORSECT trial. Oral presentation presented at the 37th ESMO Congress Vienna, Austria, 28 September – 2 October 2012.
- Yang H, Wong MKK, Signorovitch JE, et al. Overall and progression-free survival with everolimus, temsirolimus, or sorafenib as second targeted therapies for metastatic renal cell carcinoma: a retrospective US chart review. Presented at the ASCO annual meeting, June 1-5, 2012, Chicago, Illinois.
- Chen CC, Hess GP, Liu Z, et al. Second-line treatment outcomes after first-line sunitinib therapy in metastatic renal cell carcinoma. Clinical Genitourinary Cancer. 2012. In press.
- Heng D, et al. A population-based overview of sequences of targeted therapy in metastatic renal cell carcinoma (mRCC). J Clin Oncol 30, 2012 (suppl 5; abstr 387).
- Di Lorenzo G, Casciano R, Malangone E, et al. An adjusted indirect comparison of everolimus and sorafenib therapy in sunitinib-refractory metastatic renal cell carcinoma patients using repeated matched samples. Exp Opin Pharmacother. 2011;12:1491-1497.
Emiliano Calvo, MD, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
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