Merck, known as MSD outside the United States and Canada, announced that the US Food and Drug Administration (FDA) has approved Keytruda, Merck’s anti-PD-1 therapy, for the adjuvant treatment of patients with renal cell carcinoma (RCC) at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.

The approval is based on data from the pivotal phase 3 KEYNOTE-564 trial, in which Keytruda demonstrated a statistically significant improvement in disease-free survival (DFS), reducing the risk of disease recurrence or death by 32% (HR=0.68 [95% CI, 0.53-0.87]; p=0.0010) compared to placebo. Median DFS has not been reached for either group.

“Despite decades of research, limited adjuvant treatment options have been available for earlier-stage renal cell carcinoma patients who are often at risk for recurrence. In KEYNOTE-564, pembrolizumab reduced the risk of disease recurrence or death by 32%, providing a promising new treatment option for certain patients at intermediate-high or high risk of recurrence,” said Dr. Toni K. Choueiri, director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, and professor of medicine, Harvard Medical School. “With this FDA approval, pembrolizumab may address a critical unmet treatment need and has the potential to become a new standard of care in the adjuvant setting for appropriately selected patients.”

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time during or after treatment with Keytruda, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of Keytruda. Based on the severity of the adverse reaction, Keytruda should be withheld or permanently discontinued and corticosteroids administered if appropriate. Keytruda can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, Keytruda can cause fetal harm when administered to a pregnant woman.

“Keytruda is foundational for the treatment of patients with certain advanced cancers, and this approval marks the fourth indication for Keytruda in earlier stages of cancer,” said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. “Keytruda is now the first immunotherapy approved for the adjuvant treatment of certain patients with renal cell carcinoma. This milestone is a testament to our commitment to help more people living with cancer.”

In RCC, Merck has a broad clinical development programme exploring Keytruda, as monotherapy or in combination, as well as other investigational products across multiple settings and stages of RCC, including adjuvant and advanced or metastatic disease.

Keytruda demonstrated a statistically significant improvement in DFS in patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions compared with placebo (HR=0.68 [95% CI, 0.53-0.87]; p=0.0010). The trial will continue to assess overall survival (OS) as a secondary outcome measure.

In KEYNOTE-564, the median duration of exposure to Keytruda was 11.1 months (range, 1 day to 14.3 months). Serious adverse reactions occurred in 20% of these patients receiving Keytruda. Serious adverse reactions (=1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% of those treated with Keytruda, including one case of pneumonia. Adverse reactions leading to discontinuation occurred in 21% of patients receiving Keytruda; the most common (=1%) were increased alanine aminotransferase (1.6%), colitis and adrenal insufficiency (1% each). The most common adverse reactions (all grades =20%) in the Keytruda arm were musculoskeletal pain (41%), fatigue (40%), rash (30%), diarrhea (27%), pruritus (23%) and hypothyroidism (21%).

KEYNOTE-564 (ClinicalTrials.gov, NCT03142334) is a multicenter, randomized, double-blind, placebo-controlled phase 3 trial evaluating Keytruda as adjuvant therapy for RCC in 994 patients with intermediate-high or high risk of recurrence of RCC or M1 no evidence of disease (NED). Patients must have undergone a partial nephroprotective or radical complete nephrectomy (and complete resection of solid, isolated, soft tissue metastatic lesion[s] in M1 NED participants) with negative surgical margins for at least four weeks prior to the time of screening. Patients were excluded from the trial if they had received prior systemic therapy for advanced RCC. Patients with active autoimmune disease or a medical condition that required immunosuppression were also ineligible. The major efficacy outcome measure was investigator-assessed DFS, defined as time to recurrence, metastasis or death. An additional outcome measure was OS. Patients were randomized (1:1) to receive Keytruda 200 mg administered intravenously every three weeks or placebo for up to one year until disease recurrence or unacceptable toxicity.

Keytruda is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. Keytruda is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research programme. There are currently more than 1,600 trials studying Keytruda across a wide variety of cancers and treatment settings. The Keytruda clinical programme seeks to understand the role of Keytruda across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with Keytruda, including exploring several different biomarkers.