In patients with advanced gastric cancer expressing PD-L1, pembrolizumab (Keytruda) has robust antitumor activity and an acceptable safety profile, according to results from an ongoing phase Ib study. In the study, responses to pembrolizumab were durable and similar between Asian and non-Asian patients, said lead investigator Kei Muro, MD, who presented the data at the 2014 ESMO Congress.
“These findings support the potential of the PD-L1 pathway in gastric cancer and support further development of pembrolizumab as a treatment option for patients with advanced gastric cancer,” said Muro.
Pembrolizumab is a highly selective, humanized IgG4/kappa isotype monoclonal antibody designed to block the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thus reactivating the immune system to eradicate the host tumor, explained Muro, from the Aichi Cancer Center Hospital, Nagoya, Japan. The drug recently became the first PD-1 inhibitor approved by the FDA when it was granted marketing approval for advanced melanoma.
The phase Ib study presented at ESMO evaluated pembrolizumab monotherapy at 10 mg/kg every 2 weeks in patients with recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction whose archived tumor samples were determined to be positive for PD-L1 expression using a prototype immunohistochemistry assay (n = 39).
Tumors were classified as PD-L1–positive based on ≥1% of tumor cells demonstrating expression of the PD-L1 marker, or any positive staining in tumor stroma. Treatment continued for up to 24 months or until a complete response was achieved, disease progression occurred, or unacceptable toxicity. Enrollment was designed to include an equal number of patients from Asia-Pacific and non-Asian patients. The primary efficacy endpoint was overall response rate (ORR) assessed by RECIST v1.1.
Of the 39 patients enrolled, 19 were from Asia-Pacific and 20 were from other areas of the world. Most patients had received two or more prior lines of therapy; Asian patients were more likely to have received two or more therapies than non-Asians (79% vs 55%).
At a median follow-up of approximately 6 months, the ORR was 31% (31.6% in Asians and 30% in non-Asians). There were no complete responses and six partial responses each in Asians and non-Asians.
In Asian patients, the median time to response was 8 weeks (range, 7-8 weeks) and six of the six responses are ongoing. The response duration ranged from 8+ to 16+ weeks and the median duration of response has not been reached.
In the non-Asian group, the median time to response was 12 weeks (range, 7-17 weeks) and five of the six responses are ongoing. The response duration ranged from 9+ to 20+ weeks, and the median duration of response has also not been reached.
There was preliminary evidence of a relationship between PD-L1 expression and ORR (P
= .071). “Preliminary data correlating PD-L1 expression with clinical outcomes will be further explored,” said Muro.
Per RECIST v1.1, of evaluable patients who had measurable disease with one post-baseline scan, “overall, 41% of patients experienced a decrease from baseline in the size of the target lesion,” Muro said.
Adverse events were consistent with previously reported safety data for pembrolizumab. The most common adverse events deemed treatment-related were hypothyroidism and fatigue (five cases of each). Grade ≥3 adverse events deemed to be treatment-related occurred in three patients (one case each of hypoxia, peripheral neuropathy, and pneumonitis). There were no infusion-related reactions and no patients discontinued pembrolizumab due to a treatment-related adverse reaction.
A phase II study in advanced gastric cancer is expected to begin enrollment in the first quarter of 2015, said Muro.
Muro K, Bang Y, Shankaran V, et al. A phase 1b study of pembrolizumab (Pembro; MK-3475) in patients (Pts) with advanced gastric cancer. Presented at: ESMO 2014 Congress; September 26-30, 2014; Madrid, Spain. LBA15.
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