Gastric cancer (GC) is the fifth most common malignancy and the third leading cause of cancer-death worldwide [1], with an overall survival for advanced disease of ∼1 year. Although classically considered as a single disease, GC is highly heterogeneous from the morphological and molecular standpoints. Noteworthy, GC heterogeneity encompasses not only inter-patient variability (intertumoral heterogeneity) but also variations within the same tumor (intratumoral heterogeneity). The latter includes spatial heterogeneity in different tumor areas, and temporal heterogeneity, along progression from primary to recurrent and/or metastatic disease [2]. Despite this feature, for therapeutic purposes, GC patients have been treated with identical chemo and/or radiotherapy regimens and targeted therapies [3, 4], except for the HER2 positive population [5]....

The global KEYNOTE-590 trial was the first to show a significant improvement in survival with immunotherapy plus chemotherapy in the first-line treatment of esophageal cancer (EC) and supported the approval of pembrolizumab plus chemotherapy in this setting. After a median follow-up of 22.6 months, pembrolizumab plus chemotherapy compared with placebo plus chemotherapy had a manageable safety profile and significantly improved survival of participants with previously untreated advanced EC. Results of a median follow-up of 58.8 months (range 49.2-70.6 months) are reported. Adults with previously untreated advanced EC or Siewert type 1 gastroesophageal junction cancer were randomly assigned 1 : 1 to receive chemotherapy with or without pembrolizumab. Study outcomes were efficacy and safety. Overall, 749 participants received pembrolizumab plus chemotherapy (n = 373) or placebo plus chemotherapy (n = 376). Median overall survival was 12.3 months versus 9.8 months [hazard ratio (HR) 0.72, 95% confidence interval (CI) 0.62-0.84] with pembrolizumab plus chemotherapy versus placebo plus chemotherapy; 5-year survival rates were 10.6% and 3.0%. Median progression-free survival (PFS) was 6.3 months versus 5.8 months (HR 0.64, 95% CI 0.54-0.75); 5-year PFS rates were 5.5% and not reached. Grade ≥3 treatment-related adverse events occurred in 71.9% and 67.6% of participants in the pembrolizumab plus chemotherapy and placebo plus chemotherapy groups, respectively. Data from KEYNOTE-590 continue to show durable efficacy after 5 years, and pembrolizumab plus chemotherapy more than tripled the 5-year overall survival rate compared with placebo plus chemotherapy, with no new safety signals. These results support first-line therapy with pembrolizumab plus chemotherapy as standard for previously untreated patients with advanced EC with programmed death-ligand 1 combined positive score ≥1.