Results from a phase 3 randomized, placebo-controlled clinical trial, funded by Merck & Co/MSD, demonstrated for the first time, in fifty years, an overall survival benefit from an adjuvant therapy in patients diagnosed with kidney cancer. [1][2]

Adjuvant treatment with pembrolizumab (Keytruda®; Merck & Co/MSD), an immunotherapy drug, significantly prolonged overall survival (OS) in patients with clear-cell renal-cell carcinoma (ccRCC) at high risk for recurrence.  This is the conclusion based on an analysis of results from the KEYNOTE-564 study. The results show that pembrolizumab was associated with a 38% reduction in risk of death compared with placebo.[1][2]

“We can now tell our patients that pembrolizumab after surgery not only delays recurrences but also helps them live longer,” explained the study’s lead investigator Toni Choueiri, MD, of Dana-Farber Cancer Institute.

Choueiri, director of the Lank Center for Genitourinary Oncology at Dana-Farber, presented the findings at the American Society of Clinical Oncology (ASCO) Genitourinary Cancer Symposium on January 27, 2024. [LBA359][3]

Study design
The KEYNOTE-564 trial was designed to evaluate adjuvant pembrolizumab following nephrectomy (removal of the cancerous kidney) within 12 weeks prior to randomization. The double-blind, phase 3 study, carried out at hundreds of sites internationally, enrolled 994 patients who were randomized to pembrolizumab once every three weeks for about a year, or a placebo. Pembrolizumab targets a molecular pathway that cancer cells commandeer to evade attack by the body’s immune system. By blocking this “checkpoint” pathway, the drug helps free the immune system’s army of T-cells to combat tumors.

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For inclusion in the trial, patients had to have a clear-cell component to their tumor and be at intermediate or high risk of recurrence. Some patients with resected metastases after nephrectomy were also eligible. For patients with ccRCC, surgery is intended to be curative. However, between 30 and 50% of patients can experience recurrence after surgery. Recurrences often result in metastatic disease, which is usually incurable.

Reducing recurrence
Investigators have been trying to find ways to reduce recurrences and prolong survival for this patient group since 1973, the date of the first randomized controlled trial of an adjuvant therapy. An adjuvant therapy is a medicine intended to enhance efficacy after primary treatment of the cancer, which in this case is surgery.

“Since 1973, more than 12,000 patients with kidney cancer participated in adjuvant studies versus a control arm and none of the studies showed the experimental arm extends lives until now with the KEYNOTE-564 study,” says Choueiri. “We showed pembrolizumab extends survival. It doesn’t only delay recurrence.”

In the first interim analysis of the KEYNOTE-564 study, Choueiri and colleagues reported that adjuvant pembrolizumab improved disease-free survival in patients with kidney cancer at high risk of relapse. Pembrolizumab was approved in 2021 as adjuvant treatment for patients with kidney cancer based on these KEYNOTE-564 results.

This third interim analysis was completed after a median of 57.2 months of follow up. Adjuvant pembrolizumab significantly prolonged overall survival versus placebo in trial participants. Overall survival benefits with pembrolizumab were consistent across subgroups, irrespective of stage, risk stratification, immunological biomarkers, and other characteristics.

Approximately 18% of patients stopped therapy due to side-effects associated with pembrolizumab. No treatment related deaths were reported with pembrolizumab. The investigators reported previously that adjuvant pembrolizumab did not result in clinically meaningful deterioration of health-related quality of life.

Prior to the approval of pembrolizumab, there was no widespread accepted standard of care for patients with ccRCC after treatment with surgery. Now, with adjuvant pembrolizumab as standard of care for this patient group, Choueiri and colleagues are investigating whether it can be improved by combining pembrolizumab with the small molecule inhibitor of hypoxia-inducible factor 2 alpha HIF-2a inhibitor belzutifan (Welireg®; Merck & Co), which is generally used to treat solid tumors in patients with von Hippel-Lindau disease, also known as Von Hippel–Lindau syndrome, a rare genetic disorder with multisystem involvement.[4]

Clinical trials
Safety and Efficacy Study of Pembrolizumab (MK-3475) as Monotherapy in the Adjuvant Treatment of Renal Cell Carcinoma Post Nephrectomy (MK-3475-564/​KEYNOTE-564) – ID NCT03142334

Highlights of prescribing information
Pembrolizumab (Keytruda®; Merck & Co/MSD) [Prescribing Information]
Belzutifan (Welireg®; Merck & Co)[Prescribing Information]

[1] Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Chang YH, Hajek J, Symeonides SN, Lee JL, Sarwar N, Thiery-Vuillemin A, Gross-Goupil M, Mahave M, Haas NB, Sawrycki P, Gurney H, Chevreau C, Melichar B, Kopyltsov E, Alva A, Burke JM, Doshi G, Topart D, Oudard S, Hammers H, Kitamura H, Bedke J, Perini RF, Zhang P, Imai K, Willemann-Rogerio J, Quinn DI, Powles T; KEYNOTE-564 Investigators. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med. 2021 Aug 19;385(8):683-694. doi: 10.1056/NEJMoa2106391. PMID: 34407342.
[2] Labaki C, Choueiri TK. Perioperative immunotherapy for renal cell carcinoma: looking beyond the data. Nat Rev Clin Oncol. 2023 Feb;20(2):65-66. doi: 10.1038/s41571-022-00710-5. PMID: 36418478.
[3] Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, 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 42, 2024 (suppl 4; abstr LBA359)
[4] Choueiri TK, Powles T, Voss MH, Plimack ER, Gurney H, Song Y, Perini RF, Rodriguez-Lopez K, Rini BI. LITESPARK-012: pembrolizumab plus lenvatinib with or without belzutifan or quavonlimab for advanced renal cell carcinoma. Future Oncol. 2023 Dec;19(40):2631-2640. doi: 10.2217/fon-2023-0283. Epub 2023 Oct 26. PMID: 37882432.

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