The selective VEGFR TKI tivozanib has demonstrated single agent activity following VEGFR TKI and ICI, and in combination with ICI. TiNivo-2 was designed to test the combination of the PD-1 inhibitor nivolumab and tivozanib vs tivozanib monotherapy following tumor progression on prior ICI-based therapy.
TiNivo-2 enrolled pts with advanced clear-cell RCC who had 1–2 prior lines of therapy, including an ICI. Pts were randomized to receive tivozanib (0.89 mg) plus nivolumab or tivozanib alone (1.34 mg). The primary endpoint was PFS by independent radiology review (IRR); the key secondary endpoint was OS, other secondary endpoints included investigator-assessed PFS, ORR, DoR, and safety/tolerability. A sample size of 343 pts with 220 events provided ≥80% power to detect a 50% improvement in PFS, 12 m vs 8 m, assessed by IRR.
343 pts were randomized to tivozanib–nivolumab (n=171) or tivozanib (n=172). Baseline characteristics were well balanced. With a median IRR-assessed PFS of 5.7 m for tivozanib–nivolumab and 7.4 m for tivozanib (HR 1.10 [95% CI 0.82. 1.43]), the study did not meet its primary endpoint. Among those with ICI as immediate prior therapy (n=244), mPFS was 7.4 m (95% CI, 5·55-9·56) with tivozanib–nivolumab and 9.2 m (95% CI, 7·43-9·99) with tivozanib. Data for subgroups and OS and ORR are in the table. 205 (60%) pts experienced a grade 3 or higher AE, the most common was hypertension (22% both arms; others <5%). AEs leading to death occurred in 7 (4.2%) pts with tivozanib–nivolumab and 5 (2.9%) with tivozanib; 1 (tivozanib arm) was deemed treatment related.
| Tivozanib–Nivolumab n=171 | Tivozanib N=172 | |
| Median PFS ITT, mo (95% CI) | 5.7 (4.04, 7.43) | 7.4 (5.55, 9.23) |
| Median PFS ICI as most recent therapy, mo (95% CI) | 7.4 (5.55, 9.56) | 9.2 (7.43, 9.99) |
| Median PFS non-ICI as most recent therapy, mo (95% CI) | 3.7 (2.73, 5.42) | 3.7 (1.94, 7.16) |
| Median PFS study treatment 2nd line, mo (95% CI) | 7.3 (5.42, 9.33) | 9.2 (7.43, 9.99) |
| Median PFS study treatment 3rd line, mo (95% CI) | 4.8 (3.15, 7.49) | 5.5 (2.89, 7.36) |
| Median OS, mo (95% CI) | 17.7 (9.63, NR) | 22.1 (15.24, NR) |
| Best ORR (95% CI) | 19.3% (13.7-26.0) | 19.8% (14.1-26.5) |
Table: LBA73 Open table in a new tab
ICI combination rechallenge did not improve clinical outcomes, suggesting the avoidance of sequential ICI in advanced RCC outside of clinical trials. These results support tivozanib monotherapy at 1.34 mg daily as 2nd-line therapy for pts following progression on previous ICI combination therapy.