The Right Drug for the Right Patient: Navigating Systemic Therapy Options in Metastatic Renal Cell Carcinoma and Future Directions

Authors: Toni K. Choueiri MD and Robert J. Motzer MD
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Targeted therapies have changed the landscape of metastatic renal cell carcinoma (mRCC), with a current median survival of approximately 30 months reported in contemporary trials, representing a drastic improvement over the 12- to 13-month overall survival (OS) in the cytokines era. Drugs that target vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), and mTOR inhibitors have shown success in the clinic. In the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Kidney Cancer, the choice for “best option” is based on the published level of evidence and NCCN panel member consensus. Nevertheless, pointing toward one ideal therapy remains challenging in many cases. New directions in targets and trials are focusing on agents that target mechanisms of resistance to targeted therapy and immune checkpoint blockers with the hope that the next few years will bring more drugs with high levels of evidence and value in the care of patients with mRCC.

How to Choose First-Line and Subsequent Therapies

Currently, the choice of therapy is first and foremost based on the strength of the clinical data in terms of efficacy, often using progression-free survival (PFS) as the clinical end point. Randomized phase III clinical trials represent the backbone for category 1 recommendations in the NCCN Guidelines.1 These appropriately powered studies compare an experimental single agent or combination therapy with the existing or acceptable standard. For systemic therapy–naïve patients with mRCC, “optimal” first-line options include sunitinib, pazopanib, the combination of bevacizumab and interferon-alpha, and temsirolimus (in poor-risk RCC only). These recommendations are all based on significantly improving efficacy over the control arm, interferon-alpha, or placebo. However, this “embarrassment of riches” regarding recommendations may leave the practicing physician puzzled, mainly because most of these options have not been compared head-to-head, and even when compared, some were proved noninferior in terms of efficacy.2 Inherent to the clinical practice of oncology, therapy is also based on patient and physician factors, which often are influenced by comorbidities, ease of schedule (eg, intravenous vs oral), toxicity profiles, costs, and drug availability.3 In addition, although the populations in clinical trials were grossly similar, they were not identical.

After patients experience progression on first-line antiangiogenic drugs, the 2 category 1 options include everolimus and axitinib, which provide superiority over placebo and sorafenib, respectively. Again, both drugs were not compared head-to-head, and indirect comparisons suggest that the PFS range is not highly different.3 Despite that, the 2 phase II trials share in common that both were conducted in the salvage setting, and the timing they were conducted in, the control groups, and the lines of therapy allowed were quite dissimilar between the new trial and the previous pivotal trials. Both studies included extensive quality of life (QoL) data, but the absence of head-to-head comparisons between both agents limit QoL data interpretation.

Alternative schedules of certain drugs, such as sunitinib, are emerging as a way to provide maximal time on therapy to limit the high rate of treatment discontinuation due to adverse events (especially outside clinical trials). However, the data remain of lower quality, and the comparison cannot be generalized in the absence of head-to-head studies.4

The Next Generation of Drugs: Circumventing Resistance to Antiangiogenics and Novel Immune Checkpoint Blockers

Nearly all patients treated with currently approved targeted drugs will eventually experience disease progression. Understanding the underlying mechanisms behind VEGF resistance is an area of ongoing research. Examples of such targets include the fibroblast growth factor receptor (FGFR), MET, and the angiopoietin and endoglin pathways. Proteins along these pathways may be involved in acquired resistance to antiangiogenic agents. Usually the novel drug, often a small molecule, has a dual mechanism of action, with the goal of targeting the resistant pathway while maintaining VEGFR inhibition. Thus far, the initial clinical experience with these agents has been encouraging, despite a few setbacks. Dovitinib, a small molecule that inhibits VEGFR and FGFR, failed to show superior efficacy compared with sorafenib in a head-to-head third-line phase III trial.5 Conversely, another similarly designed small molecule, levantinib, showed a clinically meaningful PFS versus second-line everolimus as a single agent or in combination with everolimus in a randomized phase II study.6

MET is upregulated after VEGF inhibition in several animal models and has therefore been characterized as a possible resistance mechanism to drugs targeting angiogenesis.7 One small prospective clinical trial (N=25) showed a promising PFS of 12.9 months and a response rate of 28% with cabozantinib, a receptor tyrosine kinase inhibitor (TKI) against VEGFR and MET, in a highly pretreated RCC population.8 Cabozantinib is being compared with standard everolimus in a randomized phase III trial (METEOR) in patients with VEGFR-TKI–refractory RCC (ClinicalTrials.gov identifier: NCT01865747). A first-line Alliance for Clinical Trials in Oncology–led randomized phase II trial is comparing the efficacy of cabozantinib versus sunitinib as first-line therapy in patients with mRCC with poor- or intermediate-risk prognostic features (ClinicalTrials.gov identifier: NCT01835158).

Recently, new agents targeting the immune checkpoint programmed death-1 (PD-1) and its ligand PD-L1 are actively being investigated in many tumor types, including mRCC.9 An initial phase I study investigating nivolumab, an IgG4 antibody against PD-1, reported on 34 patients with mRCC and showed a promising median OS of 22.4 months and overall response rate (ORR[KC1] ) of 29% in patients who had been heavily treated.” High-grade treatment-related adverse events were uncommon and reversible.10 Shortly after this study, 2 larger randomized studies with nivolumab showed an ORR of approximately 20%, coupled with a median OS of 18.2 to 25.5 months, which is quite encouraging.11,12 A phase III trial of nivolumab with an OS primary end point recently finished accrual and will compare this drug with standard-of-care everolimus in more than 800 patients with mRCC previously treated with a VEGF inhibitor (ClinicalTrials.gov identifier: NCT01668784).

Another alternative to PD-1 inhibition is the more selective ligand inhibition through targeting PD-L1 with MPDL3280A. This drug was administered to 69 patients with mRCC, showing a median PFS of 24 weeks and an ORR of 15%, with responses seen in patients at poor risk and with sarcomatoid histology. Similarly to nivolumab, the drug was well tolerated.13 Studies of combination strategies with PD-1 and PD-L1 inhibitors and targeted agents are ongoing.9

Another combination strategy involves a dual immune checkpoint blockade. One study reported on 44 patients (80% of whom had received prior systemic agents) treated with nivolumab plus ipilimumab, the latter being a CTLA-4 blocker; CTLA-4 is another distinct checkpoint on the immune cell. The median PFS was approximately 38 weeks, the ORR was 50%, and toxicity favored the combination using low-dose ipilimumab,14 leading to an ongoing large phase III trial with this combination (ClinicalTrials.gov identifier: NCT02231749).

Overall, the coming years have the potential to bring a new generation of systemic therapies in mRCC, with checkpoint inhibitors and novel targeted therapy based on circumventing resistance to antiangiogenic drugs.15 These strategies will hopefully lead to progress in achieving increased and sustained survival in mRCC and to more options for patients based on the highest level of evidence.

References

  • 1.

    Hudes GR, Carducci MA, Choueiri TK. NCCN Task Force report: optimizing treatment of advanced renal cell carcinoma with molecular targeted therapy. J Natl Compr Canc Netw 2011;9(Suppl 1):S129.

    • Search Google Scholar
    • Export Citation
  • 2.

    Motzer RJ, Huston TE, Cella D. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013;369:722731.

  • 3.

    Sonpavde G, Choueiri TK, Escudier B. Sequencing of agents for metastatic renal cell carcinoma: can we customize therapy? Eur Urol 2012;61:307316.

    • Search Google Scholar
    • Export Citation
  • 4.

    Kalra S, Rini BI, Jonasch E. Alternate sunitinib schedules in patients with metastatic renal cell carcinoma. Ann Oncol 2015;26:13001304.

  • 5.

    Motzer RJ, Porta C, Vogelzang NJ. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol 2014;15:286296.

    • Search Google Scholar
    • Export Citation
  • 6.

    Motzer R, Hutson T, Glen H. Randomized phase 2 three-arm trial of lenvatinib (LEN), everolimus (EVE), and LNE+EVE in patients (pts) with metastatic renal cell carcinoma (mRCC) [abstract]. J Clin Oncol 2015;33(Suppl): Abstract 4506.

    • Search Google Scholar
    • Export Citation
  • 7.

    Sennino B, Ishiguro-Oonuma T, Wei Y. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov 2012;2:270287.

    • Search Google Scholar
    • Export Citation
  • 8.

    Choueiri TK, Pal SK, McDermott DF. A phase I study of cabozantinib (XL184) in patients with renal cell cancer. Ann Oncol 2014;25:16031608.

  • 9.

    Harshman LC, Drake CG, Choueiri TK. PD-1 blockade in renal cell carcinoma: to equilibrium and beyond. Cancer Immunol Res 2014;2:11321141.

  • 10.

    McDermott DF, Drake CG, Sznol M. Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab. J Clin Oncol 2015;33:20132020.

    • Search Google Scholar
    • Export Citation
  • 11.

    Motzer RJ, Rini BI, McDermott DF. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol 2014;33:14301437.

    • Search Google Scholar
    • Export Citation
  • 12.

    Choueiri TK, Fishman MN, Escudier BJ. Immunomodulatory activity of nivolumab in previously treated and untreated metastatic renal cell carcinoma (mRCC): biomarker-based results from a randomized clinical trial [abstract]. J Clin Oncol 2014;32(Suppl 5):Abstract 5012.

    • Search Google Scholar
    • Export Citation
  • 13.

    McDermott DF, Sznol M, Sosman JA: Immune correlates and long term follow up of a phase Ia study of MPDL3280A, an engineered PD-L1 antibody, in patients with metastatic renal cell carcinoma (mRCC). Ann Oncol 2015;25(Suppl):Abstract 8090.

    • Search Google Scholar
    • Export Citation
  • 14.

    Hammers HJ, Plimack ER, Infante JR. Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC) [abstract]. J Clin Oncol 2014;32(Suppl 5):Abstract 4504.

    • Search Google Scholar
    • Export Citation
  • 15.

    Albiges L, Pal SK, Choueiri TK. The future of metastatic renal cell carcinoma treatment. Genitouriurinary Cancer Symposium Daily News 2015.

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Toni K. Choueiri, MD, is a genitourinary medical oncologist at Dana-Farber Cancer Institute and Brigham and Women's Hospital, where he is the leader of the Kidney Cancer Center and Co-leader of the Kidney Cancer Program at Dana-Farber/Harvard Cancer Center (DF/HCC). He is also the Clinical Director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute. He serves on the NCCN Guidelines Panel for Kidney and Testicular Cancers and is Chairman of the Medical and Scientific Steering Committee of the Kidney Cancer Association. Dr. Choueiri has a joint appointment at Harvard Medical School as an Associate Professor of Medicine. He is interested in developing novel therapies and biomarkers in genitourinary malignancies including kidney and bladder cancers. His work is funded by ASCO, the DF/HCC Kidney SPORE, and NCI. He has over 250 peer-reviewed publications and is the overall principal investigator of multiple phase I–III trials in genitourinary cancers and renal cancer.

The ideas and viewpoints expressed in this editorial are those of the author and do not necessarily represent any policy, position, or program of NCCN.

Robert J. Motzer, MD, is a board-certified medical oncologist who is dedicated to improving the lives of patients with genitourinary tumors. Dr. Motzer's primary area of expertise is in renal cell carcinoma and germ cell tumors. For more than 25 years, Dr. Motzer has used his skills as a clinician to provide high-quality and compassionate care for cancer patients at Memorial Sloan Kettering Cancer Center.

In addition to providing patients with the highest standard of medical care, Dr. Motzer has led more than 80 clinical trials in patients with kidney and testicular cancers, including national and international multicenter clinical trials. His research has helped to identify five targeted drugs — sunitinib, pazopanib, axitinib, temsirolimus, and everolimus—as effective treatments for patients with advanced kidney cancer. He has also developed a system to aid in the prediction of treatment outcomes for patients taking medications for advanced kidney cancer; this (“MSK”) risk system is widely applied by physicians internationally to direct the care of patients. In the area of testicular cancer, his efforts focus on developing better treatments for patients with high-dose chemotherapy and stem cell infusion. He has published more than 400 original articles, scientific reviews, chapters and abstracts.

  • 1.

    Hudes GR, Carducci MA, Choueiri TK. NCCN Task Force report: optimizing treatment of advanced renal cell carcinoma with molecular targeted therapy. J Natl Compr Canc Netw 2011;9(Suppl 1):S129.

    • Search Google Scholar
    • Export Citation
  • 2.

    Motzer RJ, Huston TE, Cella D. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013;369:722731.

  • 3.

    Sonpavde G, Choueiri TK, Escudier B. Sequencing of agents for metastatic renal cell carcinoma: can we customize therapy? Eur Urol 2012;61:307316.

    • Search Google Scholar
    • Export Citation
  • 4.

    Kalra S, Rini BI, Jonasch E. Alternate sunitinib schedules in patients with metastatic renal cell carcinoma. Ann Oncol 2015;26:13001304.

  • 5.

    Motzer RJ, Porta C, Vogelzang NJ. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol 2014;15:286296.

    • Search Google Scholar
    • Export Citation
  • 6.

    Motzer R, Hutson T, Glen H. Randomized phase 2 three-arm trial of lenvatinib (LEN), everolimus (EVE), and LNE+EVE in patients (pts) with metastatic renal cell carcinoma (mRCC) [abstract]. J Clin Oncol 2015;33(Suppl): Abstract 4506.

    • Search Google Scholar
    • Export Citation
  • 7.

    Sennino B, Ishiguro-Oonuma T, Wei Y. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov 2012;2:270287.

    • Search Google Scholar
    • Export Citation
  • 8.

    Choueiri TK, Pal SK, McDermott DF. A phase I study of cabozantinib (XL184) in patients with renal cell cancer. Ann Oncol 2014;25:16031608.

  • 9.

    Harshman LC, Drake CG, Choueiri TK. PD-1 blockade in renal cell carcinoma: to equilibrium and beyond. Cancer Immunol Res 2014;2:11321141.

  • 10.

    McDermott DF, Drake CG, Sznol M. Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab. J Clin Oncol 2015;33:20132020.

    • Search Google Scholar
    • Export Citation
  • 11.

    Motzer RJ, Rini BI, McDermott DF. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol 2014;33:14301437.

    • Search Google Scholar
    • Export Citation
  • 12.

    Choueiri TK, Fishman MN, Escudier BJ. Immunomodulatory activity of nivolumab in previously treated and untreated metastatic renal cell carcinoma (mRCC): biomarker-based results from a randomized clinical trial [abstract]. J Clin Oncol 2014;32(Suppl 5):Abstract 5012.

    • Search Google Scholar
    • Export Citation
  • 13.

    McDermott DF, Sznol M, Sosman JA: Immune correlates and long term follow up of a phase Ia study of MPDL3280A, an engineered PD-L1 antibody, in patients with metastatic renal cell carcinoma (mRCC). Ann Oncol 2015;25(Suppl):Abstract 8090.

    • Search Google Scholar
    • Export Citation
  • 14.

    Hammers HJ, Plimack ER, Infante JR. Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC) [abstract]. J Clin Oncol 2014;32(Suppl 5):Abstract 4504.

    • Search Google Scholar
    • Export Citation
  • 15.

    Albiges L, Pal SK, Choueiri TK. The future of metastatic renal cell carcinoma treatment. Genitouriurinary Cancer Symposium Daily News 2015.

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