15 January 2019 - - US-based Merck (NYSE: MRK) has made the first presentation of results from KEYNOTE-181, a Phase 3 trial investigating Keytruda, Merck's anti-PD-1 therapy, as monotherapy for the second-line treatment of advanced or metastatic esophageal or esophagogastric junction carcinoma, the company said.

In this pivotal study, Keytruda met a primary endpoint by significantly improving overall survival in patients with squamous cell carcinoma or adenocarcinoma who progressed after standard therapy and whose tumors expressed PD-L1 (Combined Positive Score [CPS] ≥10), with a 31% reduction in the risk of death compared to chemotherapy (paclitaxel, docetaxel or irinotecan) (HR=0.69 [95% CI, 0.52-0.93]; p=0.0074).

This represents the first time an anti-PD-1 therapy has demonstrated a survival benefit for this patient population.

The primary endpoint of OS was also evaluated in patients with squamous cell histology and in the entire intention-to-treat study population.

While directionally favourable, statistical significance for OS was not met in these two patient groups. These results, as well as other study findings, are being presented at the 2019 Gastrointestinal Cancers Symposium (ASCO GI) in San Francisco in an oral presentation on Thursday, Jan. 17 (Abstract #2).

As previously announced, data from KEYNOTE-181 will be submitted to the US Food and Drug Administration and other regulatory authorities for review.

Merck is continuing to study Keytruda across multiple settings and stages of gastrointestinal cancer including gastric, hepatocellular carcinoma and esophageal through a broad clinical programme comprised of more than 9,000 patients in 65 studies involving Keytruda, including 7,000 patients in 35 Merck-affiliated studies.

In esophageal cancer, the Phase 3 trial KEYNOTE-590, evaluating Keytruda in combination with chemotherapy as a first-line treatment, is ongoing.

KEYNOTE-181 is a randomised, open-label, Phase 3 trial (ClinicalTrials.gov, NCT02564263) investigating KEYTRUDA monotherapy compared to chemotherapy in more than 600 patients with advanced or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus, or Siewert type I adenocarcinoma of the esophagogastric junction that has progressed after first-line standard therapy.

The primary endpoint is OS (evaluated in all patients as well as in patients with PD-L1 CPS ≥10 and in patients with squamous cell carcinoma).

Secondary endpoints are progression-free survival, objective response rate and safety/tolerability.

In the study, a total of 628 patients were randomised 1: 1 to receive either Keytruda (200 mg fixed dose every three weeks) or investigator's choice of any of the following chemotherapy regimens, all given intravenously: docetaxel (75 mg/m2 on Day 1 of each 21-day cycle), paclitaxel (80-100 mg/m2 on Days 1, 8, and 15 of each 28-day cycle), or irinotecan (80 mg/m2 on Day 1 of each 14-day cycle).

Of these 628 patients, 401 had squamous cell carcinoma, and 222 had a PD-L1 CPS ≥10.

Median follow-up for the study was 7.1 months for Keytruda and 6.9 months for chemotherapy.

Among patients in the study whose tumors expressed PD-L1 (CPS ≥10) (n=222/628), the median OS in the Keytruda group was 9.3 months (95% CI, 6.6-12.5) compared to a median OS of 6.7 months for patients in the chemotherapy group (95% CI, 5.1-8.2).

In addition, the estimated 12-month OS rate in these patients was 43% for Keytruda compared with 20% for chemotherapy.
In patients with squamous cell carcinoma (n=401/628), there was a clinically meaningful improvement in OS with Keytruda compared to chemotherapy, which did not meet statistical significance per the pre-specified statistical plan (HR=0.78 [95% CI, 0.63-0.96]; p=0.0095).

Among these 401 patients, median OS was 8.2 months in the Keytruda group (95% CI, 6.7-10.3) compared with 7.1 months in the chemotherapy group (95% CI, 6.1-8.2).

In the entire ITT study population (n=628), while also directionally favorable, the difference in OS was not statistically significant (HR=0.89 [95% CI, 0.75-1.05]; p=0.0560), with a median OS of 7.1 months for both treatment groups.

Per the pre-specified statistical analysis plan, the secondary endpoints of PFS and ORR were not formally tested, as OS was not reached in the full ITT study population.

The safety of Keytruda in KEYNOTE-181 was consistent with what has been seen in previous trials among patients treated with KEYTRUDA monotherapy. Treatment-related adverse events (TRAEs) occurred in 64.3% of patients taking KEYTRUDA compared with 86.1 % for chemotherapy.

The most common TRAEs in the Keytruda group with an incidence of 5% or more were fatigue (11.8%), hypothyroidism (10.5%), decreased appetite, asthenia, nausea and diarrhea. Grade 3-5 TRAEs occurred in 57 patients (18.2%) taking Keytruda compared with 121 (40.9%) on chemotherapy. There were five treatment-related deaths in each of the groups.

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.