Adding Nivolumab to Tivozanib Fails to Improve Outcomes in Metastatic Renal Cell Carcinoma

Toni Choueiri, MD

The phase 3 TiNivo-2 study (NCT04987203), which evaluated the combination of nivolumab (Opdivo) and tivozanib (Fotivda) in patients with metastatic renal cell carcinoma (RCC) who had progressed on or after treatment with a PD-(L)1 inhibitor, showed that the addition of nivolumab to tivozanib did not lead to improved clinical outcomes in this patient population, according to findings presented at the 2024 ESMO Annual Congress.¹

“TiNivo-2 was the first phase 3 trial to evaluate the efficacy and safety of a PD-1 inhibitor following progression on or after treatment with a PD-[L]1 therapy,” Toni Choueiri, MD, of Dana-Farber Cancer Institute in Boston Massachusetts, said in a presentation of the data at the 2024 ESMO Annual Congress. “TiNivo-2 is a negative study, but I strongly believe it’s important. It is practice changing, and it should make us think twice now…These results support tivozanib monotherapy at 1.34 kg as a second-line therapy option in patients following progression on previous immune checkpoint inhibitor [ICI] therapy.”

At a median follow-up of 11.8 months in the tivozanib plus nivolumab arm (n = 171) and 12.5 months in the tivozanib monotherapy arm (n = 172), the median progression-free survival (PFS) was not improved with the doublet vs monotherapy (stratified HR, 1.10; 95% CI, 0.84-1.43; P = .49). Findings from the primary analysis of centrally reviewed PFS, which was the study’s primary end point, revealed that the median PFS was 5.7 months (95% CI, 4.0-7.4) for the combination vs 7.4 months (95% CI, 5.6-9.2) for tivozanib alone in the intention-to-treat population.

When examining centrally reviewed PFS by subgroups, no group appeared to benefit from the doublet vs monotherapy, according to Choueiri. The lowest HR was 0.92 (95% CI, 0.61-1.37) in patients 65 years of age or older, and the highest HR was 1.37 (95% CI, 0.69-2.73) in patients with International Metastatic RCC Database Consortium (IMDC) favorable-risk disease.

“This trial confirms and expands key conclusions from the [phase 3] CONTACT-03 study [NCT04338269]. [TiNivo-2] is the second phase 3 trial in RCC and solid tumors that suggests that ICI rechallenge should be generally discouraged regardless of treatment sequence. We [also] believe that the reduced dose of tivozanib in the combination arm may have impacted the efficacy, and that reflects in the lower median PFS [observed],” Choueiri said.

Diving Into TiNivo-2’s Design and Difference in Dosing Between Arms

Patients with locally advanced or metastatic clear cell RCC were enrolled following disease progression on 1 or 2 lines of therapy, 1 of which was an ICI they progressed on during or following at least 6 weeks of therapy. Patients needed to have an ECOG performance status of 0 or 1, measurable disease per RECIST 1.1 criteria, and a time from immediate prior line of therapy received to random assignment of 6 months or less.

“What remains unknown, in large part, is the optimal sequence [of therapies in RCC] in patients whose disease has progressed after treatment with an ICI. If we rechallenge with the same or a different ICI, does this improve clinical outcomes? Could outcomes be impacted if we use a non-ICI drug before ICI rechallenge and an ICI break? What about using a PD-1 vs PD-L1 inhibitor, does that matter?” Choueiri asked. He noted that following encouraging efficacy seen in the phase 1/2 TiNivo study (NCT03136627) with tivozanib plus nivolumab, TiNivo-2 was initiated.

Random assignment for TiNivo-2 was done in a 1:1 fashion, and stratification factors included IMDC risk category and prior therapy received (ICI as most recent therapy vs not). Patients in the tivozanib monotherapy arm received the agent orally at 1.34 mg on days 1 to 21 of each 28-day cycle. Those in the doublet arm received a reduced dose of 0.89 mg on the same schedule plus 480 mg of intravenous nivolumab given on day 1 of each cycle.

Choueiri noted that the reduced dose was agreed upon with regulatory authorities due to the potential risk of increased rates of grade 3/4 hypertension in the combination arm.

PFS by independent radiology review served as the trial’s primary end point, and secondary end points were overall survival (OS), PFS by investigator assessment, objective response rate (ORR), duration of response (DOR), and safety/tolerability.

Baseline patient characteristics were also well balanced between the two arms. The median age of patients in the tivozanib plus nivolumab arm was 64 years (range, 37-87) compared with 63 years (range, 33-82) in the tivozanib monotherapy arm. Most patients were male (73% for the combination vs 78% for tivozanib monotherapy), White (65% vs 62%), had an ECOG performance score of 1 (55% vs 51%), received 1 prior line of therapy (65% vs 61%), and received an ICI as their most recent therapy (71% vs 71%). Additionally, patients had favorable- (18% vs 18%), intermediate- (67% vs 66%), and poor- (16% vs 16%) risk disease by IMDC, and approximately one-third of patients did not receive a prior VEGFR-TKI (31% vs 31%).

Kidney cancer, colorful medically 3D illustration: © Axel Kock - stock.adobe.comKidney cancer, colorful medically 3D illustration: © Axel Kock - stock.adobe.com

PFS by Line of Therapy and OS Data

When examining PFS by line of therapy, higher PFS rates were observed in the second-line setting, although tivozanib monotherapy bested tivozanib plus nivolumab. The median PFS among patients who received tivozanib plus nivolumab (n = 111) in the second-line setting was 7.3 months (95% CI, 5.4-9.3) vs 9.2 months (95% CI, 7.4-10.0) among patients treated with the monotherapy in this setting (n = 105; HR, 1.15; 95% CI, 0.82-1.62; P = .4283).

Those who received treatment in TiNivo-2 as third-line therapy experienced a median PFS of 4.8 months (95% CI, 3.2-7.5) in the doublet arm (n = 60) vs 5.5 months (95% CI, 2.9-7.4) in the monotherapy arm (n = 67; HR, 0.97; 95% CI, 0.65-1.45; P = .8866).

“I believe [these data] debunk the theory that break and rechallenge is better,” Choueiri added.

Furthermore, data revealed that the median OS was 17.7 months (95% CI, 15.1–not reached [NR]) in the tivozanib plus nivolumab arm compared with 22.1 months (95% CI, 15.2-NR) in the tivozanib monotherapy arm (HR, 1.00; 95% CI, 0.68-1.46; P = .9868). However, Choueiri noted that OS data were not mature; at data cutoff, 32% of events had occurred.

Additionally, the ORR was 19.3% (95% CI, 13.7%-26.0%) in the doublet arm vs 19.8% (95% CI, 14.1%-26.5%) in the singlet arm. One patient in each arm achieved a complete response. Patients also experienced stable disease (43.3% vs 47.1%), progressive disease (28.7% vs 25.0%), or were not evaluable (8.8% vs 8.1%). The median DOR was 15.77 months (95% CI, 5.65-NR) with the doublet compared with 9.66 months (95% CI, 3.71-NR) with monotherapy.

Safety Findings Are Comparable Between Arms

Adverse effects (AEs) leading to death occurred in 7 patients in the doublet arm and 5 patients in the tivozanib monotherapy arm. Patients experienced grade 2 or greater AEs (61% for the doublet vs 60% for the singlet), serious AEs (32% vs 37%), and treatment-emergent AEs leading to discontinuation (16% vs 19%), dose interruption (49% vs 54%), and dose reduction of tivozanib (11% vs 22%). The median duration of treatment was 6.3 months (range, 0.0-20.7) and 7.4 months (range, 0.1-17.9), respectively.

The most common any-grade AEs observed were hypertension (37% vs 40%), fatigue (29% vs 40%), diarrhea (30% vs 36%), and nausea (16% vs 28%), in the doublet and monotherapy arms, respectively.

Disclosures: Dr Choueiri cited receiving institutional and/or personal, paid and/or unpaid support for research, advisory boards, consultancy, and/or Honoria in the past 5 years, ongoing or not, from: Alkermes; Arcus Biosciences; AstraZeneca; Aravive; Aveo; Bayer; Bristol-Myers Squibb; Calithera; Circle Pharma; Deciphera Therapeutrics; Eisai; EMD Serono; Exelixis; GSK; Gilead; HiberCell; IQVIA; Infinity; Ipsen; Janssen Oncology; Kanaph Therapeutics; Lilly; Merck; NiKang Therapeutics; Neomorph; Neucon/Precede Biosciences; Novartis; OncoHost; Pfizer; Roche; Sanofi-Aventis; Scholar Rock; Surface Oncology; Takeda; Tempest Therapeutics; UpToDate; and CME events. He also cited having institutional patents filed on molecular alterations and immunotherapy response/toxicity and ctDNA. Choueiri also has equity in Tempest; Pionyr, Osel; Precede Biosciences; Curesponse; InnDura Therapeutics; and Premium. He is on committees for the NCCN; GU Steering Committee; ASCO; ESMO; ACCRU; and KidneyCAN.

REFERENCE:

Choueiri TK, Motzer RJ, Beckermann K, et al. Tivozanib–nivolumab vs tivozanib monotherapy in patients with renal cell carcinoma (RCC) following 1 or 2 prior therapies including an immune checkpoint inhibitor (ICI): Results of the phase III TiNivo-2 study. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA73.