Patients with clear cell renal cell carcinoma (ccRCC) experienced improved overall survival (OS; the time a patient lives after treatment regardless of disease status) when treated with adjuvant (postsurgical) Keytruda (pembrolizumab) as compared to patients treated with placebo, according to data from the third prespecified interim analysis of the phase 3 KEYNOTE-564 trial presented at the 2024 Genitourinary Cancers Symposium.
“This is the first study to show a statistically significant and clinically meaningful survival improvement with any adjuvant therapy in kidney cancer and this further supports adjuvant (Keytruda) as a standard of care after surgery in this disease setting,” Dr. Toni Choueiri, lead study author and the director of the Lank Center for Genitourinary Oncology, co-leader of the Kidney Cancer Program, and a senior physician at Dana-Farber Cancer Institute in Boston noted during the presentation.
At a median follow-up of 57.2 months in the intention-to-treat population, the median OS was not reached (NR) in either the Keytruda (496 patients) or placebo (498 patients) arms (meaning more than half of the patients in both arms were still alive). Findings revealed OS rates were 98.6% versus 98% at 12 months, 96.3% versus 93.9% at 24-months, 93.9% versus 89.5% at 36 months and 91.2% versus 86% at 48 months in the Keytruda versus placebo arms, respectively.
“In patients with ccRCC at increased risk of recurrence following surgery (there was a) 38% reduction in the risk of death with adjuvant Keytruda (versus placebo) with a survival benefit seen across key subgroups. A continued disease-free survival (DFS; the time a patient lives without signs of disease) benefit was seen (as well),” Choueiri, who is also the Jerome and Nancy Kohlberg Chair and a professor of medicine at Harvard Medical School in Boston, added.
Data from the study’s first protocol-specified interim analysis demonstrated that patients experienced a significant DFS benefit with adjuvant Keytruda versus placebo (hazard ratio [HR; the chance of an event happening], 0.68). After the DFS primary end point was met at the first interim analysis, it has not been formally tested again.
At this third interim analysis, the median DFS was not reached in the Keytruda group or in the placebo group, meaning more than half of the patients in both groups did not have signs or symptoms of disease. DFS rates were as follows at 12 months (85.5% versus 76.1%), 24 months (78.2% versus 67.2%), 26 months (72.4% versus 62.9%) and 48 months (64.9% versus 56.6%), respectively, according to the updated data presented.
Examining Enrollment Criteria and Patient Characteristics
Patients with histologically confirmed ccRCC who had not received prior systemic therapy were randomly assigned to receive Keytruda 200 mg or placebo every three weeks for up to 17 cycles. Eligible patients underwent surgery up to 12 weeks prior to randomization and had post-nephrectomy intermediate-high risk of recurrence, defined as pT2 (grade 4 or sarcomatous, no disease in the lymph nodes) or pT3 (any grade, no disease in the lymph nodes), or post-nephrectomy high-risk of recurrence, defined as pT4 (any grade, no disease in the lymph nodes) or any pT (any grade, node-positive disease). Additional enrollment criteria included receival of post-nephrectomy as well as complete resection of metastasis. Patients also needed to have an ECOG performance status of 0 or 1, meaning they could perform daily tasks with little to no assistance.
As of December 2022, all patients completed or discontinued study therapy as patients were randomly assigned and treated with Keytruda (498 patients) or placebo (496 patients) from June 30, 2017 to Sept. 20, 2019. Of those who completed therapy with Keytruda (298 patients) versus placebo (366 patients), discontinuations (190 versus 130, respectively) occurred due to relapse (51 versus 101), side effects (105 versus 11), withdrawal by patient (21 versus 10), physician decision (nine versus six), noncompliance with protocol (three versus two) or protocol violation (one versus zero). The median time from random assignment to data cutoff was 57.2 months.
Baseline characteristics were generally well-balanced between the two arms; the median age in the Keytruda and placebo arms was 60 years versus 60 years. Most patients in both arms were male (70% versus 72.1%,), from outside the U.S. (77% versus 76.5%), had M0 disease rather than M1 (94.2% versus 94.4%) and had an ECOG performance status of 0 (84.9% versus 85.5%). Disease risk categories were M0 intermediate-high (85.1% versus 86.9%), M0 high risk (8.1% versus 7.4%) and M1 no evidence of disease (5.8% versus 5.6%), respectively.
Further, sarcomatoid features in patients given adjuvant Keytruda versus placebo were present (10.5% versus 11.8%, respectively), absent (83.5% versus 83.3%), or unknown (6% versus 4.8%) and regarding PD-L1 status, patients had a combined positive score of less than 1 (25% versus 22.7%), at least 1 (73.6% versus 76.9%) or missing (1.4% versus 0.4%).
Further Findings
Key subgroups achieved an OS benefit when treated with the PD-1 inhibitor vs placebo; patients who were male, had M1 no evidence of disease and were younger than 65 experienced the most pronounced benefit.
Additionally, all subgroups experienced a DFS benefit with Keytruda versus placebo. The most notable benefits were seen in those with M1 no evidence of disease, M0 high risk disease, sarcomatoid features and those 65 years or older.
Of patients who experienced recurrence in the Keytruda (161 patients) and placebo (210 patients) arms, 79.5% (128 patients) compared with 81.4% (171 patients) received subsequent therapy, respectively. Subsequent therapy included radiation (24.2% versus 19.3%), surgery (17.4% versus 13.3%), and systemic anticancer therapy (79.7% versus 84.8%) encompassing a PD-(L)1 inhibitor (41.2%), VEGFR/VEGFR inhibitor (92.2% versus 84.8%) or other therapy (31.4% versus 41.4%).
Safety Data Remains Consistent with That Previously Reported
“The question is after 57.2 months of follow-up is there any impact in terms of toxicity (from approximately) one year of (Keytruda treatment)?” Choueiri asked. “We showed the result in the prior analysis of 30.1 months (and) the numbers stayed the same — the steroid use, the grade 3 (side effects), the serious (side effects) are the same. With 27.1 (more months of) follow-up there was no difference.”
With an identical median duration of therapy for both arms as that of the prior analysis — 11.1 months in the Keytruda and in the placebo arm — no differences greater than 1% were observed regarding rates of any-cause side effects, serious side effects, treatment-related side effects or immune-mediate side effects and infusion reactions observed in the prior analysis versus this third prespecified interim analysis.
Serious side effects were reported in 20.7% of patients treated with Keytruda and 11.5% of those given placebo, leading to discontinuation in 10% versus 1% of patients, respectively, according to identical data from both analyses. Additionally, no treatment-related side effects led to death in either arm.
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