Benefit of nivolumab–tivozanib, nivolumab beyond progression shown in metastatic RCC
medwireNews: Studies presented at the ESMO 2019 Congress propose that patients with metastatic renal cell carcinoma (RCC) may benefit from a combination of nivolumab and the VEGFR tyrosine kinase inhibitor (TKI) tivozanib, or by continuing with single-agent nivolumab past initial disease progression.
As reported in Barcelona, Spain, the phase Ib/II TiNivo trial findings for the 25 patients in the maximum tolerated dose cohort achieved an objective response rate (ORR) of 56% and a disease control rate of 96% for the combination of tivozanib 1.5 mg/day plus nivolumab 240 mg every 2 weeks.
The corresponding rates were 50% and 92% for the 12 treatment-naïve patients and 62% and 100% for the 13 participants who had previously received one line of treatment for metastatic RCC.
Overall, 64% of the patients had at least 25% tumor shrinkage and eight patients were continuing with treatment at time of data cutoff, said Philip Barthelemy (CHRU Strasbourg–Nouvel Hôpital Civil, France) and co-authors of the poster.
Median progression-free survival (PFS) was 18.9 months for both the whole cohort and the treatment-naïve patients, and unreached for the second-line treatment arm, they added.
Safety analysis showed that one or more grade 3–4 treatment-related adverse events (AEs) occurred in 80% of the patients but after excluding uncomplicated hypertension, this rate fell to 64%.
“Notably, grade 3/4 fatigue, diarrhea, and elevations of hepatic enzymes were low, as predicted by single-agent experience with tivozanib,” the researchers said, highlighting the “low discontinuation rate” and the “small number of dose reductions due to AEs.”
The team concluded that “[p]lans are underway for an additional randomized trial.”
A second poster, presented by Sophie Hans (Hôpital Européen Georges Pompidou, Paris, France) and co-authors described their review of 109 “real world” metastatic RCC patients who continued with nivolumab after progressive disease (PD) at one center between 2013 and 2018.
The cohort included patients with an IMDC favorable (19.3%), intermediate (48.6%), poor (27.5%), or unknown (4.6%) risk prognosis, and all but two patients had received at least one prior line of treatment before nivolumab, such as sunitinib, pazopanib, or everolimus.
After a median 22.6 months of follow-up, 74 patients experienced PD on nivolumab, and these patients had a median PFS of 2.47 months and overall survival (OS) of 17.90 months, whereas OS was unreached for the 22 patients without PD.
Analysis showed that patients who experienced progression on nivolumab had more aggressive disease than those who did not despite a significantly shorter median time from diagnosis (31 vs 114 months).
For example, patients with PD were a significant five times more likely to have IMDC poor-risk disease (9.7 vs 33.8%) than those without, 6.6 times more likely to have a ECOG PS of 2 or above (41.9 vs 9.7%), and 4.6 times more likely to have bone metastases when beginning nivolumab (47.3 vs 16.1%).
Almost half (47.0%) of the patients continued to receive nivolumab after PD – albeit 48.5% of progressions were not confirmed by RECIST – and 8.5% achieved a partial response to treatment and 40% stable disease.
The researchers highlighted that patients who continued nivolumab after PD had “more indolent disease,” with a longer median time to beginning nivolumab therapy than those who stopped nivolumab (27.0 vs 19.0 months) and a longer median time to first unconfirmed PD on nivolumab (3.1 vs 2.4 months).
Moreover, patients who continued nivolumab after PD had a median OS of 41.2 months, significantly longer than the 8.05 months for those who stopped nivolumab after progression, they add.
“While pseudoprogression is a rare phenomenon (4% of progressors), half of patients may benefit from the continuation of nivolumab beyond progression,” the authors summarized.
And they noted: “The only factor associated with a lack of clinical benefit to the pursuit of nivolumab beyond progression was the appearance of new lesions as PD.”
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This independent news article was supported by an educational grant from Pfizer and Merck KGaA