MDACC 2018: Debate: What is the Best Salvage Therapy After Failure of Immune Checkpoint Inhibition?

Houston, TX (UroToday.com) Dr. Msaouel opened the debate supporting the use of Cabozantinib for salvage therapy after failure of immune checkpoint inhibitors.  His argument was broken down into three points: Use of previously established first line, use of previously established second line and assumption that after failure of an immune checkpoint inhibition is a unique biologic scenario. 

Since Cabozantinib is the previously established first-line recommendation for intermediate/poor risk patients, it was argued that it should be the first line for salvage.  In the CABOSUN trial1, Cabozantinib was superior to Sunitinib in terms of objective response rate (ORR) (20% vs 9%), median progression-free survival (PFS) (8.6 vs 5.3%), HR 0.48, and median overall survival (OS) 26.6 versus 21.2 months, HR 0.80.   The median OS was inconclusive per statistical analysis.  For these reasons, it is reasonable to choose Cabozantinib over other anti-VEGF TKI for salvage therapy. What if we went with the previously established second line recommendation?  Cabozantinib is one of the category one preferred options primary derived from data from the METEOR trial comparing Cabozantinib versus Everolimus2, which showed an improved ORR (17% vs 3%, p<0.001), Median PFS (7.4 vs 3.9 months, HR 0.51), Median OS 21.4% vs 16.5 months, HR 0.66) in Cabozantinib when compared to Everolimus.  Additionally, a network meta-analysis found that Cabozantinib produces a higher probability of longer PFS compared with Axitinib during the analyzed 3 years3.  Finally, when looking at a failure of immune checkpoint inhibition as a unique biologic scenario, this might be the only situation where the use of Cabozantinib may not be as supported when compared to Axitinib or possibly Lenvatinib with Everolimus.  However, since there is a lack of high quality randomized clinical trials, it would make the most sense to use Cabozantinib as the first line, since it has the most robust data. Finally, there may not be another chance for treatment, therefore choosing the strongest regimen would be the most conservative action.  In terms of non-clear cell RCC, the data is not as robust and it is difficult to compare Cabozantinib with Axitinib, although the biologic rationale would support favoring Cabozantinib in papillary RCC. 

Dr. Zurita-Saavedra focused on the Axitinib as the best option for salvage therapy, as it is potent and selective, tolerable, has clinical activity in the resistant setting and is approved as a second-line treatment.  Axitinib is more potent than Sorafenib, Pazopanib, and Sorafenib.  It has rapid absorption and a short half-life of 3-5 hours.  At GU ASCO in 2018, Bracarda showed that when compared to Sorafenib, Axitinib showed longer PFS.  Axitinib has also shown to be titratable and results in an improvement of ORR 4.  Importantly, Axitinib was shown to be active after PD-1 inhibitor treatment 5.

Dr. Shah reported on the phase II study of Levnatinib versus Everolimus versus Lenvantinib plus Everolimus in mRCC 6, which demonstrated mPFS, OS, ORR and DCR in these treatment regimens 7 (slide) in support of their use after failure of immune checkpoint inhibition.  Additionally, Levnatinib has a proven OSS benefit where Axitinib does not. The most common side effects of Levnatinib plus Everolimus are diarrhea, hypertriglyceridemia, hypertension, stomatitis, and hypothyroidism, all of which are easily managed.  Finally, this regimen is easily titratable, making it a very appealing option. 

MDACC 2018 UroToday Debate What is the Best Salvage Therapy After Failure of Immune Checkpoint Inhibition


Presented by: Pavlos Msaouel, MD, (Cabozanitinib), Amado J. Zurita-Saavedra, MD, (Axitinib), Amishi Y. Shah, MD, (Lenvatinib Plus Everolimus), Genitourinary Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA

Written by Dr. Amy H. Lim, MD, PhD, Urologic Oncology Fellow and Ashish M. Kamat, MD, (@UroDocAsh), Professor, Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX at the 13th Update on the Management of Genitourinary Malignancies, The University of Texas (MDACC - MD Anderson Cancer Center) November 9-10, 2018, Dan L. Duncan Building, Houston, TX

References:
1. Choueiri TK, Hessel C, Halabi S, Sanford B, Michaelson MD, Hahn O, et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): Progression-free survival by independent review and overall survival update. Eur J Cancer. 2018;94:115-25.
2. Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(7):917-27.
3. Amzal B, Fu S, Meng J, Lister J, Karcher H. Cabozantinib versus everolimus, nivolumab, axitinib, sorafenib, and best supportive care: A network meta-analysis of progression-free survival and overall survival in second line treatment of advanced renal cell carcinoma. PLoS One. 2017;12(9):e0184423.
4. Rini BI, Melichar B, Ueda T, Grünwald V, Fishman MN, Arranz JA, et al. Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial. Lancet Oncol. 2013;14(12):1233-42.
5. Nadal R, Amin A, Geynisman DM, Voss MH, Weinstock M, Doyle J, et al. Safety and clinical activity of vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitors after programmed cell death 1 inhibitor treatment in patients with metastatic clear cell renal cell carcinoma. Ann Oncol. 2016;27(7):1304-11.
6. Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16(15):1473-82.
7. Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016;17(1):e4-5.
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