Prior results from the global, phase II KEYNOTE-059 study demonstrated manageable safety and promising antitumor activity for pembrolizumab alone and pembrolizumab plus chemotherapy in patients with gastric, or gastro-esophageal junction (G/GEJ) cancer.1 During ESMO 2017, updated results of this trial demonstrated a 12% objective response rate (ORR) among patients with pretreated metastatic G/GEJ cancer who were treated with pembrolizumab monotherapy.2 Also in the cohorts of newly diagnosed metastatic G/GEJ patients promising response rates were reported with both pembrolizumab monotherapy and with the combination of pembrolizumab and chemotherapy.
The expected survival of patients with metastatic gastric cancer is less than one year and very few new drugs have been approved for this disease in the past decade. The phase II KEYNOTE-059 is one of the largest studies to investigate the potential of immunotherapy in recurrent or metastatic gastric cancer. The study includes 3 cohorts: cohort 1 consists of 259 patients with metastatic G/GEJ cancer who received pembrolizumab alone, after pretreatment with 2 or more lines of chemotherapy, while cohorts 2 (N = 25) and 3 (N = 31) include patients with newly diagnosed metastatic G/GEJ who received a combination of pembrolizumab and chemotherapy (cohort 2), or pembrolizumab alone (cohort 3). Patients were enrolled in cohorts 1 and 2 regardless of their tumor PD-L1 expression, while cohort 3 enrolled only patients with PD-L1-positive tumors (combined positive score of ≥1% using the PD-L1 IHC 22C3 pharmDx assay). The primary endpoints of KEYNOTE-059 were safety (all 3 cohorts) and ORR (cohorts 1 and 3).
After a median follow-up of 6 months, the investigators found an ORR rate of 12% (CR in 3%) with pembrolizumab alone in the pretreated patients (cohort 1). Of note, in this cohort, patients who expressed programmed death-ligand 1 (PD-L1) (57%, N = 148) were more likely to respond than those who did not, with ORR of 16% and 6%, respectively. Among patients who received pembrolizumab as third line treatment, the ORR was 16%, with a disease control rate (DCR) of 31%, while the ORR was 7% for patients who received the drug as fourth line treatment or more (DCR 23%). In total, 42% of patients in cohort 1 experienced a reduction in the target lesion size. Importantly, many of the responses were durable with a median duration of response (DoR) of 14.2 months (ranging from 2.4 to more than 19.4 months). The median progression-free (PFS) and overall survival (OS) in cohort 1 was 2.0 and 5.5 months, respectively. At 6 months, 14.6% of patients in cohort 1 were free of progression and 45.7% of patients were alive at that time point. Grade 3 to 5 treatment-related adverse events occurred in 18% of patients in cohort 1 and 3% had to discontinue treatment as a result. Grade 3 immune-related adverse events were seen in 5% of patients.
In patients with newly diagnosed metastatic cancer, both the combination therapy (cohort 2) and pembrolizumab alone (cohort 3) were safe and showed some promising activity. In cohort 2, an ORR of 60% was observed (4% CR) with a DCR of 80%. Again PD-L1 expressing patients were more likely to have a response than patients who did not express PD-L1 (ORR: 69% versus 38%). In this cohort, 96% of patients experienced a reduction in target lesion and some of the observed responses were maintained for more than 1 year. The median PFS and OS in cohort 2 were 6.6 and 13.8 months, respectively (6-months PFS and OS rate 68% and 76%). As indicated before, cohort 3 included only PD-L1 expressing patients who were treated upfront with pembrolizumab monotherapy. In this cohort, an ORR of 26% was reported (7% CR) with a DCR of 36%. In cohort 3, the median PFS was 3 months and the median OS was not yet reached.
In summary, these updated results confirm the manageable safety and promising antitumor activity of pembrolizumab alone, or in combination with chemotherapy in patients with advanced G/GEJ cancer. Especially the findings in cohort 1 are of interest. The expected response rate in these heavily pretreated patients was close to zero so these findings are very encouraging. There is currently no standard of care for metastatic gastric cancer treated in the third line or beyond. The KEYNOTE-059 cohort 1 results confirm that the efficacy previously reported for the PD-1 inhibitor nivolumab in patients from East Asia in the ONO-4538 randomized trial can be applied to Western populations. It is likely that pembrolizumab will become a standard treatment option in this setting in the near future.
1. Fuchs CS, Doi T, Woo-Jun Jang R, et al. KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer. Journal of Clinical Oncology 2017;35 suppl 4003.
2. Wainberg Z, Jalal S, Muro K, et al. KEYNOTE-059 Update: Efficacy and Safety of Pembrolizumab Alone or in Combination with Chemotherapy in Patients With Advanced Gastric or Gastroesophageal (G/GEJ) cancer. Presented at ESMO 2017; Abstract LBA28_PR.