Immunotherapy Makes Its Mark in First-Line Gastric Cancer Treatment

In the first-line treatment of advanced gastric and gastroesophageal junction cancers, the efficacy of pembrolizumab (Keytruda) immunotherapy was demonstrated by the KEYNOTE-062 study, published on September 3, 2020, in JAMA Oncology.

Adenocarcinoma of the stomach and gastroesophageal junction is the third leading cause of cancer deaths worldwide, with approximately 1 million new cases and 783,000 deaths in 2018. Around 50% of gastric cancers are advanced at diagnosis. For cancers that are inoperable or have metastasized at diagnosis and are HER2 negative, standard treatment begins with systemic chemotherapy. These first-line regimens are doublet or triplet fluoropyrimidine- and platinum-based combinations (for example, FLOT). With these regimens, median overall survival is 1 year or less, and adverse effects are also notable.

Pembrolizumab (Keytruda) targets one of the immune checkpoints that suppress the immune system's response to cancer, the PD-1 and PD-L1 interaction. It is a monoclonal antibody that binds to PD-1 to activate T cells and is an immunotherapy drug. Pembrolizumab has received FDA approval in 16 different cancer types to date.

Immunotherapy had previously received FDA approval for gastric cancer, but this was for 3rd-line treatment rather than first-line, in PD-L1-positive patients (see pembrolizumab approval for gastric cancer in 2017). 

The KEYNOTE-O62 Study

• The study enrolled patients with HER2-negative, PD-L1 ≥1, previously untreated, inoperable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma.
• It was designed as a randomized, controlled, partially blinded phase III clinical trial.
• 29 countries and 200 centers participated.
• Patients were enrolled between September 18, 2015, and May 26, 2017.
• Patients were divided into 3 arms:
  1. 256 patients in the pembrolizumab (immunotherapy alone) arm
  2. 257 patients in the pembrolizumab plus standard chemotherapy (cisplatin + 5FU or capecitabine) arm
  3. 250 in the chemotherapy-alone arm, for a total of 763 patients.
• The proportion of patients with PDL-1 ≥10 was 36% in all arms.
• MSI-H patients accounted for 6% in all arms.
• Patients were followed for a median of 29.4 months.

Results

• Treatment-related adverse effects:
  • 54.3% in the pembrolizumab arm
  • 94% in the pembrolizumab + chemotherapy arm
  • 91.8% in the chemotherapy arm

• Adverse effects leading to treatment discontinuation:
  • 3.6% in the pembrolizumab arm
  • 27.9% in the pembrolizumab + chemotherapy arm
  • 18.0% in the chemotherapy arm

Efficacy comparisons were as follows:

• There was no difference in overall survival between pembrolizumab and chemotherapy alone in patients with PD-L1 ≥ 1:
  • 10.6 months with pembrolizumab
  • 11.1 months with chemotherapy alone

• There was a difference in the 24-month overall survival rate between pembrolizumab and standard chemotherapy in patients with PD-L1 ≥ 1:
  • 26.5% with pembrolizumab
  • 19.2% with chemotherapy alone

• There was a difference in overall survival between pembrolizumab and chemotherapy in patients with PD-L1 ≥ 10 (HR, 0.69; 95% CI, 0.49-0.9):
  • 17.4 months with pembrolizumab
  • 10.8 months with standard chemotherapy

• 24-month overall survival with pembrolizumab versus chemotherapy in patients with PD-L1 ≥ 10:
  • 39% with pembrolizumab
  • 22.2% with standard chemotherapy

• Pembrolizumab + chemotherapy did not provide a significant additional overall survival advantage over chemotherapy alone in patients with PD-L1 ≥ 1 or PD-L1 ≥ 10:
  • In those with PD-L1 ≥ 1
    • 12.5 months with pembrolizumab + chemotherapy
    • 11.1 months with chemotherapy alone
  • In those with PD-L1 ≥ 10
    • 12.3 months with pembrolizumab + chemotherapy
    • 10.8 months with chemotherapy alone
• Response rates with pembrolizumab + chemotherapy versus chemotherapy alone in patients with PD-L1 ≥ 1:
  • Complete response:
    • 9.3% with pembrolizumab + chemotherapy
    • 5.6% with chemotherapy alone
  • Objective response:
    • 48.6% with pembrolizumab + chemotherapy
    • 37.2% with chemotherapy alone
• Regardless of PD-L1 ≥ 1 or PD-L1 ≥ 10 status, all MSI-H patients receiving pembrolizumab alone or pembrolizumab + chemotherapy had significantly better overall and progression-free survival than those receiving chemotherapy alone.

The Study's Importance and Implications

• KEYNOTE-062 is the first phase III study in HER2-negative advanced gastric and gastroesophageal junction adenocarcinoma showing that 1st-line pembrolizumab in patients with PDL-1 CPS ≥1 has fewer adverse effects and similar overall survival to standard chemotherapy.
• Regardless of PD-L1 CPS ≥10, which predicts immunotherapy efficacy, MSI-H (microsatellite-high) tumors were shown to benefit from 1st-line immunotherapy over chemotherapy, with an overall survival contribution, in this first such study.
• Because it has fewer adverse effects, immunotherapy should be considered as first-line treatment for advanced PD-L1-positive gastric adenocarcinoma in patients with a poor general condition.
• Adding pembrolizumab to standard chemotherapy did not provide a clinically meaningful benefit in this study.
• Based on these findings, international guideline recommendations for 1st-line HER2-negative, PD-L1-positive gastric and gastroesophageal adenocarcinoma, and our clinical practice, will change.