Updated KEYNOTE-012 Shows Activity for Pembrolizumab in Gastric Cancer

Sandra Hanner
Published: Thursday, Jan 15, 2015

Ronald Levy, MD

Among patients with metastatic gastric cancer treated with the anti-PD-1 monoclonal antibody pembrolizumab, the agent showed promising antitumor activity and a manageable toxicity profile, according to updated findings from the KEYNOTE-012 study presented at the 2015 Gastrointestinal Cancers Symposium.

The gastric cancer cohort of KEYNOTE-012 involved 39 patients whose tumors expressed PD-L1. Of 162 previously treated patients screened, 40% expressed the ligand. PD-L1 expression was assessed in archival tumor samples using a prototype immunohistochemistry assay and the 22C3 antibody. Positivity was defined as staining in the stroma or in ≥1% of tumor cells.

Patients received pembrolizumab 10 mg/kg every 2 weeks for up to 24 months or until complete response, disease progression, or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by independent central review.

“At 8.8 months’ follow-up, there was strong evidence of anticancer activity,” Kei Muro, MD, of the Aichi Cancer Center Hospital in Nagoya, Japan, reported in an update of the initial analysis presented in September at ESMO 2014.

The ORR with pembrolizumab was 22.2% (95% CI, 10.1-39.2) by RECIST v.1 central review and 33.3% (95% CI, 19.1-50.2) by investigator review. The eight responses were all partial responses; stable disease was observed in another five patients. Responses were similar for Asian and non-Asian populations.

For four patients, response was not assessed or able to be determined. Approximately 53% of patients had some degree of tumor shrinkage.

“Six of the eight responders were still responding at the time of this analysis,” Muro noted. The median time to response was “rapid” at 8 weeks, he said, and median response duration was 24 weeks (range, 8 to 33-plus).

Median progression-free survival (PFS) was 1.9 months (95% CI, 1.8-3.5). At 6 months, the PFS rate was 24%, and the overall survival (OS) rate was 69%. Median OS had not been reached, he reported.

The investigators concluded that the safety and tolerability profile of pembrolizumab was acceptable in this population. Four patients (10.3%) had a treatment-related adverse event of grade 3-5. One death was reported from hypoxia.

“We found a trend toward improved outcomes with higher levels of PD-L1 expression,” Muro added. This was observed for ORR, PFS, and OS. He acknowledged, however, that the current trend was “weak” and requires further investigation (Table).

Table: Association Between PD-L1 Expression and Pembrolizumab Efficacy

Outcome Central Review
P Value
Investigator Review
P Value
ORR .102 .100
PFS .162 .051
OS .124
The phase 2 KEYNOTE-059 study of pembrolizumab monotherapy or in combination with cisplatin plus 5-fluorouracil for advanced gastric cancer will be initiated early in 2015.

Ronald Levy, MD, professor and chief of the Division of Oncology at Stanford University School of Medicine, presented a keynote lecture on anti-PD-1 monoclonal antibodies, showing enthusiasm for immune therapies in cancer in general. “We have found out that we can use the immune system to kill cancer, and this includes gastrointestinal cancers,” he said.

Commenting on the KEYNOTE-012 findings, in particular, he noted, “Not many of the tumor cells need to express this ligand for this drug to work,” however, he acknowledged that only 40% of patients had that 1% necessary for eligibility, and the majority did not respond.

“Why do some patients respond and not others?” Levy asked. “Is it PD-L1 expression by the tumor cells or stromal cells in the environment? They can talk to the incoming T cells and shut them off, but they are not perfect as predictors.”

Efforts are underway to try to boost these response rates through combinatorial therapy, he said, and potentially by increasing the expression of the target, the PD-1 ligand.


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