Prolonging Ipilimumab–Nivolumab Dose Interval May Reduce Toxicity In Advanced RCC

Author: By Hannah Kitt, medwireNews Reporter 

medwireNews: Patients with advanced renal cell carcinoma (RCC) may benefit from first-line ipilimumab plus nivolumab given at 12-week intervals instead of the conventional 3-week intervals, with fewer grade 3–4 treatment-related adverse events (TRAEs) and comparable efficacy, suggests research. 

Findings from the PRISM trial of patients with treatment-naïve locally advanced or metastatic RCC were presented at the ESMO Congress 2021 by Naveen Vasudev, from the University of Leeds in the UK, who said that “this positive phase II study supports the continued exploration of [ipilimumab–nivolumab] regimens.” 

The primary endpoint of grade 3–4 TRAEs within 12 months of receiving at least one dose of therapy occurred in 32.8% of the 128 patients who were randomly assigned to receive four cycles of the modified-dose schedule of ipilimumab 1 mg/kg and nivolumab 3 mg/kg every 12 weeks. This was accompanied by intervening doses of nivolumab 240 mg every 2 weeks for weeks 3–11 and 480 mg on weeks 17, 21, 29 and 33. 

This rate of grade 3–4 TRAEs was significantly lower than the 53.1% observed among 64 patients who were given the standard-dose schedule of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg every 3 weeks for four cycles then nivolumab 480 mg every 4 weeks from week 16. This 20.3 percentage point difference translated into a significant odds ratio of 0.43 in favour of the modified regimen. 

Of note, grade 3–4 colitis was less common with the modified versus conventional schedule (3.9 vs 6.3%), as was the incidence of elevated lipase (1.6 vs 9.4%), arthralgia (1.6 vs 7.8%), hypophysitis (0.8 vs 3.1%), pneumonitis (0.8 vs 1.6%), hyperthyroidism (0.8 vs 1.6%) and elevated creatinine (0.0 vs 1.6%).  

However, diarrhoea and elevated alanine transaminase of grade 3 or 4 were more common with the modified versus standard schedule, at rates of 5.5% versus 4.7% and 4.7% versus 3.1%, respectively. 

In total, 22.7% of the modified treatment arm discontinued therapy due to TRAEs compared with 39.1% of the standard treatment arm; there was one treatment-related death in the former group, none in the latter. 

The secondary endpoint of progression-free survival (PFS) was 10.8 months among patients given at least one dose of the modified regimen and 9.8 months among those given the standard regimen. The study was not powered to demonstrate noninferiority of the efficacy of the modified versus standard regimen, but Naveen Vasudev said that “informally, these two PFS curves look very similar, suggesting no really meaningful difference.” 

He added that the 12-month PFS rate was 46.1% with modified treatment, which was comparable to the historic PFS seen with standard treatment, referring to the rate of 39.7% observed in the COMPARZ trial.  

The objective response rates were a respective 45.3% and 35.9% for the modified and standard treatment groups, with complete and partial response rates of 6.3% versus 1.6% and 39.1% versus 34.4%, respectively, and corresponding median durations of response of 16 and 17 months.  

Naveen Vasudev reported that the overall survival data are not yet mature, with 12-month rates of 88.3% and 83.7% with the modified and standard regimen, respectively, and median durations unreached in both groups.  

The PFS results were similar in a subgroup analysis of patients with intermediate or poor IMDC risk scores, with comparable efficacy seen between the patients given modified and standard therapy, as indicated by corresponding median PFS durations of 10.5 and 8.6 months.  

Discussant Brian Rini from Vanderbilt University Medical Center in Nashville, Tennessee, USA, said this study showed that the modified dose “can clearly reduce toxicity” and “is unlikely to reduce short-term efficacy.”  

He added that this longer dose interval “is probably most useful for long-term efficacy endpoints […] and so we just may not see that difference in this relatively short follow-up.” 

Reference  

LBA29 - Vasudev NS, Ainsworth G, Brown S, et al. Nivolumab in combination with alternatively scheduled ipilimumab in first-line treatment of patients with advanced renal cell carcinoma: A randomized phase II trial (PRISM). Ann Oncol 2021;32(suppl_5): S1283–S1346. doi: 10.1016/annonc/annonc741