Patients with metastatic renal cell carcinoma (RCC) — a type of kidney cancer — did not experience benefits after receiving a combination of Opdivo (nivolumab) and Fotivda (tivozanib). Patients previously experienced disease progression (worsening) on or after treatment with a PD-(L)1 inhibitor.
Findings were based on the phase 3 TiNivo-2 study and presented at the 2024 ESMO Congress.
Study highlights:
- Patients with metastatic renal cell carcinoma (RCC) who received Opdivo and Fotivda after experiencing disease worsening on a PD-(L)1 inhibitor did not experience improved outcomes.
- Fotivda alone was shown to be a more effective option for these patients compared to the combination therapy.
- The study suggests that rechallenging patients with another immune checkpoint inhibitor (ICI) after progression on one is generally not recommended.
- The optimal sequence of therapies for patients with RCC who progress on an ICI remains uncertain.
“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,” Dr. Toni Choueiri of Dana-Farber Cancer Institute in Boston, said in a presentation of the data at the meeting. “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 [Fotivda] monotherapy at 1.34 kilograms 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 Fotivda plus Opdivo group with 171 patients and 12.5 months in the Fotivda monotherapy group with 172 patients, the median progression-free survival (PFS; time patients live without their disease worsening or spreading) was not improved with the doublet versus monotherapy. Findings from the primary analysis of PFS, which was the study’s primary goal, revealed that the median PFS was 5.7 months for the combination versus 7.4 months for Fotivda alone in the intention-to-treat population.
“This trial confirms and expands key conclusions from the [phase 3] CONTACT-03 study. [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 [Fotivda] in the combination [group] may have impacted the efficacy, and that reflects in the lower median PFS [observed],” Choueiri said.
Patient Characteristics and Study Findings
Patients with locally advanced or metastatic clear cell RCC were enrolled following disease progression on one or two lines of therapy, one of which was an ICI they progressed on during or following at least six weeks of therapy.
Patients needed to have an ECOG performance status of 0 or 1, meaning they were able to perform daily tasks independently; measurable disease; and a time from the immediate prior line of therapy received to their random assignment of six 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?” Choueiri asked. He noted that following the encouraging efficacy seen in the phase 1/2 TiNivo study with [Fotivda] plus nivolumab, TiNivo-2 was initiated.
Choueiri noted that the reduced dose was agreed upon with regulatory authorities due to the potential risk of increased rates of grade 3/4 (severe to life-threatening) hypertension (high blood pressure) in the combination treatment group.
The trial’s main goal was PFS and secondary goals were overall survival (OS; time patients live, regardless of disease status), objective response rate (ORR; percentage of patients whose tumors shrunk or disappeared), duration of response and safety/tolerability.
The median age of patients in the Fotivda plus Opdivo group was 64 years compared with 63 years in the Fotivda monotherapy group. Most patients were male (73% for the combination versus 78% for Fotivda monotherapy), White (65% versus 62%), had an ECOG performance score of 1 (55% versus 51%), received one prior line of therapy (65% versus 61%) and received an ICI as their most recent therapy (71% versus 71%). Additionally, patients had favorable- (18% versus 18%), intermediate- (67% versus 66%) and poor- (16% versus 16%) risk disease and approximately one-third of patients did not receive a prior VEGFR-TKI (31% versus 31%).
More Survival Findings for Patients With Metastatic Kidney Cancer
When examining PFS by line of therapy, higher PFS rates were observed in the second-line setting, although Fotivda monotherapy outdid Fotivda plus Opdivo. The median PFS among patients who received Fotivda plus Opdivo (111 patients) in the second-line setting was 7.3 months versus 9.2 months among patients treated with the monotherapy in this setting.
Those who received treatment in TiNivo-2 as third-line therapy experienced a median PFS of 4.8 months in the doublet group of 60 patients versus 5.5 months in the monotherapy group with 67 patients.
“I believe [these data] debunk the theory that break and rechallenge is better,” Choueiri added.
Data revealed that the median OS was 17.7 months in the Fotivda plus Opdivo group compared with 22.1 months in the Fotivda monotherapy group. However, Choueiri noted that OS data were not mature because at the data cutoff, only 32% of events had occurred in patients.
Additionally, the ORR was 19.3% in the doublet group versus 19.8% in the singlet group. One patient in each group achieved a complete response, meaning they no longer showed signs of cancer. Patients also experienced stable disease (43.3% versus 47.1%), progressive disease (28.7% versus 25%) or were not evaluable (8.8% versus 8.1%). The median duration of response was 15.77 months with the doublet compared with 9.66 months with monotherapy.
Safety Outcomes in Patients With Metastatic Kidney Cancer
Side effects leading to death occurred in seven patients in the doublet group and five patients in the Fotivda monotherapy group. Patients experienced grade 2 (serious) or greater side effects (61% for the doublet versus 60% for the singlet), serious side effects (32% versus 37%) and treatment-emergent side effects leading to discontinuation (16% versus 19%), dose interruption (49% versus 54%) and dose reduction of Fotivda (11% versus 22%). The median duration of treatment was 6.3 months and 7.4 months, respectively.
The most common any-grade side effects observed were hypertension (37% versus 40%), fatigue (29% versus 40%), diarrhea (30% versus 36%) and nausea (16% versus 28%), in the doublet and monotherapy groups, respectively.
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