In the Journals

Nivolumab shows limited activity in untreated brain metastases from renal cell carcinoma

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.

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.”

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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.

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