FDA Grants Accelerated Approval to Pembrolizumab for Advanced Gastric Cancer

FDA also approved the PD-L1 IHC 22C3 pharmDx (Dako) to select patients with gastric cancer for treatment with pembrolizumab

On 22 September, 2017, ESMO the US Food and Drug Administration (FDA) granted accelerated approval to pembrolizumab (KEYTRUDA, Merck & Co., Inc.) for patients with recurrent locally advanced or metastatic, gastric or gastro-oesophageal junction adenocarcinoma whose tumours express PD-L1 as determined by an FDA-approved test. Patients must have had disease progression on or after two or more prior systemic therapies, including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy.

Approval is based on the results of KEYNOTE 059 (NCT02335411), an open-label, multicentre, non-comparative, multi-cohort trial that enrolled 259 patients with gastric or gastro-oesophageal junction adenocarcinoma. Among the 259 patients, 55% (n=143) had tumours expressing PD-L1 and either microsatellite stable (MSS), or undetermined microsatellite instability (MSI) or mismatch repair (MMR) status.

PD-L1 expression was evaluated by the PD-L1 IHC 22C3 pharmDx Kit (Dako) and PD-L1 positivity was based on a combined positive score (CPS) ≥ 1. CPS is determined by the number of PD-L1 staining cells (tumour cells, lymphocytes, macrophages) divided by total number of tumour cells evaluated, multiplied by 100.

For the 143 patients with tumours expressing PD-L1 and who were either MSS or had unknown MSI or dMMR status, the objective response rate (ORR) was 13.3% (95% CI: 8.2, 20.0); 1.4% had complete responses and 11.9% had partial responses. Among the 19 responding patients, the response duration ranged from 2.8+ to 19.4+ months, with 11 patients (58%) having response durations of 6 months or longer and 5 patients (26%) having response durations of 12 months or longer.

Among the 259 patients enrolled in KEYNOTE 059, 7 (3%) had tumours that were determined to be MSI-high. Responses were observed in 4 of these 7 patients (ORR 57%), with one complete response. The response duration ranged from 5.3+ to 14.1+ months.

Adverse reactions occurring in patients with gastric cancer were similar to those presently described in product labelling. The most common adverse reactions are fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhoea, nausea, rash, pyrexia, cough, dyspnoea, and constipation. Pembrolizumab is associated with immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.

The recommended pembrolizumab dose for gastric cancer is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

The FDA also approved the PD-L1 IHC 22C3 pharmDx (Dako), to select patients with gastric cancer for treatment with pembrolizumab. If PD-L1 expression is not detected in an archival gastric cancer specimen, FDA recommends assessing the feasibility of a fresh tumour biopsy. Information on FDA-approved tests for PD-L1 expression in NSCLC or in gastric cancer is available here.

Full prescribing information is available here

FDA granted pembrolizumab priority review for this indication. As a condition of accelerated approval, further studies are required.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.