Pembrolizumab approved for advanced gastric cancer

On September 22, 2017, the FDA granted accelerated approval to pembrolizumab (KEYTRUDA, Merck) for use in patients with locally advanced or metastatic, gastric or gastroesophageal junction (GEJ) adenocarcinoma positive for PD-L1 as determined by an FDA-approved companion diagnostic (CDx) and progressing after ≥2 prior systemic therapies, including a fluoropyrimidine- and platinum-containing regimen, and, when appropriate, HER2-targeted therapy.

KEYNOTE-059

Pembrolizumab for gastric and GEJ adenocarinoma was approved by the FDA based on the results of the open-label, multicenter, multi-cohort KEYNOTE-059 (NCT02335411) trial in 259 patients with gastric or gastroesophageal junction adenocarcinoma. In the KEYNOTE-059, 143 (55%) patients were found positive for PD-L1 and had microsatellite stable (MSS), unconfirmed microsatellite instability (MSI), or mismatch repair (MMR) status. In this group, a 13.3% (95% CI, 8.2-20.0) objective response rate (ORR) was reported.  Two (1.4%) patients had a complete response (CR) and 17 (11.9%) patients had a partial response (PR). The duration of response (DOR) ranged 2.8+ to 19.4+ months. Eleven patients had a response durations ≥6 months, 5  patients had a response duration ≥12 months.

MSI-High

Seven (3%) of the 259 KEYNOTE-059 patients were found to have MSI-high (MSI-h) tumours. The ORR in this small subgroup was 57% (4 out of 7 patients), one CR was reported. The DOR ranged from 5.3+ to 14.1+ months.

Safety

The investigators reported the safety profile of pembrolizumab in gastric and GEJ adenocarcinoma patients was consistent with the US FDA approved label. Common adverse reactions included fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhoea, nausea, rash, pyrexia, cough, dyspnoea, and constipation. Pembrolizumab is associated with immune-mediated side effects (irAEs), including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. An up-to-date list of AEs can be found here.

PD-L1 Staining

The CDx for pembrolizumab is the PD-L1 immunohistochemistry (IHC) 22C3 pharmDx (Dako). PD-L1 positivity was determined by the combined positive score (CPS). A CPS≥1 was considered PD-L1 positive. The CPS is determined by dividing the number of PD-L1 staining cells (tumour cells, lymphocytes, macrophages) by the total number of tumour cells evaluated and then multiplied by 100. The FDA updated the approval for the 22c3 IHC to include the selection of patients with gastric and GEJ adenocarcinoma for treatment with pembrolizumab.

Pembrolizumab prescribing information