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Nivolumab shows limited activity in untreated brain metastases from renal cell carcinoma
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Nivolumab demonstrated limited activity among patients with untreated brain metastases from clear cell renal cell carcinoma who experienced progression after vascular endothelial growth factor receptor-directed therapy, according to results of a phase 2 study published in Journal of Clinical Oncology.
“Brain metastases occur in approximately 10% of patients with metastatic clear cell renal cell carcinoma and are associated with dismal prognosis,” Ronan Flippot, MD, of Gustave Roussy Cancer Campus at Universitè Paris-Saclay in France, and colleagues wrote. “The anti-PD-1 nivolumab first demonstrated improved survival compared with everolimus [Afinitor, Novartis] in patients whose disease progressed after VEGFR-targeted therapies. However, the safety and activity of immune checkpoint inhibitors have not been reported in patients with metastatic clear cell renal cell carcinoma and brain metastases, because they have been excluded from pivotal trials.”
Flippot and colleagues assigned 73 patients to one of two cohorts. Cohort A included 39 patients (median age, 61 years; range, 39-77; 90% men) with previously untreated brain metastases, and cohort B included 34 patients (median age, 58 years; range, 33-78; 85% men) who received prior therapy for brain metastases.
All patients received 3 mg/kg IV nivolumab (Opdivo, Bristol-Myers Squibb) every 2 weeks until disease progression, unacceptable toxicity, patient withdrawal of consent, death or at the investigator’s discretion.
Best intracranial response rate in cohort A served as the study’s primary endpoint.
Median follow-up was 23.6 months for cohort A and 20.2 months for cohort B.
Results showed an intracranial response rate of 12% in cohort A, including four complete responses, with no objective responses among patients with multiple or larger-than-1-cm brain lesions. Other best responses in cohort A included intracranial progressive disease among half of evaluable patients (n = 17) and stable disease at 8 weeks or later among 13 patients.
Median intracranial PFS was 2.7 months (95% CI, 2.3-4.6) in cohort A and 4.8 months (95% CI, 3-8) in cohort B (adjusted HR = 2.04; 95% CI, 1.08-3.83).
Researchers observed 12-month OS rates of 67% (95% CI, 49.6-79.1) in cohort A and 59% (95% CI, 40.6-73.2) in cohort B.
Most patients in cohort A (72%) later required focal brain therapy.
Patients experienced no unexpected toxicities with nivolumab.
“Our results suggest that single-agent nivolumab has limited activity in patients with untreated brain metastases from clear cell renal cell carcinoma and who experienced progression after VEGFR-directed therapy,” Flippot and colleagues wrote. “These patients may benefit from systematic brain imaging and from focal brain therapy before initiation of immune checkpoint inhibitors.”
The results highlight the need to better determine the efficacy of immune checkpoint inhibitors in this patient population,” Robert A. Figlin, MD, professor of biomedical sciences and medicine, director of the division of hematology/oncology, and deputy director of integrated oncology at Cedars-Sinai Medical Center, and colleagues wrote in an accompanying editorial.
“The combination of nivolumab plus ipilimumab [Yervoy, Bristol-Myers Squibb], a first-line treatment option for intermediate- to poor-risk clear cell renal cell carcinoma, could have much better activity than nivolumab in this population and should be evaluated prospectively in the setting of brain metastases,” Figlin and colleagues wrote. “This should also be the case for emerging regimens, such as the recently reported combinations of immune checkpoint inhibitors with angiogenesis inhibitors and other agents — work that is already being done in melanoma and NSCLC.” – by John DeRosier
Disclosures: The study was supported by Bristol-Myers Squibb. The study authors report no relevant financial disclosures. Figlin reports stock and other ownership interests in 4Dx and Revelar; consultant/advisory roles with Accelera, Bristol-Myers Squibb, CBT Pharmaceuticals, Johnson & Johnson and Precision Health Economics; and research funding from Argos Therapeutics, Bristol-Myers Squibb, Calithera Biosciences, Exelixis, Merck and Peloton Therapeutics. Please see the editorial for all other authors’ relevant financial disclosures.
Perspective
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Nancy B. Davis, MD
Although a negative study, NIVOREN is one of a kind in attempting to prospectively delineate the intracranial efficacy of nivolumab in patients with metastatic renal cell carcinoma (mRCC) and untreated brain metastases. Brain metastases are uncommon in renal cell carcinoma — occurring in up to 10% of patients — and are associated with a poor prognosis and survival limited to 1 to 10 months following diagnosis. There are no standard guidelines available for screening patients with renal cell carcinoma for brain metastases. Additionally, trials evaluating new therapies for mRCC have historically excluded patients with untreated brain metastases.
It has been previously shown that sunitinib (Sutent, Pfizer Oncology) and sorafenib (Nexavar, Baryer) do not cross the blood brain barrier well and, thus, may not prevent the development of new brain metastases in patients with mRCC undergoing tyrosine kinase inhibitor therapy.
The advent of immune checkpoint inhibitor therapy has had a dramatic effect on outcomes for patients with mRCC, and other cancers, who achieve responses. Sadly, there remain a good deal of patients who do not benefit.
Although there were no new safety signals for nivolumab in this study, there is now prospective — although small — evidence to proceed with treatment of brain metastases in patients with mRCC prior to the initiating nivolumab. This remains important, as nivolumab may still be administered as a single agent to patients with mRCC post TKI therapy. However, it does not necessarily speak to what should be done with asymptomatic brain metastases prior to treatment with ipilimumab plus nivolumab or other first-line immunotherapy plus TKI therapy combinations.
In fact, in metastatic melanoma, a previous study published in The New England Journal of Medicine showed that ipilimumab (Yervoy, Bristol-Myers Squibb) and nivolumab had meaningful clinical benefit in patients with untreated, asymptomatic brain metastases, with 50% of patients exhibiting early and durable intracranial response. Whether that was only due to the anti-CTLA-4 activity of ipilimumab or to the combination anti-CTLA-4 plus anti-PD-1 is not known. Further study would have to be undertaken in the mRCC population to see if the combination had as much benefit as it did with metastatic melanoma.
Finally, the authors make an argument in favor of early central nervous system screening for brain metastases in patients with mRCC prior to initiating nivolumab therapy. Historically, imaging has been done for symptoms consistent with, or suspicious for, brain metastases. Would it be so difficult to routinely do imaging in this population? Probably not, although yield may be quite low given the low rate of CNS metastases in renal cell carcinoma. Given the cost of testing, and the likelihood of a high number needed to treat, it is doubtful that the recommendation for CNS imaging will change from “if clinically indicated” to “routine.”
References:
Dudek AZ, et al. Clin Genitourin Cancer. 2019;doi:10.1016/j.clgc.2012.11.001.
Tawbi HA, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1805453.
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