In a landmark change of disease management, the US Food and Drug Administration (FDA) approved sunitinib in 2006 as a first-line therapy for advanced renal cell carcinoma (RCC).1 The drug, a novel tyrosine kinase inhibitor (TKI), was associated with higher response rates, longer progression-free survival (PFS), and less toxicity than interferon-alpha, the previous standard of care.2

The results of a recent phase 3 trial suggest, however, that sunitinib could largely be replaced by immunotherapy in the first-line setting, though this TKI may be finding new, albeit limited, use in the adjuvant setting. In November 2017, it gained FDA approval for patients who have undergone a nephrectomy and are at high risk of recurrence, though the approval is controversial.3

The phase 3 trial, CheckMate-214, included 1096 previously untreated patients with advanced RCC.4 Researchers randomly assigned 546 patients to receive oral sunitinib daily for 4 weeks, while 550 received a combination of immune checkpoint inhibitors, nivolumab and ipilimumab, intravenously over several months.

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The patients who received nivolumab and ipilimumab had an 18-month overall survival (OS) rate of 75% vs 60% with sunitinib. The median OS had not been reached in the nivolumab and ipilimumab group vs 26 months in the sunitinib group. The objective response rate (ORR) was also higher with the immunotherapy combination than sunitinib, at 42% and 27%, respectively.

Grade 3 or 4 adverse events, furthermore, occurred in 46% of patients who received immunotherapy compared with 63% in the sunitinib group.

The combination of nivolumab and ipilimumab “will be approved any day” as first-line therapy for patients with advanced RCC, Brian Rini, MD, of the Cleveland Clinic in Ohio, told Cancer Therapy Advisor. Nivolumab is already FDA-approved for patients with advanced RCC who progress following anti-angiogenic therapy.5

The immunotherapy combination “will largely supplant the use of sunitinib” except for in patients who cannot tolerate nivolumab and ipilimumab, said Dr Rini, one of the investigators of CheckMate-214, the results of which were published in the New England Journal of Medicine in April.4 Other combinations are being tested, he added.

The tolerability of nivolumab and ipilimumab will probably not be an issue for most patients, said Bradley McGregor, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, who was not involved in the trial. Dr McGregor noted that CheckMate-214 used a lower dose of ipilimumab (1 mg per kilogram every 3 weeks for a total of 4 doses) than clinicians use to treat metastatic melanoma (3 mg per kilogram), which could result in lower rates of immune-related toxicities.