In this population of patients with recurrent or metastatic PD-L1-positive gastric cancer, pembrolizumab had a manageable toxicity profile and promising antitumour activity… .— Kei Muro, MD and colleagues
The KEYNOTE-012 phase Ib trial assessed single-agent pembrolizumab (Keytruda) in patients with advanced programmed cell death ligand 1 (PD-L1)–positive gastric cancer, triple-negative breast cancer, urothelial cancer, and head and neck cancer. The activity of pembrolizumab in study patients with advanced gastric cancer was reported by Kei Muro, MD, of Aichi Cancer Center Hospital, Nagoya, Japan, and colleagues in The Lancet Oncology,1 and the activity of pembrolizumab in those with metastatic triple-negative breast cancer was reported by Rita Nanda, MD, of the University of Chicago, and colleagues in the Journal of Clinical Oncology.2
The trial was performed at 13 sites in the United States, Israel, Japan, South Korea, and Taiwan. Patients with PD-L1–positive disease, defined as expression in stroma or ≥ 1% of tumor cells by immunohistochemistry, received intravenous pembrolizumab at 10 mg/kg every 2 weeks for 24 months or until disease progression or unacceptable toxicity. The study included 39 patients with PD-L1–positive recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction and 32 women with metastatic PD-L1–positive triple-negative breast cancer.
Outcome in Gastric Cancer
Of 39 patients with gastric cancer enrolled and evaluable for safety, 36 were evaluable for response on central assessment. Most patients were heavily pretreated. Median follow-up was 10.8 months.
This phase Ib study describes preliminary evidence of clinical activity and a potentially acceptable safety profile of pembrolizumab given every 2 weeks to patients with heavily pretreated, advanced triple-negative breast cancer.— Rita Nanda, MD, and colleagues
Response was observed in eight patients (22%, 95% confidence interval [CI] = 10%–39%); all responses were partial responses. Stable disease was observed in 14%. A decrease in the target lesion size was observed in 17 (53%) of 32 patients with at least one post-baseline tumor assessment. Median time to response was 8 weeks, and median duration of response was 40 weeks (interquartile range = 40 weeks to not reached). Of the eight responders, four were alive without disease progression and with no additional anticancer therapy at the last analysis.
Grade 3 or 4 treatment-related adverse events were reported in five patients (13%), consisting of grade 3 fatigue in two, grade 3 pemphigoid in one, grade 3 hypothyroidism in one, grade 3 peripheral sensory neuropathy in one, and grade 4 pneumonitis in one. No treatment-related deaths were observed.
The investigators concluded: “In this population of patients with recurrent or metastatic PD-L1-positive gastric cancer, pembrolizumab had a manageable toxicity profile and promising antitumour activity, warranting further study in phase II and III trials.”
Outcome in Triple-Negative Breast Cancer
Among the 32 women with metastatic triple-negative breast cancer enrolled, 27 were evaluable for response. Most patients were heavily pretreated. Median follow-up was 10.0 months.
Among evaluable patients, the overall response rate was 18.5% (95% CI = 6.3%–38.1%), including a complete response in one patient and a partial response in four patients. Stable disease was observed in seven patients (26%). Median time to response was 17.9 weeks, and median duration of response was not reached (range = 15.0–47.3+ weeks). Three responders remain on study and have received pembrolizumab for at least 1 year, with response durations of 24.1, 24.7, and 47.3 weeks as of last analysis.
Grade ≥ 3 treatment-related adverse events occurred in 15.6% of patients, including grade 3 anemia, aseptic meningitis, lymphopenia, headache, and pyrexia. One patient died of disseminated intravascular coagulation accompanied by grade 4 decreased blood fibrinogen, both of which were possibly related to study treatment.
The investigators concluded: “This phase Ib study describes preliminary evidence of clinical activity and a potentially acceptable safety profile of pembrolizumab given every 2 weeks to patients with heavily pretreated, advanced triple-negative breast cancer. A single-agent phase II study examining a 200-mg dose given once every 3 weeks (ClinicalTrials.gov identifier: NCT02447003) is ongoing.” ■
1. Muro K, Chung HC, Shankaran V, et al: Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): A multicentre, open-label, phase 1b trial. Lancet Oncol. May 3, 2016 (early release online).