Dr. Agarwal started his talk by highlighting the poor prognostic factors associated with response to VEGF inhibitors, namely (i) Karnofsky Performance status <80%, (ii) time to therapy interval <1 yr, (iii) anemia, (iv) hypercalcemia, (v) neutrophilia, and (vi) thrombocytosis. These factors have subsequently been translated into the IMDC prognostic criteria: favorable (0 factors, median OS 43 months), intermediate (1-2 factors, median OS 22 months), poor risk (3-6 factors, median OS 8 months).
In the first-line targeted therapy for metastatic clear cell renal cell carcinoma (mccRCC), there are many agents including sunitinib, pazopanib, bevacizumab + interferon, etc. Specifically for poor risk patients, temsirolimus is considered the most appropriate agent. As mentioned in Dr. Vaishampayan’s talk earlier, high dose IL-2 should also be considered as first line therapy, even in the targeted therapy era. Certainly there are upcoming new first-line treatments, including cabozantinib, which leads to VHL inactivation, upregulation of MET, VEGF, and AXL, subsequently leading to inhibition of tumor progression, growth and invasion. The recently published CABOSUN trial  demonstrated that cabozantinib derived a significant benefit in progression-free survival (PFS; 8.2 vs 5.6 months, HR 0.66, 95%CI 0.46-0.95) and objective response rate (ORR) over sunitinib in the first line, specifically for patients with intermediate or poor risk mRCC. Results of the IMmotion 150 trial of atezolizumab + bevacizumab vs atezolizumab vs sunitinib will be presented at this meeting (Abstract 4505).
Additionally, there have been multiple clinical trials assessing targeted therapy in the second line after first line disease progression. The AXIS trial was published in 2011, assessing axitinib vs sorafenib reporting that axitinib resulted in a significantly longer PFS (6.7 vs 4.7 months; HR 0.67, 95%CI 0.54-0.81) compared to sorafenib . The METEOR trial (cabozantinib vs everolimus) demonstrated a significantly improved PFS with cabozantinib (median PFS 7.4 vs 3.9 months; HR 0.51, 95%CI 0.41-0.62) . An updated analysis of this trial demonstrated a continued benefit of cabozantinib with regards to OS (median 21.4 vs 16.5 months; HR 0.66, 95%CI 0.53-0.83) .
Lenvatinib was also tested in the second line, specifically lenvatinib + everolimus and lenvatinib alone and found that PFS for patients treated with combination therapy (HR 0.40, 95%CI 0.24-0.68) and lenvatinib alone (HR 0.61, 95%CI 0.38-0.98) had improved compared to everolimus alone . Finally, in a landmark study incorporating immunotherapy, nivolumab vs everolimus (CheckMate 025) showed an improved OS for patients taking nivolumab (median OS 25.0 vs 19.6; HR 0.73, 95%CI 0.60-0.89) . The challenge with selecting an appropriate second line therapy is that we don’t have validated biomarkers, although PD-L1 expression has been tested in the CheckMate-025 trial. In a subset analysis of the METEOR trial looking at patients with bone-metastasis, patients treated with cabozantinib had an improved PFS compared to those treated with everolimus (7.4 vs 2.7 months, HR 0.33), suggesting that patients with bone metastasis may benefit from cabozantinib therapy. As Dr. Agarwal mentions, there may be additional considerations at play for selecting second line therapy, including (i) PO vs IV administration, (ii) co-pays for oral agents, and (iii) physician comfort for the agent administered.
Dr. Agarwal concluded with excellent summary algorithm slides for sequencing possibilities in the current era. After first-line therapy with either sunitinib, pazopanib or bevacizumab + IFN, it is reasonable to consider either nivolumab, cabozantinib, lenvatinib-everolimus or axitinib in the second line setting. If patients are treated with first line high-dose IL-2 or other immunotherapy agents, potential second line agents include axitinib, pazopanib or sunitinib. Finally, if patients are treated with first-line temsirolimus, possible second line agents include nivolumab, cabozantinib, sunitinib or pazopanib. Dr. Agarwal concluded with a pertinent statement “Clinical trials should be offered for every line since cure is unlikely with current therapy.”
Presented By: Neeraj Agarwal, Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT, USA
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre
at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA
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