Adjuvant pembrolizumab decreased the risk for death by 38% vs placebo in patients with clear cell renal cell carcinoma at high risk for recurrence after surgery, according to the latest interim findings from the phase 3 KEYNOTE-564 study.
These phase 3 findings are the first to show improved overall survival with any adjuvant therapy in this disease setting, first author Toni K. Choueiri, MD, reported, to applause from attendees at the American Society of Clinical Oncology Genitourinary Symposium(ASCO GUCS).
"Between 1973 and now, 17 randomized controlled studies with over 12,000 enrolled patients with kidney cancer [investigated] adjuvant therapies in renal cell carcinoma. Zero survival improvements. Zero overall survival benefit," said Choueiri, director of the Lank Center for Genitourinary Oncology and coleader of the Kidney Cancer Program at Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
"These results further support adjuvant pembro as a standard of care after surgery in this disease setting," said Choueiri.
"This is a breakthrough" and "a very happy day for our patients," invited discussant Pedro C. Barata, MD, said following the presentation.
When it comes to selecting therapy for patients, it is always important to consider factors such as quality of life and patient preference and to balance the pros and cons of a given therapy, but after these overall survival outcomes, "I think the scale tilts toward favoring adjuvant pembrolizumab," said Barata, director of the Genitourinary Medical Oncology Research Program at University Hospitals Seidman Cancer Center, Cleveland, Ohio.
In 2021, the US Food and Drug Administration approved pembrolizumab in the adjuvant setting for patients with renal cell carcinoma at intermediate-high or high risk for recurrence after surgery, based on the disease-free survival (DFS) findings from the first interim KEYNOTE-564 analysis.
The double-blind, multicenter trial randomized nearly 1000 adults with histologically confirmed clear cell renal cell carcinoma to either adjuvant pembrolizumab at 200 mg or placebo (carrier saline) once every 3 weeks for 1 year or until disease recurrence, intolerable toxicity, or withdrawal of consent.
Participants had good performance status, had not received prior systemic therapy for renal cell carcinoma, and had undergone nephrectomy and/or resection of metastatic lesions within 12 weeks prior to enrollment.
In the first interim analysis, the trial met its primary endpoint of DFS — patients receiving adjuvant pembrolizumab demonstrated significantly longer DFS (hazard ratio [HR], 0.68) — but overall survival data were immature at the time. A second interim analysis, reported in The Lancet Oncology in 2022, continued to show better DFS in the pembrolizumab arm (HR, 0.63).
The current interim analysis, at a median follow-up of 57 months, found a significant overall survival benefit among patients in the pembrolizumab arm (median not reached; HR, 0.62). The estimated overall survival at 48 months was 91.2% with adjuvant pembrolizumab vs 86.0% with placebo.
"The overall survival curves started separating at 1 year and continue to separate," Choueiri said.
DFS outcomes in the current analysis were also consistent with those previously reported (HR, 0.72), and the overall survival and DFS benefits were observed across key patient subgroups, including patients with M stage 0 intermediate/high disease (HR, 0.63), who comprised 85% of participants.
The overall survival benefit was apparent regardless of the presence or absence of sarcomatoid features or programmed cell death ligand 1 status, and no new safety signals were observed, Choueiri said.
Among the 488 patients who ultimately received adjuvant pembrolizumab, 298 completed the study therapy and 190 discontinued for various reasons, including relapse in 51 patients and adverse events in 105. Among the 496 patients in the placebo arm, 366 completed the study therapy and 130 discontinued it, largely due to relapse (77.7%).
Following documented recurrence, about 80% of patients in both arms received subsequent therapy, which included anticancer drugs, radiation therapy, and surgery.
"So, where do we go from here?" Barata asked. "We have to optimize patient selection," he said, adding that only about half of post-nephrectomy patients with high-risk features will require adjuvant treatment.
Possible approaches for better patient selection might include assessments of circulating tumor DNA or minimal residual disease as well as whole exome sequencing or whole transcriptome sequencing to identify tumors more likely to derive benefit from immunotherapy, or "even using different immunotherapy strategies like neoantigen vaccination as is being done in other tumors," Barata explained.
Multiple studies are exploring different approaches and combinations for adjuvant therapy for renal cell carcinoma, so "the story is not over," Barata said.
KEYNOTE-564 was funded by Merck Sharp & Dohme, LLC, a subsidiary of Merck & Co. Choueiri and Barata each disclosed numerous pharmaceutical industry relationships.
Sharon Worcester, MA, is an award-winning medical journalist based in Birmingham, Alabama, writing for Medscape, MDedge, and other affiliate sites. She currently covers oncology, but she has also written on a variety of other medical specialties and healthcare topics. She can be reached at sworcester@mdedge.com or on X (formerly known as Twitter) @SW_MedReporter.