ASCO GU 2018: Tyrosine Kinase Inhibitors for Renal Cell Carcinoma: Past, Present, and Future

San Francisco, CA (UroToday.com) Dr. Robert Motzer from Memorial Sloan Kettering Cancer Center provided one of the kidney cancer Keynote Lectures at the 2018 GU ASCO meeting in San Francisco. Currently there are 10 FDA-approved drugs for advanced/metastatic RCC since 2005, and we have certainly seen an improved survival with the targeted therapies:

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According to Dr. Motzer there several key phase 2 studies for mRCC that he highlighted:

  • High-dose bevacizumab vs placebo [1] – 116 patients were randomized to low-dose antibody (n=37) vs high-dose antibody (n=39) vs placebo (n=40). The study was stopped at the interim analysis secondary to a significant prolongation of time to disease progression among high-dose bevacizumab vs placebo (HR 2.55, p<0.001).
  • Bay 43-9006 Study 100391: RCC bidimensional tumor investigator assessed measurements at week 12: Change from baseline in target lesions [2] – Bay 43-9006 (sorafenib) was assessed in 89 patients progressing on cytokine therapy, demonstrating >50% shrinkage of tumor in 13 patients, >25-50% in 24 patients and <25%-25% in 45 patients. 
  • SU11248 for RCC: Objective response rate and % reduction of target lesions by individual patient assessment [3] – 63 patients progressing on cytokine therapy received SU11248 (sunitinib) monotherapy with no patients achieving complete response, however 40% achieving partial response, 27% with stable disease and 33% with progressive disease. Median time progression was 8.7 months. 
There are also several phase 3 milestones for mRCC that Dr. Motzer highlighted:

  • TARGETS: sorafenib vs placebo [4] – 903 pre-treated patients were randomized to sorafenib (n=451) or placebo (n=452) with a median time to progression of 5.5 months for sorafenib and 2.8 months for placebo (HR 0.44, 95%CI 0.35-0.55) and improvement in OS (HR 0.72, 95%CI 0.54-0.94). 
  • Study 1034: Sunitinib vs interferon-alfa [5] – 750 untreated patients were randomized to sunitinib (n=375) vs interferon-alfa (n=375) with a median time to progression of 11 months for sunitinib and 5 months for interferon-alfa (HR 0.42, 95%CI 0.32-0.54).
  • AXIS: axitinib vs sorafenib [6] – 723 pre-treated patients experiencing progression were randomized to axitinib (n=361) vs sorafenib (n=362) with a median time to progression of 6.7 months for axitinib compared to 4.7 months for sorafenib (HR 0.665, 9%CI 0.544-0.812).
  • METEOR: cabozantinib vs everolimus [7] – 658 patients that had progressed on VEGFR-targeted therapy were randomized to cabozantinib (n=330) vs everolimus (n=328) with a median time to progression of 7.4 months with cabozantinib compared to 3.8 months with everolimus (HR 0.58, 95%CI 0.45-0.75). OS also favored cabozantinib over everolimus (HR 0.67, 95%CI 0.51-0.89). 
  • COMPARZ: pazopanib vs sunitinib [8] – 1,110 untreated patients were randomized to receive pazopanib (n=557) vs sunitinib (n=553). Pazopanib was noninferior to sunitinib with respect to PFS (HR 1.05, 95%CI 0.90-1.22). Additionally, OS was similar between pazopanib and sunitinib (HR 0.91, 95%CI 0.76-1.08). 
Although there have been landmark phase 3 trials for mRCC, Dr. Motzer notes there have been several phase 3 trial “misses”:

  • GOLD: dovitinib vs sorafenib [9] – 570 patients requiring third-line therapy were randomized to receive dovitinib (n=284) vs sorafenib (n=286), with a median time to progression of 3.7 months for dovitinib compared to 3.6 months for sorafenib (HR 0.86, 95%CI 0.72-1.04). Dr. Motzer notes that this was the first phase 3 trial comparing third-line treatments, but was based on a paucity of outcome data from a phase 2 study in patients with previously treated with TKIs and mTOR inhibitors.
  • Axitinib vs sorafenib in the first line [10] – 288 untreated patients were randomized to receive axitinib (n=192) vs sorafenib (n=96) with a median time to progression of 10.1 months for axitinib compared to 6.5 months for sorafenib (HR 0.77, 95%CI 0.56-1.05). Dr. Motzer notes that this study had 90% power to detect a 78% improvement in PFS from 5.5 months with sorafenib to 9.8 months with axitinib, corresponding to an HR of 0.56 (overall 1-sided alpha = 0.025). Furthermore, he notes that sorafenib likely wasn’t the best comparator drug, considering that in the real world sunitinib was primarily being used. 
  • TIVO-1: tivozanib vs sorafenib in the first line [11] – 517 untreated patients were randomized to receive tivozanib (n=260) or sorafenib (n=257) with a median time to progression of 11.9 months for tivozanib compared to 9.1 months for sorafenib (HR 0.797, 95%CI 0.639-0.993). Among patients treated with sorafenib, 156 subsequently received tivozanib. Dr. Motzer notes that the issue with this study was that most of the recruitment was in parts of the world where there wasn’t availability of VEGF targeted therapies in the first-line. As such, nearly 70% of the patients in the sorafenib arm ultimately received tivozanib; the final OS actually showed a trend toward longer survival in the sorafenib arm (HR 1.245, 95%CI 0.954-1.624) likely secondary to such a high crossover rate. 
According to Dr. Motzer, there are several studies that have generated headlines and further questions:

  • CheckMate 214: nivolumab + ipilimumab vs sunitinib in the first line setting [12] – Dr. Motzer highlighted the impressive results in the IMDC intermediate/poor risk patients: among 425 patients receiving nivolumab + ipilimumab the median OS was not reached (95%CI 28.2-NR), compared to the 422 patients receiving sunitinib where the median OS was 26.0 months (95%CI 22.1-NR). This resulted in a HR favoring nivolumab + ipilimumab (HR 0.63, 99.8%CI 0.44-0.89).
  • CABOSUN: cabozantinib vs sunitinib in the first line setting (all poor/intermediate risk) [13] – there were 79 patients randomized to cabozantinib vs 78 patients receiving sunitinib. Patients receiving cabozantinib had a median PFS of 8.2 months (95%CI 6.2-9.0) compared to 5.6 months (95%CI 3.4-8.1) for sunitinib, resulting in a significant HR favoring cabozantinib (HR 0.69, 95%CI 0.48-0.99).
  • Adjuvant sunitinib: ASSURE [14] vs S-TRAC [15] - ASSURE found no disease-free survival (DFS) or OS benefit for either sunitinib or sorafenib among clear cell and non-clear cell RCC ≥T2Gr3/4 patients. S-TRAC reported a DFS benefit (1-2 years, HR 0.76, 95%CI 0.59-0.98), but no OS benefit with the immature data (and underpowered) among patients with clear cell RCC ≥T3 disease. As Dr. Motzer notes, 44% of patients (sunitinib) in ASSURE and 28% of patients in S-TRAC discontinued therapy secondary to toxicity.
  • PROTECT: Adjuvant pazopanib [16] - 1,538 patients had either resected pT2 (high grade) or ≥pT3 clear cell RCC after nephrectomy and were randomized to pazopanib vs placebo for 1 year. The starting dose (800 mg) following treatment of 403 patients was lowered to 600 mg to improve tolerability. Subsequently, the primary endpoint was changed to DFS with pazopanib 600 mg (n=1,135), which was performed after 350 DFS events in an intention-to-treat (ITT) analysis. The primary analysis (DFS ITT for patients receiving pazopanib 600 mg) was not significant (HR 0.86, 95%CI 0.70-1.06). 
Looking ahead, Dr. Motzer further highlighted several important points. In a phase II study assessing atezolizumab + bevacizumab vs sunitinib [17], patients receiving atezolizumab + bevacizumab had a median time to progression of 14.7 months compared to those receiving sunitinib (7.8 months) and atezolizumab (5.5 months). This resulted in a nearly significant HR ratio of 0.64 (95%CI 0.38-1.08) for atezolizumab + bevacizumab vs sunitinib. Certainly, the TKI/immunotherapy combinatorial trials are gaining interest, including a phase Ib trial of 55 patients receiving axitinib + avelumab [18]. The partial response rate for these patients was 53% and ORR was 58%. At ESMO 2017, initial results of lenvatinib + pembrolizumab (n=30) were presented, noting a 63% and partial response rate of 63% [19].

Dr. Motzer concluded this Keynote Lecture with a table highlighting ongoing phase 3 VEGF/PD-1 blockade combination studies in the first-line setting:
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Presented by: Robert J. Motzer, MD Memorial Sloan Kettering Cancer Center, New York, NY

Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, @zklaassen_md at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA


Read More: 
2018 ASCO GU - Renal Cell Cancer: Keynote Lecture: The Future of Immuno-Oncology in Renal Cell Carcinoma

References: 

1. Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349(5):427-434.

2. J Clin Oncol 2004;4:23 abstr 4501

3. Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24(1):16-24. 

4. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356(2):125-134.

5. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356(2):115-124.

6. 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(9807):1931-1939.

7. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015;373(19):1814-1823.

8. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013;369(8):722-731.

9. Motzer RJ, Porta C, Vogelzang NJ, et al. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: An open-label, randomized phase 3 trail. Lancet Oncol 2014;15(3):286-296.

10.  Hutson TE, Lesovoy V, Al-Shukri S, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: A randomized open-label phase 3 trial. Lancet Oncol 2013;14(13):1287-1294.

11. Motzer RJ, Nosov D, Eisen T, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: Results from a phase III trial. J Clin Oncol 2013;31(30):3791-3799.

12. Escudier B, Tannir N, McDermott D, et al. CheckMate 214: Efficacy and safety of Nivolumab + Ipilimumab vs Sunitinib for treatment-naïve advanced or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. ESMO 2017 abst LBA5.

13. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus Sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: The Alliance A031203 CABOSUN Trial. J Clin Oncol 2017;35(6):591-597.

14. Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): A double-blind, placebo-controlled, randomised, phase 3 trial. Lancet 2016;387(10032):2008-2016.

15. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. N Engl J Med 2016;375(23):2246-2254.

16. Motzer RJ, Haas NB, Donskov F, et al. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with locally advanced renal cell carcinoma (RCC) (PROTECT). J Clin Oncol 2017;35(35):3916-3923.

17. McDermott D, Huseni M, Rini B, et al. Molecular correlates of differential response to atezolizumab +/- bevacizumab vs sunitinib in a phase II study in untreated metastatic renal cell carcinoma (RCC) patients. AACR 2017 abstr CT081.

18. Choueiri TK, Larkin JMG, Oya M, et al. First-line avelumab + axitinib therapy in patients (pts) with advanced renal cell carcinoma (aRCC): Results from a phase Ib trial. ASCO 2017 abstr 4504. 

19. Lee C, Makker V, Rasco D, et al. A phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with renal cell carcinoma. ESMO 2017 abstr 847O.
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