Merck’s KEYTRUDA® (pembrolizumab) reduced the risk of distant metastasis or death by 40% versus placebo as adjuvant treatment in resected, high-risk stage III melanoma

Michelle Dryden September 19, 2020September 19, 2020Comments Off

Long-Term Findings From EORTC1325/KEYNOTE-054 Show Adjuvant KEYTRUDA Demonstrated a Sustained Recurrence-Free Survival Benefit Versus Placebo Across Stage IIIA (>1 mm Lymph Node Metastasis), IIIB and IIIC Melanoma

Merck Is Advancing a Broad Clinical Program Evaluating KEYTRUDA for the Early Treatment of Cancer

KENILWORTH, N.J., & BRUSSELS–(BUSINESS WIRE)–$MRK #MRK–Merck (NYSE: MRK), known as MSD outside the United States and Canada, and the European Organisation for Research and Treatment of Cancer (EORTC) today announced new and updated findings from the Phase 3 EORTC1325/KEYNOTE-054 trial evaluating KEYTRUDA, Merck’s anti-PD-1 therapy, as adjuvant therapy in resected, high-risk stage III melanoma. Late-breaking, first-time study results showed that with 3.5 years of follow-up, adjuvant KEYTRUDA met the key secondary endpoint of distant metastasis-free survival (DMFS), reducing the risk of distant metastasis or death by 40% versus placebo (HR=0.60 [95% CI, 0.49-0.73]; p<0.001), with 3.5-year DMFS rates of 65.3% and 49.4%, respectively. In addition, KEYTRUDA demonstrated a sustained recurrence-free survival (RFS) benefit versus placebo across stage IIIA (>1 mm lymph node metastasis), IIIB and IIIC melanoma, with 3.5-year RFS rates of 59.8% for KEYTRUDA versus 41.4% for placebo (HR = 0.59 [95% CI, 0.49-0.70]; p<0.001). The RFS and DMFS benefits were observed across key subgroups, including disease stages (both according to AJCC-7 and AJCC-8), BRAF mutation status and PD-L1 expression.

“Despite surgical intervention, patients diagnosed with high-risk stage III melanoma can experience disease recurrence, and for those with distant metastasis, they often face a significantly worse prognosis,” said Alexander Eggermont, study chair, Chief Scientific Officer Princess Máxima Center, Utrecht, Netherlands. “These new and updated data, including first-time results for distant metastasis-free survival are significant, showing that adjuvant KEYTRUDA not only delayed recurrence but also delayed distant metastasis, further reinforcing the benefits of KEYTRUDA for these patients with stage III melanoma.”

“In KEYNOTE-054, adjuvant treatment with KEYTRUDA also continued to demonstrate long-term improvements in the prevention of new disease compared to placebo, with nearly 60% of patients alive and recurrence-free after 3.5 years,” said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. “Taken together with the new distant metastasis-free survival results shown in this trial, these data point to the important role KEYTRUDA plays in melanoma in the adjuvant setting and are encouraging for the evaluation of KEYTRUDA in earlier disease states in other tumor types.”

These late-breaking data were presented as a proffered paper at the European Society for Medical Oncology (ESMO) Virtual Congress 2020 on Saturday, Sept. 19 (Abstract #LBA46). As announced, data spanning more than 15 types of cancer will be presented from Merck’s broad oncology portfolio and investigational pipeline at the congress. A compendium of presentations and posters of Merck-led studies is available here. Follow Merck on Twitter via @Merck and keep up to date with ESMO news and updates by using the hashtag #ESMO20.

KEYTRUDA is currently approved for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection in more than 70 countries based on the results from EORTC1325/KEYNOTE-054. Merck’s broad clinical development program in melanoma and skin cancers is addressing areas of unmet need by investigating KEYTRUDA in earlier stages of disease and in combination with other anti-cancer therapies across multiple potential registration-enabling studies, including KEYNOTE-716, LEAP-003 and LEAP-004.

EORTC1325/KEYNOTE-054 Trial Design and Additional Subgroup Data (Abstract #LBA8)

EORTC1325/KEYNOTE-054 (ClinicalTrials.gov, NCT02362594) is a Phase 3, randomized, double-blind study sponsored by Merck and conducted in collaboration with the EORTC designed to evaluate adjuvant therapy with KEYTRUDA versus placebo in patients with resected, high-risk melanoma (stage IIIA [>1 mm lymph node metastasis], IIIB and IIIC). The co-primary endpoints are RFS for all patients and RFS in patients whose tumors expressed PD-L1. Secondary endpoints include DMFS and overall survival (OS) in all patients and in patients whose tumors expressed PD-L1. Data from a three-year analysis of RFS were presented in the virtual scientific program of the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting. In accordance with the trial protocol, the study is continuing in order to evaluate the secondary endpoint of OS; however, upon documented recurrence, patients were eligible for crossover/re-challenge with KEYTRUDA.

Key Subgroup Analysis Results From EORTC1325/KEYNOTE-054
		3.5-Year DMFS Rate, %	DMFS, HR	P-Value (Log Rank)*
PD-L1 Positive (n=853)	KEYTRUDA	66.7%	0.61 (95% CI, 0.49-0.76)	<0.001
PD-L1 Positive (n=853)	Placebo	51.6%	0.61 (95% CI, 0.49-0.76)	<0.001
PD-L1 Negative (n=116)	KEYTRUDA	58.0%	0.49 (99% CI, 0.24-0.99)	0.008
PD-L1 Negative (n=116)	Placebo	40.2%	0.49 (99% CI, 0.24-0.99)	0.008
With BRAF V600 E/K Mutation (n=440)	KEYTRUDA	63.7%	0.53 (99% CI, 0.36-0.77)	<0.001
With BRAF V600 E/K Mutation (n=440)	Placebo	43.4%	0.53 (99% CI, 0.36-0.77)	<0.001
Without BRAF Mutation (n=449)	KEYTRUDA	62.1%	0.73 (99% CI, 0.50-1.07)	0.035
Without BRAF Mutation (n=449)	Placebo	51.4%	0.73 (99% CI, 0.50-1.07)	0.035
*Stratified by stage given at randomization

In addition, the DMFS benefit demonstrated with KEYTRUDA was similar in patients with AJCC-7 stage IIIA (HR=0.64), IIIB (HR=0.58) and IIIC (HR=0.61) melanoma. Adjuvant KEYTRUDA decreased the incidence of distant metastasis as a first recurrence by 43% (at 3.5 years: 24.9% versus 39.5%, HR= 0.57 [95% CI, 0.46-0.72]; p<0.001).

No new safety data were identified as part of the 42-month analysis. The safety profile of KEYTRUDA was consistent with what has been seen in previously reported studies among patients with advanced melanoma. Grade 3-5 immune-related adverse events occurred in 7.7% of patients who received KEYTRUDA and 0.6% of patients who received placebo.

About EORTC

European Organisation for the Research and Treatment of Cancer (EORTC) is an academic clinical research organization, bringing together investigators from all disciplines, across all tumour types, to conduct research that improves quality of life and survival of cancer patients. It conducts research from translational to large, prospective, multi-centre, phase III clinical trials evaluating new therapies and treatment strategies as well as quality of life of patients. EORTC network comprises more than 5300 professionals in over 1000 hospitals and institutes in more than 30 countries, supported by Headquarters in Brussels, Belgium.

About Melanoma

Melanoma, the most serious form of skin cancer, is characterized by the uncontrolled growth of pigment-producing cells. The incidence of melanoma has been increasing over the past few decades – approximately 287,000 new cases were diagnosed worldwide in 2018. In the U.S., melanoma is one of the most common types of cancer diagnosed and is responsible for the vast majority of skin cancer deaths. In 2020, more than 100,000 people are expected to be diagnosed, and nearly 7,000 people are expected to die of the disease in the U.S. alone.

About KEYTRUDA^® (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-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 program. There are currently more than 1,200 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program 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.

Selected KEYTRUDA^® (pembrolizumab) Indications

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) ≥1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [combined positive score (CPS) ≥10], as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Selected Important Safety Information for KEYTRUDA^® (pembrolizumab)

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grades 3-5 in 1.5% of patients.

Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib)

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hepatotoxicity in Combination With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause adrenal insufficiency (primary and secondary), hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Adrenal insufficiency occurred in 0.8% (22/2799) of patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (<0.1%). Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of adrenal insufficiency, hypophysitis (including hypopituitarism), thyroid function (prior to and periodically during treatment), and hyperglycemia. For adrenal insufficiency or hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 adrenal insufficiency or hypophysitis and withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 adrenal insufficiency or hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment.

Contacts

Media Contacts:

Merck:

Pamela Eisele

(267) 305-3558

Ayn Wisler

(908) 740-5590

EORTC:

Davi Kaur

+32 (0)2 774 1513

Investor Contacts:

Merck:

Peter Dannenbaum

(908) 740-1037

Courtney Ronaldo

(908) 740-6132

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Michelle Dryden (Author)