Late Breaking Abstract – ASCO 2019 Front-Line Keytruda® Monotherapy for Patients with Advanced Gastric or Gastroesophageal Junction Adenocarcinoma

SUMMARY: The American Cancer Society estimates that in the US, about 27,510 cases of Gastric Cancer will be diagnosed in 2019 and about 11,140 people will die of the disease. The average age at diagnosis is 68 years and Gastric Cancer is one of the leading causes of cancer-related deaths in the world. Risk factors for gastric cancer include age, gender, ethnicity, geography and infection with Helicobacter pylori. Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with Gastric and GastroEsophageal (GE) Adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. These patients frequently are treated with Platinum containing chemotherapy along with a Fluoropyrimidine and, if appropriate, HER2/neu-targeted therapy. This can however be associated with significant toxicities impacting patient’s quality of life.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. KEYTRUDA® in the Phase II KEYNOTE-059 trial demonstrated promising antitumor activity and durable responses in patients with advanced Gastric/GastroEsophageal Junction cancer, who had progressed on more than 2 lines of therapy, with higher Objective Response Rates noted in patients with PD-L1-positive tumors.

KEYNOTE-062 is a randomized, phase III controlled study in which KEYTRUDA® monotherapy was compared to standard chemotherapy as first line treatment, in select patients with advanced Gastric or GastroEsophageal Junction (GEJ) Adenocarcinoma. This trial enrolled 763 newly diagnosed patients of whom 69% had Gastric Adenocarcinoma cancer and 30% had GEJ Adenocarcinoma. Patients were randomized 1:1:1 to receive KEYTRUDA® 200 mg IV every 3 weeks for up to 2 years (N=256), KEYTRUDA® plus Cisplatin 80 mg/m2 IV every three weeks along with either 5-Fluorouracil 800 mg/m2 daily on Days 1-5 every three weeks or XELODA® (Capecitabine) 1000 mg/m2 twice a day on Days 1-14 every three weeks (N=257 ) or placebo plus Cisplatin and either 5-FU or XELODA® given at a similar dose and schedule as the second group (N=250). The median patient age was 62 years and PD-L1 expression was assessed by Combined Positive Score (CPS). The Primary endpoints were Overall Survival (OS) in patients whose tumors expressed PD-L1 CPS 1 or more and CPS 10 or more in the KEYTRUDA® monotherapy group and in combination with chemotherapy group, as well as Progression Free Survival (PFS) in patients whose tumors expressed PD-L1 CPS 1 or more in the combination arm. Secondary endpoints included Overall Response Rate (ORR) and Duration of Response (DOR) in patients whose tumors express PD-L1 CPS 1 or more. In the current trial, all patients had a PD-L1 CPS of at least 1, and 281 patients (37%) had a PD-L1 CPS score of 10 or more. The median follow-up was 11.3 months.

The trial met its Primary endpoint and among patients with a PD-L1 CPS of 1 or more, Overall Survival was noninferior to chemotherapy. The median Overall Survival was 10.6 months in the KEYTRUDA® monotherapy group compared with 11.1 months in the chemotherapy group (HR=0.91). Among patients with a PD-L1 CPS 10 or more, Overall Survival with KEYTRUDA® was superior to chemotherapy. The median Overall Survival was 17.4 months for those receiving KEYTRUDA® compared with 10.8 months for those receiving chemotherapy. After 2 years, 39% of people taking KEYTRUDA® were alive compared with 22% of those taking chemotherapy (HR=0.69). The OS and PFS rates for the combination of KEYTRUDA® and chemotherapy were comparable with those of chemotherapy alone, regardless of PD-L1 CPS. The efficacy outcomes were not influenced by age, tumor size or location, histological subtype, number of metastatic sites and prior gastrectomy status.

It was concluded that KEYTRUDA® monotherapy is noninferior to chemotherapy for OS among patients with PD-L1 CPS 1 or more. There was however a clinically meaningful improvement in OS among patients with PD-L1 CPS 10 or more. Further, there was a more favorable safety profile for KEYTRUDA® over chemotherapy, making this a more desirable treatment option for elderly patients, for whom platinum based chemotherapy may not be appropriate. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: The phase III KEYNOTE-062 study. Tabernero J, Van Cutsem E, Bang Y-J, et al. J Clin Oncol 37, 2019 (suppl; abstr LBA4007)