US-FDA approves Merck’s Keytruda plus gemcitabine & cisplatin to treat patients with locally advanced unresectable or metastatic BCT

Merck, known as MSD outside of the United States and Canada, announced that the US Food and Drug Administration (FDA) has approved Keytruda, Merck’s anti-PD-1 therapy, in combination with gemcitabine and cisplatin, for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer (BTC). The approval was based on results from the phase 3 KEYNOTE-966 trial, in which Keytruda plus chemotherapy demonstrated a statistically significant improvement in the study’s primary endpoint of overall survival (OS), reducing the risk of death by 17% (HR=0.83 [95% CI, 0.72-0.95]; one-sided p=0.0034) compared to chemotherapy alone at the trial’s pre-specified final analysis for OS. Median OS was 12.7 months (95% CI, 11.5-13.6) for Keytruda plus chemotherapy versus 10.9 months (95% CI, 9.9-11.6) for chemotherapy alone. This approval marks the sixth indication for Keytruda in gastrointestinal cancers.

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.

“Cancers of the biliary tract can be highly aggressive tumours, underscoring the need for additional treatment options for the growing number of patients facing this challenging disease,” said Dr. Robin Kate Kelley, professor of clinical medicine in the division of hematology/oncology, University of California, San Francisco. “Today's approval of pembrolizumab in combination with chemotherapy offers patients with locally advanced unresectable or metastatic biliary tract cancer a new immunotherapy regimen that has demonstrated the potential to help these patients live longer.”

“Many patients with biliary tract cancer are diagnosed with locally advanced or metastatic disease, at which point they are not eligible for surgery and face poor survival outcomes with limited treatment options,” said Dr. Marjorie Green, senior vice president and head of late-stage oncology, global clinical development, Merck Research Laboratories. “With this approval, Merck is proud to offer a new treatment option to certain patients with locally advanced unresectable or metastatic biliary tract cancer, and their healthcare providers, that has shown an overall survival benefit compared to chemotherapy alone.”

KEYNOTE-966 is a multicenter, double-blind, randomized, placebo-controlled Phase 3 trial (ClinicalTrials.gov, NCT04003636) evaluating Keytruda in combination with gemcitabine and cisplatin for the treatment of patients with locally advanced unresectable or metastatic BTC who had not received prior systemic therapy in the advanced disease setting. The trial enrolled 1,069 patients.

Patients were randomized (1:1) to Keytruda (200 mg) on Day 1 plus gemcitabine (1,000 mg/m2) and cisplatin (25 mg/m2) on Day 1 and Day 8 every three weeks (n=533), or placebo on Day 1 plus gemcitabine (1,000 mg/m2) and cisplatin (25 mg/m2) on Day 1 and Day 8 every three weeks (n=536). Study medications were administered via intravenous infusion. Treatment continued until unacceptable toxicity or disease progression. For Keytruda, treatment continued for a maximum of 35 cycles (or approximately 24 months). For gemcitabine, treatment could be continued beyond eight cycles, while for cisplatin, treatment could be administered for a maximum of eight cycles. Administration of Keytruda with chemotherapy was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. Assessment of tumor status was performed at baseline and then every six weeks through 54 weeks, followed by every 12 weeks thereafter.

The major efficacy outcome measure was OS. Additional efficacy outcome measures were progression-free survival (PFS), objective response rate (ORR) and duration of response (DOR) as assessed by blinded independent central review (BICR) according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ.

At the trial’s pre-specified final analysis for PFS and ORR, Keytruda plus chemotherapy reduced the risk of disease progression or death by 14% (HR=0.86 [95% CI, 0.75-1.00]) compared to chemotherapy alone. Median PFS was 6.5 months (95% CI, 5.7-6.9) for Keytruda plus chemotherapy versus 5.6 months (95% CI, 5.1-6.6) for chemotherapy alone; however, this result did not reach statistical significance at this analysis. The ORR for Keytruda plus chemotherapy was 29% (95% CI, 25-33), with a complete response (CR) rate of 2.1% (n=11) and a partial response (PR) rate of 27% (n=142), and the ORR for chemotherapy alone was 29% (95% CI, 25-33), with a CR rate of 1.3% (n=7) and a PR rate of 27% (n=146). At the trial’s pre-specified final analysis for OS, median DOR was 8.3 months (95% CI, 6.9-10.2) for Keytruda plus chemotherapy (n=156) versus 6.8 months (95% CI, 5.7-7.1) for chemotherapy alone (n=152).

The median duration of exposure to Keytruda was six months (range, 1 day to 28 months). Keytruda was discontinued due to adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of Keytruda (=1%) was pneumonitis (1.3%). Adverse reactions leading to interruption of Keytruda occurred in 55% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of Keytruda (=2%) were decreased neutrophil count (18%), decreased platelet count (10%), anaemia (6%), decreased white blood count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased alanine aminotransferase (ALT) (2.6%), increased aspartate aminotransferase (AST) (2.5%) and biliary obstruction (2.3%).

In the Keytruda plus chemotherapy versus placebo plus chemotherapy arms, there was a difference of =5% incidence in adverse reactions between patients who received Keytruda versus placebo for pyrexia (26% vs. 20%), rash (21% vs. 13%), pruritus (15% vs. 10%) and hypothyroidism (9% vs. 2.6%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.

There was a difference of =5% incidence in laboratory abnormalities between patients who received Keytruda plus chemotherapy versus placebo plus chemotherapy for decreased lymphocytes (69% vs. 61%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.

Biliary tract cancer (BTC) is a group of rare and highly aggressive cancers in the liver, gallbladder and bile ducts. Biliary tract cancer is the second most common type of primary liver cancer after hepatocellular carcinoma (HCC), accounting for approximately 15% of all liver cancers. In the US, there are about 20,000 patients diagnosed with BTC each year. Biliary tract cancer is most frequently diagnosed in patients between 50 and 70 years old, and approximately 70% of BTC patients are diagnosed at an advanced stage. Patients diagnosed with BTC face a very poor prognosis, with a five-year relative survival rate of 2-3% for those diagnosed with advanced disease and 9-11% for those diagnosed across all stages.

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 programme. There are currently more than 1,600 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.

Merck is committed to helping provide patients and their caregivers support throughout their treatment with Keytruda. The KEY+YOU Patient Support Program provides a range of resources and support.

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumour types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers.

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