Modified Ipilimumab Dosing in Ipilimumab/Nivolumab Combo Improves Toxicity in Advanced RCC

Use of an alternate scheduling for ipilimumab (Yervoy) for the combination of nivolumab (Opdivo) and ipilimumab as frontline therapy for patients with advanced renal cell carcinoma (RCC) led to a significant reduction in the number of patients experiencing grade 3 or 4 toxicity, which met the primary end point of the phase 2 PRISM trial.¹

“Amongst this cohort of treatment-naive advanced RCC patients given [ipilimumab] every 12 weeks instead of every 3 weeks, led to a significant reduction in the proportion of patients experiencing a grade 3 or treatment-related adverse event,” said Naveen Vasudev, PhD, MRCP, MBChB, BMSc, in a presentation of the findings at the European Society for Medical Oncology Congress 2021. “Efficacy end points…were comparable between the 2 treatment arms.”

Nivolumab and ipilimumab is an approved frontline therapy for patients with intermediate- and poor-risk advanced RCC based on findings from the phase 3 CheckMate 214 trial (NCT02231749), which showed overall survival (OS) benefit over sunitinib (Sutent) in this patient population.² However, the optimal scheduling of ipilimumab in the regimen has yet to be defined in this setting as reduced dose and frequency of the CTLA-4 inhibitor can be better tolerated. In the CheckMate 214 trial, 47% of patients experienced a grade 3/4 treatment-related adverse event (TRAE) and 22% discontinued treatment due to a TRAE.

The PRISM trial enrolled patients with locally advanced or metastatic treatment-naive clear cell RCC. All patients had to have a Karnofsky performance status of 70% or higher and any International Metastatic RCC Database Consortium (IMDC) risk group was allowed.

Patients were randomized 2:1 to either a modified (nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 12 weeks x 4 with intervening nivolumab 240 or 480 mg every 2 or 4 weeks) or standard (nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks x 4 followed by nivolumab 480 mg every 4 weeks) dosing of ipilimumab. Treatment continued until progression or unacceptable toxicity. These arms were compared with a historical control of 12-month progression-free survival (PFS) rate with sunitinib from the COMPARZ trial (NCT00720941), which was the standard of care at the time of the initiation of the PRISM trial.³

The primary end point of the PRISM trial was the proportion of patients experiencing at least 1 grade 3/4 TRAE within 12 months of starting therapy. Secondary end points included PFS rate in the modified arm at 12 months vs the historical control with sunitinib, tolerability, median PFS, objective response rate (ORR), OS, duration of response (DOR), and health-related quality of life (HRQOL).¹

Vasudev, a clinical associate professor and honorary consultant at the University of Leeds/St. James’ Institute of Oncology in England. noted that the study was designed to allow for formal comparison between treatment arms for the primary end point only. Due to the nature of the phase 2 trial, noninferiority comparisons were not possible.

The median age in the modified ipilimumab arm (n = 128) was 61 years (range, 39-81) and 65 years (range, 28-81) in the standard ipilimumab arm (n = 64). About three-quarters of patients were male in each arm and half of all patients had IMDC intermediate risk. More than 60% of patients had underwent prior nephrectomy. The most common site of metastasis was the lung (72% in the modified arm, 81% in the standard arm), followed by the lymph node (31% in the modified arm, 33% in the standard arm). Median follow-up was 19.7 months (range, 15.9-23.6) across both arms.

A total of 32.8% patients in the modified ipilimumab arm and 53.1% in the standard ipilimumab arm experienced a grade 3/4 TRAE within 12 months. This resulted in a difference of –20.3 percentage points (90% CI, –32.6 to –8.0) (odds ratio, 0.43; 90% CI, 0.25-0.72; P = .0075).

The most common TRAEs of any grade were diarrhea (27.3% in the modified arm vs 20.3% in the standard arm), arthralgia (18.8% vs 20.3%, respectively), hyperthyroidism (14.1% vs 12.5%), hypothyroidism (12.5% vs 10.9%), alanine aminotransferase (ALT) increase (10.9% vs 15.6%), aspartate aminotransferase (AST) increase (7.0% vs 4.7%), creatinine increase (6.3% vs 4.7%), colitis (6.3% vs 9.4%), lipase increase (5.5% vs 9.4%), and pneumonitis (5.5% vs 5.3%).

In the modified ipilimumab arm, the most common grade 3/4 TRAEs were diarrhea (5.5%), ALT increase (4.7%), and colitis (3.9%). Whereas in the standard ipilimumab arm, the most common grade 3/4 TRAEs were lipase increase (9.4%), arthralgia (7.8%), colitis (6.3%), and diarrhea (4.7%).

Overall, 22.7% of patients discontinued treatment due to a TRAE in the modified ipilimumab arm vs 39.1% in the standard ipilimumab arm. One death due to a TRAE was reported in the modified dosing arm.

Among randomized patients who received at least 1 dose of therapy (modified intent-to-treat [mITT] population, the median PFS in the modified ipilimumab arm was 10.8 months (95% CI, 8.2-14.2) and 9.8 months (95% CI, 6.6-13.3) in the standard ipilimumab arm. At 12 months, the PFS rate was 46.1% (90% CI, 38.6%-53.2%) in the modified ipilimumab arm, which was compared with the historical 12-month PFS rate of 39.7% with sunitinib.

“The rate was numerically higher in the modified [ipilimumab] arm; however, the lower limit of the confidence interval fails to exclude that historical rate. We can’t formally compare the 2 arms for efficacy…but informally these 2 PFS curves look very similar, suggesting no really meaningful difference in median PFS,” Vasudev said.

In patients with intermediate- or poor-risk disease, the median PFS was 10.5 months (90% CI, 7.0-14.2) in the modified ipilimumab arm as compared with 8.6 months (90% CI, 6.0-16.3) in the standard ipilimumab arm.

In the mITT population, the ORR was 45.3% (95% CI, 36.7%-53.9%) in the modified ipilimumab arm vs 35.9% (95% CI, 24.2%-47.7%) in the standard arm. The median duration of response in this population was 16 months (95% CI, 13–not reached [NR]) and 17 months (95% CI, 13-NR) in the modified and standard dosing arms, respectively (TABLE).

Among the intermediate/poor-risk population, the ORR was 46.7% (95% CI, 36.4%-57.0%) in the modified ipilimumab arm and 40.9% (95% CI, 26.4%-55.4%) in the standard ipilimumab arm.

The median OS in the modified ITT was not reached in either arm. At 12 months, the OS rate was 88.3% (95% CI, 81.2%-92.8%) with modified ipilimumab and 83.7% (95% CI, 71.8%-90.1%) with standard ipilimumab.

Vasudev said that the trial supports further exploration of different nivolumab/ipilimumab dosing regimens.

_References

_{1. Vasudev N, 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). Presented at: ESMO Congress 2021; September 16-21, 2021; virtual. Abstract LBA29.}

_{2. Motzer RJ, Tannir NM, McDermott DF, et al; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126}

_{3. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013;369(8):722-731. doi:10.1056/NEJMoa1303989}