Limited Anti-PD-1 Activity in mRCC Brain Mets

The PD-1 inhibitor nivolumab (Opdivo) had limited activity against previously untreated brain metastases in patients with progressive clear cell renal cell carcinoma (ccRCC), according to a subgroup analysis of a prospective study.

Four of 34 (12%) patients had intracranial responses, as compared with an extracranial response rate of 21%. All four patients had relatively small lesions, and no patients with lesions >1 cm or with multiple lesions had intracranial responses. A majority of the patients required additional focal brain therapy, reported Laurence Albiges, MD, PhD, of Gustave Roussy Institute in Villejuif, France, and colleagues.

The median intracranial progression-free survival (icPFS) was 2.7 months in patients with untreated brain metastases and 4.8 months in 34 patients with previously treated lesions, they stated in the Journal of Clinical Oncology.

“This study shows that nivolumab has limited intracranial activity in patients with untreated brain metastases from metastatic (m) ccRCC,” the authors concluded. “Moreover, only patients with limited intracranial tumor burden exhibited objective response in the brain. Patients who had received prior focal therapy had a significant decrease in the risk of intracranial progression compared with patients with untreated brain metastases, even though [that cohort] comprised numerically more patients with altered performance status, higher tumor grade, and higher number of brain metastases.”

“Current recommendations do not include systematic brain imaging in patients with metastatic ccRCC, which may result in underestimation of their true incidence,” they added. “Failing to diagnose early extracranial metastases limits the opportunity for patients to benefit from stereotactic brain radiation therapy, which provides optimal control in the context of low intracranial tumor burden. Our results suggest that systematic brain imaging in patients with mRCC and consideration of focal brain therapy before systemic therapy can be a viable strategy.”

The discordance between intra- and extracranial response to anti-PD-1 therapy was not seen in trials of patients with melanoma and lung cancer, the authors of an accompanying editorial noted. The “unexpected results” could reflect biologic characteristics unique to ccRCC metastasis to the brain, as previous research demonstrated marked genetic heterogeneity within primary ccRCC tumors. Heterogeneity in the tumor microenvironment of ccRCC also has been reported.

The study also raised a number of questions that warrant additional investigations, continued Robert A. Figlin, MD, of Cedars-Sinai Medical Center in Los Angeles, and colleagues. The issues include the intracranial response limited to small solitary tumors and the role of radiotherapy as a stimulant and potentiator of response to immunotherapy.

“The results highlight the need to better determine the efficacy of immune checkpoint inhibitors in this vulnerable population,” Figlin’s group wrote. “This could be accomplished largely be enhancing eligibility criteria for future immunotherapy trials to include patients with brain metastases and by assessing organ-specific response rates for intracranial metastases. The combination of nivolumab plus ipilimumab (Yervoy), a first-line treatment option for intermediate- to poor-risk ccRCC, could have much better activity than nivolumab alone in this population and should be evaluated prospectively in the setting of brain metastases.”

“Most importantly, as with the application of immunotherapy in general, we need to extend our understanding of the biology of brain metastases in ccRCC with the goal of optimizing the identification of patients likely to benefit from immunotherapy,” they concluded.

Although nivolumab is standard of care for mccRCC after failure of antiangiogenic therapies, the immunotherapy’s activity in ccRCC brain metastases remains unknown because patients with brain metastases historically were excluded from clinical trials, Albiges and colleagues noted. In an effort to inform the issue, the authors analyzed data from a phase II trial that evaluated nivolumab’s safety and activity in patients with mccRCC that failed VEGF-directed therapies.

Investigators identified 73 patients with asymptomatic brain metastases, including 34 who received prior therapy for the brain lesions (stereotactic radiotherapy in 88% of cases). The primary endpoint was intracranial response in the 39 patients with untreated brain metastases. Five patients with untreated lesions had rapid clinical progression that precluded assessment of intracranial response. Median duration of follow-up was 23.6 months in the patients with untreated brain metastases and 20.2 months in those with treated lesions. Median duration of nivolumab treatment was 4 to 5 months in both groups.

In the subgroup with untreated lesions, six of 34 had discordant responses to nivolumab: objective extracranial responses and either progression or stable disease as best intracranial response. All four patients who had intracranial responses also had extracranial responses, the authors reported.

The median duration of extracranial response was 2.8 months in patients with untreated brain metastases and 2.6 months in those with treated lesions. Although the median icPFS favored the patients with treated lesions, 12-month survival was numerically better in the patients with untreated lesions (66% vs 59%). Among all 39 patients with untreated brain lesions, 28 (72%) received subsequent local therapy to the brain (surgery or radiation).