Adjuvant Pembrolizumab Significantly Prolongs OS vs Placebo in ccRCC

Toni Choueiri, MD

Treatment with adjuvant pembrolizumab (Keytruda) significantly improved overall survival (OS) vs placebo in patients with clear cell renal cell carcinoma (ccRCC) according to findings from the third prespecified interim analysis of the phase 3 KEYNOTE-564 trial (NCT03142334) presented at the 2024 Genitourinary Cancers Symposium.¹

“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 pembrolizumab as a standard of care after surgery in this disease setting,” Toni Choueiri, MD, 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, Massachusetts, noted during the presentation.

At a median follow-up of 57.2 months (range, 47.9-74.5) in the intention-to-treat population, the median OS was not reached (NR) in either the pembrolizumab (n = 496) or placebo (n = 498) arms (HR, 0.62; 95% CI, 0.44-0.87; P = .002). Findings revealed OS rates were 98.6% vs 98.0% at 12 months, 96.3% vs 93.9% at 24 months, 93.9% vs 89.5% at 36 months, and 91.2% vs 86.0% at 48 months, in the pembrolizumab vs placebo arms, respectively.¹

“In patients with ccRCC at increased risk of recurrence following surgery [there was a] 38% reduction in the risk of death with adjuvant pembrolizumab [vs placebo] with a survival benefit seen across key subgroups. A continued disease-free survival [DFS] 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, Massachusetts, added.

Data from the study’s first protocol-specified interim analysis demonstrated that patients experienced a significant DFS benefit with adjuvant pembrolizumab vs placebo (HR 0.68; 95% CI, 0.53%-0.87%; P = .002).² After the DFS primary end point was met at the first interim analysis, it was not formally tested again.¹

In this third interim analysis, the median DFS was NR (95% CI, NR-NR) in the pembrolizumab group and NR (95% CI, 54.9-NR) in the placebo group (HR, 0.72; 95% CI, 0.59-0.87). DFS rates were as follows at 12 months (85.5% vs 76.1%), 24 months (78.2% vs 67.2%), 26 months (72.4% vs 62.9%), and 48 months (64.9% vs 56.6%), respectively, according to the updated data presented.¹

Examining Enrollment Criteria and Patient Characteristics

Patients with histologically confirmed ccRCC who had not received prior systemic therapy were randomly assigned 1:1 to receive pembrolizumab 200 mg or placebo every 3 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 N0) or pT3 (any grade N0), or post-nephrectomy high-risk of recurrence, defined as pT4 (any grade N0) or any pT (any grade N+) Additional enrollment criteria included receipt of post-nephrectomy as well as complete resection of metastasis. Patients also needed to have an ECOG performance status of 0 or 1.

Stratification occurred by M stage (M0 vs M1 no evidence of disease) and the M0 group was further stratified by ECOG performance status (0 vs 1) and location (US vs non-US). Secondary end points included OS and safety, with OS a key second end point.

As of December 2022, all patients completed or discontinued study therapy as patients were randomly assigned and treated with pembrolizumab (n = 488) or placebo (n = 496) from June 30, 2017, to September 20, 2019. Of those who completed therapy with pembrolizumab (n = 298) vs placebo (n = 366), discontinuations (190 vs 130, respectively) occurred due to relapse (51 vs 101), adverse effects (AEs; 105 vs 11), withdrawal by the patient (21 vs 10), physician decision (9 vs 6), noncompliance with the protocol (3 vs 2), or protocol violation (1 vs 0). The median time from random assignment to data cutoff was 57.2 months (range, 47.9-74.5).

Baseline characteristics were generally well balanced between the two arms; the median age in the pembrolizumab and placebo arms was 60 years (range, 27-81) vs 60 years (range, 25-84), respectively. Most patients in both arms were male (70.0% vs 72.1%,), from outside the US (77.0% vs 76.5%), had M0 disease rather than M1 (94.2% vs 94.4%), and had an ECOG performance status of 0 (84.9% vs 85.5%). Disease risk categories were M0 intermediate-high (85.1% vs 86.9%), M0 high risk (8.1% vs 7.4%), and M1 no evidence of disease (5.8% vs 5.6%), respectively.

Further, sarcomatoid features in patients given adjuvant pembrolizumab vs placebo were present (10.5% vs 11.8%, respectively), absent (83.5% vs 83.3%), or unknown (6.0% vs 4.8%) and regarding PD-L1 status, patients had a combined positive score of less than 1 (25.0% vs 22.7%), at least 1 (73.6% vs 76.9%), or missing (1.4% vs 0.4%).

Further Findings

Key subgroups achieved an OS benefit when treated with the PD-1 inhibitor vs placebo; patients who were male (HR, 0.50; 95% CI, 0.33-0.75), had M1 no evidence of disease (HR, 0.51; 95% CI, 0.15-1.75), and were less than 65 years old (HR, 0.51; 95% CI, 0.31-0.83), experienced the most pronounced benefit.

Additionally, all subgroups experienced a DFS benefit with pembrolizumab vs placebo. The most notable benefits were seen in those with M1 no evidence of disease (HR, 0.40; 95% CI, 0.20-0.81), M0 high-risk disease (HR, 0.61; 95% CI, 0.35-1.08), sarcomatoid features (HR, 0.63; 95% CI, 0.37-1.08), and those 65 years of age or greater (HR, 0.67; 95% CI, 0.48-0.93).

Of patients who experienced recurrence in the pembrolizumab (n = 161) and placebo (n = 210) arms, 79.5% (n = 128) compared with 81.4% (n = 171) received subsequent therapy, respectively. Subsequent therapy included radiation (24.2% vs 19.3%), surgery (17.4% vs 13.3%), and systemic anticancer therapy (79.7% vs 84.8%) encompassing a PD-(L)1 inhibitor (41.2%), VEGFR/VEGFR inhibitor (92.2% vs 84.8%), or other therapy (31.4% vs 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] 1 year of pembrolizumab [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 AEs, the serious AEs 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 (range, 0.03-14.3) in the pembrolizumab arm and 11.1 months (range, 0.03-15.4) in the placebo arm—no differences greater than 1.0% were observed regarding rates of any-cause AEs, serious AEs, treatment-related AEs, or immune-mediate AEs and infusion reactions observed in the prior analysis vs this third prespecified interim analysis.

Serious AEs were reported in 20.7% of patients treated with pembrolizumab and 11.5% of those given placebo, leading to discontinuation in 10.0% vs 1.0% of patients, respectively, according to identical data from both analyses. Additionally, no treatment-related AEs led to death in either arm.

Editor’s Note: Dr Choueiri reported having a consulting or advisory role with Alkermes, Analysis Group, Aravive, Arcus Biosciences, Arcus Biosciences, ASCO, AstraZeneca, Bayer, Bristol-Myers Squibb, Clinical Care Options, Eisai, EMD Serono, ESMO, Exelixis, Foundation Medicine, Gilead Sciences, Gilead Sciences, GlaxoSmithKline, Harborside Press, Infinity Pharmaceuticals, Ipsen, Janssen Oncology, Kanaph Therapeutics, Lancet Oncology, Lilly, Merck, Michael J. Hennessy Associates, Navinata Health, NCCN, NiKang Therapeutics, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Precede Bio, Prometheus, Roche/Genentech, Sanofi/Aventis, Scholar Rock, Tempest Therapeutics, The New England Journal of Medicine, and UpToDate. He receives honoraria from all the above in addition to HiberCell. He reported stock and other ownership interests with Curesponse, Inndura, Osel, Pionyr, Precede Bio, Primium, and Tempest Therapeutic and has received research funding from Agensys, Arcus Biosciences, AstraZeneca, AVEO, Bayer, Bristol-Myers Squibb, Calithera Biosciences, Eisai, Exelixis, GlaxoSmithKline, Ipsen, Merck, NiKang Therapeutics, Novartis, Peloton Therapeutics, Pfizer, Roche, Roche/Genentech, Seattle Genetics/Astellas, Takeda, and TRACON Pharma.

References

1. Choueiri TK, Tomczak P, Park SH, et al. Overall survival results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab versus placebo for the treatment of clear cell renal cell carcinoma (ccRCC). J Clin Oncol. 2024,42(suppl 4):LBA359. doi:10.1200/JCO.2024.42.4_suppl.LBA359
2. Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385(8):683-694. doi:10.1056/NEJMoa2106391