According to Dr. Motzer there several key phase 2 studies for mRCC that he highlighted:
- High-dose bevacizumab vs placebo  – 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  – 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  – 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.
- TARGETS: sorafenib vs placebo  – 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  – 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  – 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  – 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  – 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).
- GOLD: dovitinib vs sorafenib  – 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  – 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  – 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.
- CheckMate 214: nivolumab + ipilimumab vs sunitinib in the first line setting  – 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)  – 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  vs S-TRAC  - 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  - 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).
Dr. Motzer concluded this Keynote Lecture with a table highlighting ongoing phase 3 VEGF/PD-1 blockade combination studies in the first-line setting:
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
2018 ASCO GU - Renal Cell Cancer: Keynote Lecture: The Future of Immuno-Oncology in Renal Cell Carcinoma
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