Wainberg ZA, et al. ESMO 2017:LBA28_PR

KEYNOTE-059: Efficacy and safety of pembrolizumab alone or in combination with chemotherapy in patients with advanced gastric or gastroesophageal cancer

Background

Previous results from the phase II KEYNOTE-059 study demonstrated manageable safety and promising antitumour activity for pembrolizumab alone and pembrolizumab plus chemotherapy in patients with recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ).1 An updated analysis of these results was presented at the ESMO 2017 Annual Congress.2

Study design

  • KEYNOTE-059 is a global, multicohort, phase II study evaluating pembrolizumab alone and in combination with chemotherapy in patients with recurrent or metastatic G/GEJ.
  • In cohort 1 and 2, patients were enrolled regardless of tumour programmed death-ligand 1 (PD-L1) expression.
  • In cohort 3, only patients with PD-L1–positive tumours were enrolled.
  • PD-L1–positive expression was defined as having a combined positive score (CPS) of ≥1% using the PDL1 immunohistochemistry 22C3 pharmDx assay (Agilent Technologies).
    • CPS was calculated as the number of PD-L1–positive cells (tumour cells, lymphocytes, and macrophages) divided by the total number of tumour cells, multiplied by 100.
  • Primary endpoints were safety (all three cohorts) and overall response rate (ORR) by central review per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (cohorts 1 and 3).
  • For response assessment per RECIST version 1.1, the first scan was performed nine weeks after Cycle 1, followed by every six weeks for the first year, and every nine weeks thereafter.
  • Key secondary endpoints included:
    • ORR (cohort 2);
    • Duration of response (DOR) by RECIST version 1.1;
    • Progression-free survival (PFS); and
    • Overall survival (OS).
  • Inclusion and exclusion criteria can be found at https://clinicaltrials.gov/ct2/show/NCT02335411.

Study design

Key findings

  • At data cutoff (April 21, 2017), the median follow-up for cohorts 1 (259 patients), 2 (25 patients), and 3 (31 patients) was 5.6 months (range: 0.5–24.7), 13.8 months (range: 1.8–24.1), and 17.5 months (range: 1.7–20.7), respectively.

Cohort 1 (N = 259)

  • The median age of patients was 62 years (range: 24–89).
  • In terms of prior therapies, 134 (52%), 75 (29%), and 50 (19%) patients had 2, 3, and 4 or greater prior therapies, respectively.
  • In terms of PD-L1 expression, 148 patients (57%) were positive and 109 patients (42%) were negative for PD-L1 expression.
  • Response rates in all patients and by PD-L1 expression are reported in Table 1.
    • Of the 134 patients who received pembrolizumab as third-line therapy, ORR was 16% and the disease control rate (DCR) was 31%.
    • Of the 125 patients who received pembrolizumab as fourth or greater-line therapy, ORR was 7% and DCR was 23%.
  • Of the 223 patients with measurable disease per RECIST version 1.1 at baseline who had one or more post-baseline assessment, 95 patients (42%) experienced a reduction in target lesion size.
  • Of the 31 patients with confirmed response, the DOR was 14.2 months (range: 2.4–19.4+).
  • The median PFS in all patients was 2.0 months (95% CI: 2.0–2.1) and the 6-month PFS rate was 14.6%.
  • The median OS in all patients was 5.5 months (95% CI: 4.2–6.5) and the 6-month OS rate was 45.7%.
  • PFS and OS results by PD-L1 expression are presented in Figure 1.
  • Treatment-related adverse events (TRAEs) were reported in 159 patients (61%), with 46 patients (18%) experiencing grade 3–5 TRAEs, and 29 patients (11%) experiencing serious TRAEs.
    • Seven patients (3%) experienced grade 3 anemia, 6 patients (2%) experienced grade 3 fatigue, and 3 patients (1%) experienced grade 3 dehydration.
  • Treatment led to discontinuation in 7 patients (3%) and death in 2 patients (1 patient acute kidney injury, 1 patient pleural effusion).
  • Immune-mediated adverse events and infusion-related reactions occurred in 19% of patients. (Table 2)

Cohort 2 (N = 25)

  • The median age of patients was 64 years (range: 21–82).
  • In terms of PD-L1 expression, 16 patients (64%) were positive and 8 patients (32%) were negative for PD-L1 expression.
  • Response rates in all patients and by PD-L1 expression are reported in Table 1.
  • Of the 25 patients with measurable disease per RECIST version 1.1 at baseline who had one or more post-baseline assessment, 24 patients (96%) experienced a reduction in target lesion size.
  • The median DOR was 4.6 months (range: 2.6–20.3+).
  • The median PFS in all patients was 6.6 months (95% CI: 5.9–10.6) and the 6-month PFS rate was 68.0%.
  • The median OS in all patients was 13.8 months (95% CI: 8.6–not reached) and the 6-month OS rate was 76.0%.
  • TRAEs were reported in all patients, with 19 patients (76%) experiencing grade 3/4 TRAEs.
    • Grade 3/4 TRAEs included neutropenia (24%), stomatitis (20%), anemia (8%), decreased platelet count (8%), decreased appetite (8%), and fatigue (8%).
  • Three patients (12%) discontinued treatment due to chemotherapy-related adverse events; however, no patients discontinued treatment because of pembrolizumab-related adverse events.
  • Immune-mediated adverse events occurred in 48% of patients. (Table 2)

Cohort 3 (N = 31)

  • The median age of patients was 62 years (range: 32–75).
  • ORR was 26% (95% CI: 12–45) and DCR (complete response, partial response, and stable disease ≥6 months) was 36% (95% CI: 19–55). (Table 1)
  • Of the 31 patients with measurable disease per RECIST version 1.1 at baseline who had one or more post-baseline assessment, 24 patients (77%) experienced a reduction in target lesion size (assessments were not available for 3 patients).
  • The median DOR was 9.6 months (range: 2.1–17.8+).
  • The median PFS in all patients was 3.3 months (95% CI: 2.0–6.0) and the 6-month PFS rate was 34.9%.
  • The median OS in all patients was 20.7 months (95% CI: 9.2–20.7) and the 6-month OS rate was 72.9%.
  • TRAEs were reported in 24 patients (77%), with 7 patients (23%) experiencing grade 3–5 TRAEs.
    • Grade 3 adverse events included neutropenia, diffuse uveal melanocytic proliferation, colitis, bile duct obstruction, decreased neutrophils, dehydration, hyponatremia, and rash (each experienced in 1 patient).
  • One patient died of a TRAE event during safety follow-up (pneumonitis).
  • Immune-mediated adverse events occurred in 32% of patients. (Table 2)

Figure 1. PFS and OS by PD-L1 expression

Table 1. Response by cohort

Table 2. Immune-mediated adverse events* and infusion-related reactions by cohort

Key conclusions

  • In patients with advanced G/GEJ adenocarcinoma:
    • Pembrolizumab monotherapy showed promising antitumour activity in patients whose disease had progressed after ≥2 prior lines of therapy and in previously untreated patients with PD-L1–positive tumours; and
    • Pembrolizumab in combination with chemotherapy demonstrated promising antitumour activity in previously untreated patients.
  • Patients responded regardless of PD-L1 expression, but responses were higher in patients with PD-L1–positive tumours (cohorts 1 and 2).
  • Safety was manageable and consistent with previous reports.
  • Two randomized phase III trials studying pembrolizumab in G/GEJ are ongoing:
    • KEYNOTE-061: pembrolizumab versus paclitaxel in patients with advanced G/GEJ whose disease progressed after first-line therapy with platinum and fluoropyrimidine; and
    • KEYNOTE-062: pembrolizumab alone or in combination with chemotherapy versus chemotherapy alone as first-line therapy for advanced PD-L1–positive G/GEJ cancer.

References: 1. Fuchs CS, Doi T, Jang RW-J, et al. KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer. J Clin Oncol (ASCO Annual Meeting) 2017;35(Suppl): abstr 4003. 2. Wainberg ZA, Jalal SI, Muro K, et al. KEYNOTE-059: Efficacy and safety of pembrolizumab alone or in combination with chemotherapy in patients with advanced gastric or gastroesophageal cancer. ESMO Annual Congress Abstracts 2017:LBA28_PR.