31 July 2019 - - The US Food and Drug Administration has approved Keytruda, US-based pharmaceutical company Merck's (NYSE: MRK) anti-PD-1 therapy, as monotherapy for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (Combined Positive Score [CPS] ≥10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy, the company said.

Immune-mediated adverse reactions, which may be severe or fatal, can occur with Keytruda, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation.

Based on the severity of the adverse reaction, Keytruda should be withheld or 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.

The approval was based on data from KEYNOTE-181 (NCT02564263), a multicenter, randomized, open-label, active-controlled trial that enrolled 628 patients with recurrent locally advanced or metastatic esophageal cancer who progressed on or after one prior line of systemic treatment for advanced disease.

Patients with HER2/neu positive esophageal cancer were required to have received treatment with approved HER2/neu targeted therapy.

All patients were required to have tumor specimens for PD-L1 testing at a central laboratory; PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx kit.

Patients with a history of non-infectious pneumonitis that required steroids or current pneumonitis, active autoimmune disease, or a medical condition that required immunosuppression were ineligible.

Patients were randomised to receive either Keytruda 200 mg every three weeks or investigator's choice of any of the following chemotherapy regimens, all given intravenously: paclitaxel 80-100 mg/m2 on Days 1, 8, and 15 of every four-week cycle, docetaxel 75 mg/m2 every three weeks, or irinotecan 180 mg/m2 every two weeks.

Randomisation was stratified by tumor histology (esophageal squamous cell carcinoma [ESCC] vs. esophageal adenocarcinoma [EAC]/Siewert type I EAC of the gastroesophageal junction [GEJ]), and geographic region (Asia vs. ex-Asia).

Treatment with Keytruda or chemotherapy continued until unacceptable toxicity or disease progression.

Patients randomized to Keytruda were permitted to continue beyond the first RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ)-defined disease progression if clinically stable until the first radiographic evidence of disease progression was confirmed at least four weeks later with repeat imaging.

Patients treated with Keytruda without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every nine weeks.

The major efficacy outcome measure was overall survival evaluated in the following co-primary populations: patients with ESCC, patients with tumors expressing PD-L1 CPS ≥10, and all randomised patients.

Additional efficacy outcome measures were progression-free survival, objective response rate, and duration of response, according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ, as assessed by blinded independent central review.

The observed hazard ratios for OS were 0.77 (95% CI: 0.63, 0.96) in patients with ESCC, 0.70 (95% CI: 0.52, 0.94) in patients with tumors expressing PD-L1 CPS ≥10, and 0.89 (95% CI: 0.75, 1.05) in all randomised patients.

On further examination, in patients whose ESCC tumors expressed PD-L1 (CPS ≥10), an improvement in OS was observed among patients randomised to Keytruda as compared with chemotherapy.

In ESCC patients with PD-L1 expression (CPS ≥10), there were 68 events observed for patients receiving Keytruda and 72 events observed for patients receiving chemotherapy.

There was a median OS in patients receiving Keytruda of 10.3 months (95% CI: 7.0, 13.5) compared with 6.7 months in the chemotherapy arm (95% CI: 4.8, 8.6) (HR=0.64 [95% CI: 0.46, 0.90]).

The median PFS was 3.2 months (range, 2.1, 4.4 months) for patients receiving KEYTRUDA and 2.3 months (range, 2.1, 3.4 months) for patients receiving chemotherapy (HR=0.66 [95% CI: 0.48, 0.92]).

The ORR was 22% (95% CI: 14.0, 33.0) in patients receiving Keytruda, with a complete response rate of 5% and partial response rate of 18%. In the chemotherapy arm, the ORR was 7% (95% CI:3.0, 15.0), with a CRR of 1% and partial response rate of 6%.

The median duration of response was 9.3 months (range, 2.1+, 18.8+) in patients receiving KEYTRUDA and 7.7 months (range, 4.3, 16.8+) in the chemotherapy arm.

Among the 314 patients with esophageal cancer enrolled in KEYNOTE-181 treated with Keytruda, the median duration of exposure to Keytruda was 2.1 months (range, 1 day to 24.4 months).

Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible.

Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in 2,799 patients with melanoma or non-small cell lung cancer (NSCLC) treated with Keytruda as a single agent.

This indication was also based on data from KEYNOTE-180 (NCT02559687), a multicenter, non-randomised, open-label trial that enrolled 121 patients with locally advanced or metastatic esophageal cancer who progressed on or after at least two prior systemic treatments for advanced disease.

With the exception of the number of prior lines of treatment, the eligibility criteria were similar to and the dosage regimen identical to KEYNOTE-181.

The major efficacy outcome measures were ORR and DoR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ, as assessed by BICR.
The ORR in the 35 patients with ESCC expressing PD-L1 (CPS ≥10) was 20% (95% CI: 8.0, 37.0).

Among the seven responding patients, the DoR ranged from 4.2 to 25.1+ months, with five patients having responses of six months or longer and three patients having responses of 12 months or longer.

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 humanised 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.