What Next? Choosing Second-Line Therapy in Progressive Renal Cell Carcinoma


A 71-year-old woman presented with back pain and was incidentally found to have a left upper pole renal mass. She underwent left open partial nephrectomy; the pathology results revealed a 2.2-cm clear-cell renal cell carcinoma (RCC) with negative margins and a Fuhrman nuclear grade of 2.

Table: Trials Evaluating Second-Line Treatment in Metastatic RCC

The Case:A 71-year-old woman presented with back pain and was incidentally found to have a left upper pole renal mass. She underwent left open partial nephrectomy; the pathology results revealed a 2.2-cm clear-cell renal cell carcinoma (RCC) with negative margins and a Fuhrman nuclear grade of 2. The cancer was staged as pT1aN0M0. The patient began follow-up shortly thereafter.

Four years later she complained of neck pain; an MRI of the cervical spine showed a metastatic lesion within the C1 vertebra. She underwent posterior resection of a lateral right C1 mass and then received intensity-modulated radiotherapy to the surgical bed. Pathology results confirmed metastatic RCC, but given that she had no other evidence of systemic disease, she remained on surveillance. Six months later, a CT scan showed hypervascular nodules in the kidney near the previous resection site, and she underwent complete nephrectomy and removal of a recurrent clear-cell RCC measuring 1.2 cm in its largest diameter. She again resumed surveillance, but 6 months later, restaging scans revealed an enlarged enhancing left hilar lymph node and subcentimeter right upper and right lower lobe pulmonary nodules. In addition, a new solid right mid pole renal mass and thoracic spine lesions were noted.

Treatment with pazopanib was initiated, with dose reduction and brief interruptions due to elevated blood pressure and hypothyroidism. After 9 months of pazopanib therapy, CT scans showed a mixed response in the lung nodules and stable disease elsewhere. The enlarging lung nodules were thought to be of infectious etiology; thus, the patient underwent biopsy of a notably enlarging lesion, and a diagnosis of Mycobacterium tuberculosis was made. The patient continued on pazopanib for an additional year, until scans revealed increasing retrocaval lymphadenopathy and multiple new lytic bone lesions. After a 2-year period of disease stability on pazopanib, she had developed progressive disease. She was offered second-line therapy with a subsequent vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI), and has had stable disease thus far.


This case highlights an interesting treatment course, including the variable progression of RCC in bone and soft tissue, as well as the utility of biopsy in characterizing unusual lesions. However, it also brings to light the treatment decisions that must be made when patients progress on first-line targeted therapy. Traditionally, clinicians used an inhibitor of the mammalian target of rapamycin (mTOR) or VEGF in the first line and then, upon disease progression, switched the killing mechanism employed. However, recent pivotal trials offer insight into the sequencing of therapies, with an increasing tendency to support use of a VEGF inhibitor in the second line.

Most treatment options in RCC target the VEGF or mTOR pathways,[1,2] yet patients eventually progress on these directed therapies. Acquired mutations are uncommon causes of resistance to TKIs used in the treatment of metastatic kidney cancer,[3,4] and mechanisms of resistance are currently under investigation. Without scientific guidance as to why a therapy becomes ineffective or why response rates may differ greatly between patients, the choice of second-line therapy is based largely on clinical experience. Most patients receive a TKI as first-line therapy,[5] and then, as in this case, clinicians must choose between a subsequent VEGF inhibitor or a class switch to an mTOR inhibitor.

Sorafenib, a VEGF inhibitor, was the first targeted agent to show activity in the second-line setting,[6] and shortly afterwards, everolimus, an mTOR inhibitor, was also proven effective in the second line.[7] The phase II RECORD-3 trial evaluated the proper sequencing of VEGF and mTOR inhibition by comparing first-line sunitinib followed by second-line everolimus with the opposite sequence. The median overall survival (OS) for patients assigned to the sunitinib→everolimus sequence was 32 months, and 22.4 months for the reverse sequence (Table). Thus, the treatment paradigm of sunitinib followed by everolimus has remained a recommended approach, since this succession achieved optimal clinical benefit.[8] However, the RECORD-3 study did not examine the benefit of changing the mechanism of therapy vs the benefit of continuing therapy with the same class of drug.

Recently, additional VEGF TKI therapies have been investigated, such as axitinib, a potent and selective second-generation VEGF inhibitor. In the AXIS trial, axitinib was compared with sorafenib in patients with metastatic RCC whose disease had progressed despite first-line therapy with many agents. Axitinib resulted in significantly longer progression-free survival (PFS) compared with sorafenib (6.7 months vs 4.7 months; hazard ratio [HR] = 0.66; P < .001),[9] although there was no significant difference in OS.[10] Based on these results, axitinib has joined sorafenib and everolimus as treatment options for progressive metastatic RCC, compounding the difficulty of choosing an agent in second-line treatment planning.

The INTORSECT trial was designed to help address this conundrum through evaluation of the efficacy of sorafenib vs temsirolimus in patients whose disease had progressed on first-line sunitinib. The study revealed no significant difference in its primary endpoint of PFS and reported similar overall response rates in the two arms. Surprisingly, there was a significant OS difference favoring sorafenib (12.3 months on temsirolimus vs 16.6 months on sorafenib; HR = 1.31; P = .01).[11] This unexpected difference has raised many follow-up questions but does suggest that exposure to subsequent VEGF inhibition after the failure of first-line VEGF inhibitors could be more effective than second-line targeting of the mTOR pathway.

Patients in the INTORSECT trial were stratified based on duration of prior sunitinib (≤ or > 180 days), Memorial Sloan Kettering Cancer Center risk category, clear-cell vs non–clear-cell histology, and nephrectomy status. Interestingly, the group of individuals who had been treated with sunitinib for ≤ 180 days was the only subgroup of the population of patients treated with sorafenib that did not show preserved survival benefit. It has been postulated that patients with a shortened response to first-line TKIs may have disease that is less VEGF-dependent, and mTOR inhibition may be favored in such cases.[12] However, lack of response to first-line therapy does not preclude positive clinical outcomes with a second-line VEGF-targeted agent in patients with advanced RCC.[13] Confirmation of the hypothesis that first-line treatment choice, first-line response, and additional disease characteristics may influence second-line response to mTOR inhibition or VEGF inhibition awaits validation in future clinical trials.[14]

With little biomarker data and limited trial data to inform treatment decisions, clinicians must rely on the nuances of a patient’s clinical status and consider the interaction of the toxicity profile of the available drugs and a patient’s comorbidities when creating a treatment plan.[15] In this case, the patient’s history of Mycobacterium tuberculosis and risk of pulmonary complications contributed to avoidance of mTOR inhibitors in the second line. Additionally, her prolonged response to pazopanib suggested a potential response to a subsequent TKI. Patient characteristics and tolerance of first-line therapy, coupled with knowledge of the unique toxicities of the agents, can certainly inform the choice of second-line therapy.

Currently, clinical data from randomized trials (Table) demonstrate that maintaining VEGF inhibition even after failure of first-line TKI therapy in metastatic RCC is an appropriate strategy, with evidence of a survival benefit. This option was pursued in our patient’s case, and we are increasingly using VEGF inhibition in sequence.


There are currently no data clearly backing the use of VEGF or mTOR inhibition in the second-line treatment of metastatic RCC, just as there are no data to support the use of a particular agent in the first line and additional lines of treatment. Consequently, much of the discussion centers around comparisons of results across trials and within populations with varied therapeutic histories. However, at this time the results of multiple trials would suggest that sequencing inhibitors of the VEGF pathway in early lines of therapy for RCC is favored, barring any precluding patient characteristics. Additional lines of therapy should include mTOR inhibition, as this remains an active option in the treatment of patients with metastatic RCC. The interesting, and at times unanticipated, results presented here highlight the need for improved knowledge of disease biology and more nuanced knowledge of patient characteristics to guide clinicians in the choice of therapy for progressive RCC.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Acknowledgments:The authors would like to acknowledge Canales de Ayuda A.C. for their support of Dr. Bourlon’s visiting fellowship in urologic oncology at the University of Colorado Cancer Center.


1. Kaelin WG Jr. The von Hippel-Lindau tumor suppressor gene and kidney cancer. Clin Cancer Res. 2004;10:6290S-5S.

2. Brugarolas J. Renal-cell carcinoma-molecular pathways and therapies. N Engl J Med. 2007;356:185-7.

3. Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene. 2009;28(suppl 1):S24-31.

4. Soverini S, Branford S, Nicolini FE, et al. Implications of BCR-ABL1 kinase domain-mediated resistance in chronic myeloid leukemia. Leuk Res. 2014;38:10-20.

5. Motzer RJ, Hutson TE, McCann L, et al. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med. 2014;370:1769-70.

6. Escudier B, Eisen T, Stadler WM, et al; TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125-34.

7. Motzer RJ, Escudier B, Oudard S, et al; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449-56.

8. Motzer RJ, Barrios CH, Kim TM, et al. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Jul 21. [Epub ahead of print]

9. 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;378:1931-9.

10. Motzer RJ, Escudier B, Tomczak P, et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 2013;14:552-62.

11. Hutson TE, Escudier B, Esteban E, et al. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014;32:760-7.

12. Hwang C, Heath EI. The Judgment of Paris: treatment dilemmas in advanced renal cell carcinoma. J Clin Oncol. 2014;32:729-34.

13. Escudier B, Michaelson MD, Motzer RJ, et al. Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial. Br J Cancer. 2014;110:2821-8.

14. Everolimus as second-line therapy in metastatic renal cell carcinoma (RECORD-4). ClinicalTrials.gov; August 2014. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01491672.

15. Méndez-Vidal MJ, Martínez Ortega E, Montesa Pino A, et al. Management of adverse events of targeted therapies in normal and special patients with metastatic renal cell carcinoma. Cancer Metastasis Rev. 2012;31(suppl 1):S19-27.

16. Escudier B, Eisen T, Stadler WM, et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol. 2009;27:3312-8.

17. Motzer RJ, Escudier B, Oudard S, et al; RECORD‐1 Study Group. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer. 2010;116:4256-65.

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