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SAN FRANCISCO -- The use of adjuvant pembrolizumab (Keytruda) boosted overall survival (OS) in post-surgical patients with clear cell renal cell carcinoma (RCC) at risk for recurrence, according to findings.

Patients treated with the immune checkpoint inhibitor (ICI) had a 38% reduced risk of death compared to patients on placebo, reported Tony Choueiri, MD, of the Dana-Farber Cancer Institute in Boston.

"Between 1973 and now, there have been 17 randomized controlled trials with over 12,000 patients with kidney cancer who were enrolled on adjuvant therapies on RCC, with zero survival improvement," Choueiri said. "This is the first study to show a statistically significant and clinically meaningful survival improvement with any adjuvant therapy in kidney cancer," he said at the Genitourinary Cancers Symposium (GuCS).

However, results from a second trial presented at GuCS offered less positive results: In part B of , nivolumab (Opdivo) monotherapy as an adjuvant treatment failed to improve disease-free survival (DFS) versus placebo in patients with localized RCC at high risk of relapse after nephrectomy.

KEYNOTE-564

At a median follow up of 57.2 months, median OS was not reached in either trial arm, and resulted in an HR 0.62 (95% CI 0.44-0.87, P=0.002) in favor of pembrolizumab.

OS at 1 year was 98.6% with pembrolizumab versus 98.0% with placebo, while 4-year OS rates were 91.2% and 86.0%, respectively.

DFS results were similar to those demonstrated in an earlier interim analysis in which KEYNOTE-564 met its primary endpoint of DFS. In the latest analysis, adjuvant pembrolizumab reduced the risk of disease recurrence or death by 28% (HR 0.72, 95% CI, 0.59-0.87) compared to placebo.

The updated results "further support adjuvant pembrolizumab as a standard of care after surgery in this disease setting," Choueiri said.

The study enrolled 994 patients (median age 60; about 70% male) with high-risk clear cell RCC who were randomized to the two arms.

Most patients (over 90%) were categorized as M0, with about 85% M0 intermediate-high risk.

Treatment-related adverse events (TRAEs) occurred in 79.1% of patients in the pembrolizumab arm and 53.0% of patients in the placebo arm. Grade 3-4 TRAEs occurred in 18.6% and 1.2% of patients in the two arms, respectively.

TRAEs resulting in discontinuation of any treatment occurred in 18.2% and 0.8% of patients in the two arms.

No treatment-related deaths occurred.

CheckMate 914

Part A of the CheckMate-914 trial previously failed to show a DFS benefit with (Yervoy) compared with placebo in patients with localized RCC at high risk of post-nephrectomy relapse.

Part B was designed to complement part A by also assessing adjuvant nivolumab monotherapy. It showed that at a median follow-up of 27 months and a median treatment duration of 5.1 months, median DFS was not reached in either the nivolumab or placebo arm (HR 0.87, 95% CI, 0.62-1.21, P=.396), reported Robert Motzer, MD, of Memorial Sloan Kettering Cancer Center in New York City.

At 18 months, DFS rates were 78.4% in the nivolumab arm and 75.4% in the placebo arm.

Thus, "the primary endpoint of DFS for nivolumab monotherapy was not met," Motzer said.

Motzer added that because the primary endpoint of DFS was not reached, no formal OS analysis will be performed.

Part B included 825 patients -- 411 assigned to the nivolumab arm, 208 to placebo, and 206 to nivolumab plus ipilimumab. These patients had a median age of 59, 93% had undergone radical nephrectomy, about 80% had pT3 tumors, while 7-8% had sarcomatoid features, and about 10% had PD-L1 >1%.

Among select subgroups there was a trend favoring nivolumab in patients with sarcomatoid features, PD-L1 expression >1%, and those with a lower limit of normal hemoglobin at baseline.

Motzer also reported that DFS outcomes for nivolumab plus ipilimumab were similar in both parts A and B.

Why Only Pembrolizumab?

The results from CheckMate 914 are in line with similar immunotherapy trials that failed to show a DFS benefit as an adjuvant treatment in RCC, leading to the question of why pembrolizumab worked and other agents didn't.

GuCS discussant Pedro C. Barata, MD, of the University Hospitals Seidman Cancer Center in Cleveland, said the answer to that question "is likely multifactorial."

"I think factors like histology, different drugs, duration of treatment, patient characteristics like high risk, sarcomatoid features, safety profile, probably all played a role," he said.

Barata noted that in looking at the DFS curve for KEYNOTE-564 "it's important to remember that half of post-nephrectomy patients with high-risk features end up being cured and do not require adjuvant therapy."

However, he added, when one weighs the risks and benefits of adjuvant therapy, "I think the scale tilts towards favoring adjuvant pembrolizumab; as we found out those patients live longer."

Looking ahead, Barata said, more focus should be placed on how to better identify patients for adjuvant pembrolizumab; treat patients who progress on pembrolizumab; and clarify the role of that drug and other ICIs beyond clear cell RCC.