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Merck announces phase 3 KEYNOTE-394 trial of Keytruda significantly improve OS vs placebo in certain patients with advanced HCC previously treated with sorafenib

Kenilworth, New Jersey
Thursday, January 20, 2022, 13:00 Hrs  [IST]

Merck, known as MSD outside the United States and Canada, announced the final results from the phase 3 KEYNOTE-394 trial investigating Keytruda, Merck’s anti-PD-1 therapy, plus best supportive care (BSC) in patients in Asia with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib.

KEYNOTE-394 is the first trial with an anti-PD-1/L1 as a second-line monotherapy treatment to show an improvement in overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) compared to placebo plus BSC for these patients. These data add to the body of evidence relating to the use of Keytruda as a monotherapy in second-line HCC post sorafenib.

Keytruda plus BSC demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint of OS, reducing the risk of death by 21% (HR=0.79 [95% CI, 0.63-0.99]; p=0.0180) compared to placebo plus BSC for patients with previously treated advanced HCC. For patients treated with Keytruda plus BSC, median OS was 14.6 months (95% CI, 12.6-18.0) compared to 13.0 months (95% CI, 10.5-15.1) for patients treated with placebo plus BSC. The percentage of patients who were alive at two years was 34.3% for Keytruda plus BSC compared to 24.9% for placebo plus BSC. These data will be presented at the 2022 American Society of Clinical Oncology Gastrointestinal Cancers (ASCO GI) Symposium (Abstract #352788) on Friday, January 21 at 10:15 a.m. ET.

“Hepatocellular carcinoma is a leading cause of cancer death across the world, and there are limited treatment options shown to extend survival for patients following treatment with sorafenib,” said Dr. Shukui Qin, director, Cancer Center of Jinling Hospital, and professor, Nanjing University of Chinese Medicine. “These overall survival data are very encouraging for patients with HCC previously treated with sorafenib and show the potential of Keytruda to extend the lives of these patients.”

Treatment-related adverse events (TRAEs) occurred in 66.9% of patients in the Keytruda plus BSC arm and 49.7% of patients in the placebo plus BSC arm, and Grade 3-5 TRAEs occurred in 14.4% of patients in the Keytruda plus BSC arm and 5.9% of patients in placebo plus BSC arm. Immune-mediated adverse events (AEs) of any grade occurred in 18.1% of patients receiving Keytruda plus BSC and 10.5% of patients receiving placebo plus BSC. Grade 3-5 immune-mediated AEs occurred in 3.0% of patients receiving Keytruda plus BSC. There were three deaths (due to gastrointestinal haemorrhage, autoimmune hepatitis, and soft tissue infection) in the Keytruda arm related to the study intervention.

“Patients with advanced HCC still have a high unmet medical need with low survival rates, reinforcing the need for treatment options that can improve overall survival,” said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. “We are pleased to share these new data from KEYNOTE-394 and are committed to advancing research for patients with this difficult-to-treat cancer through our broad global program in HCC.”

In the US, Keytruda is indicated for the treatment of patients with HCC who have been previously treated with sorafenib based on ORR and duration of response (DOR) data from KEYNOTE-224. This indication is approved under accelerated approval based on tumour 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. Data from KEYNOTE-394 are being discussed with global regulatory authorities and will be evaluated as a potential confirmatory study in the US.

Merck is dedicated to advancing research in HCC and has a global development program of seven clinical trials that have enrolled or are expected to enroll approximately 3,000 patients. In HCC, Keytruda is being studied across multiple settings and lines of therapy as monotherapy and in combination with other treatments, including therapies through our collaborations.

KEYNOTE-394 (ClinicalTrials.gov, NCT03062358) is a randomized, double-blind Phase 3 trial evaluating Keytruda plus BSC versus placebo plus BSC in Asian patients with advanced HCC previously treated with sorafenib or oxaliplatin-based chemotherapy. The primary endpoint is OS. Additional endpoints include PFS, ORR, and DOR. The study enrolled 453 patients who were randomized to receive either Keytruda (intravenously every three weeks for up to 35 cycles of treatment [up to approximately two years]) plus BSC (including pain management and management of other potential complications including ascites per local standards of care) or placebo plus BSC.

Additional efficacy endpoint results of the trial showed Keytruda plus BSC reduced the risk of disease progression or death by 26% (HR=0.74 [95% CI, 0.60-0.92]; p=0.0032) compared to placebo plus BSC. Median PFS was 2.6 months (95% CI, 1.5-2.8) for KEYTRUDA plus BSC and 2.3 months (95% CI, 1.4-2.8) for placebo plus BSC. KEYTRUDA plus BSC showed an ORR of 12.7% (95% CI, 9.1-17.0) and a median DOR of 23.9 months (range, 2.8 to 32.0+), where placebo plus BSC showed an ORR of 1.3% (95% CI, 0.2-4.6) and a median DOR of 5.6 months (range, 3.0+ to 5.6).

Liver cancer is one of the leading causes of cancer-related deaths worldwide. It is estimated there were more than 905,000 new cases of liver cancer and more than 830,000 deaths from the disease globally in 2020. In the US, it is estimated there will be more than 41,000 new cases of liver cancer diagnosed and more than 30,000 deaths from this disease in 2022. An estimated 75% to 90% of primary liver cancer cases are hepatocellular carcinoma (HCC). Worldwide, major factors that increase the risk of HCC are chronic hepatitis B and chronic hepatitis C, alcohol use, and metabolic syndrome.

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 tumour 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 tumour cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research program. 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.


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