Do Brain Metastases Rule Out Immunotherapy in RCC?

An interim analysis of the CheckMate 920 phase IIIb/IV trial indicates that the combination of nivolumab and ipilimumab is safe and effective in advanced renal cell carcinoma (RCC) patients with brain metastases, with encouraging antitumor activity. These findings, which were presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting (abstract 4517), are in line with previous studies of this dosing regimen.

Previous clinical trials, including CheckMate 214, have typically excluded patients with brain metastases. CheckMate 920 included treatment-naïve RCC patients who received nivolumab/ipilimumab. The sub-analysis included 28 patients (median age, 60 years) with an RCC of any histology who had non-active brain metastases and a Karnofsky performance status of 70% or greater.

Subjects were followed for a minimum of 6.5 months. The overall response rate was 29% (95% CI, 13%–49%). There were no complete responses. Among 4 patients with sarcomatoid features, 2 achieved best overall response. The median progression-free survival was 9 months (95% CI, 2.9–not estimable), and median overall survival was not reached (95% CI, 13.1–not estimable). In total, 15 of 28 patients received all 4 doses (mean, 3.2 doses).

Two patients had brain lesions measuring 10 mm or larger that had not been previously irradiated. A 14-mm lesion was reduced to 2 mm at week 10, and an 18-mm lesion was too small to measure at week 12 and week 22.

There were no grade 5 treatment-related adverse events or deaths. The most common treatment-related adverse events were fatigue and diarrhea (both 36%), and the most common grade 3 to 4 treatment-related adverse event was increased lipase (14%). There were no cases of clinical pancreatitis. Treatment-related central nervous system adverse events included headache, myasthenia gravis, and tremor (1 patient each).

Immune-mediated adverse events included rash (any grade, 43%; grade 3-4, 4%), diarrhea/colitis (any grade, 39%; grade 3-4, 14%), hypothyroidism (any grade, 29%; grade 3-4, 0%), nephritis and renal dysfunction (any grade, 21%; grade 3-4, 7%), and hyperthyroidism (any grade, 11%; grade 3-4, 0%).

“It’s a small study looking at an interesting issue,” commented Timothy Gilligan, MD, associate professor of medicine and vice chair for education at the Cleveland Clinic Taussig Cancer Institute. “People assume that in patients with brain metastases, the drug won’t work,” he told Cancer Network.

“I think this is arguing that brain metastases should not be an exclusion criteria for immunotherapy, and I think people are pretty much practicing that way at this point. In some ways this has more implications to me for trial design, to encourage people writing trials to include brain metastases, otherwise you have this population of patients and you’re not sure how the data applies to them because they weren’t allowed to be in the study,” said Gilligan.

In the current trial, the drugs worked extracranially and sometimes intracranially.

Nivolumab/ipilimumab has also shown activity in patients with brain metastases in other contexts, including melanoma and NSCLC.