KEYNOTE-012 Triple-Negative Breast Cancer, Gastric Cancer Results Suggest Pembrolizumab Potential

Patients with advanced programmed death-ligand 1-positive triple-negative breast cancer or gastric cancer may benefit from pembrolizumab therapy

medwireNews: KEYNOTE-012 study findings indicate that pembrolizumab may have clinical activity against advanced triple-negative breast cancer (TNBC) and gastric cancer expressing programmed death-ligand 1 (PD-L1).

The phase Ib trial’s TNBC results, published in the Journal of Clinical Oncology, include data for 32 women with recurrent or metastatic disease, with PD-L1 expression in the stroma or at least 1% of tumour cells by immunohistochemistry, who received pembrolizumab 10 mg/kg every 2 weeks until confirmed progression.

Patients received a median of five doses and toxicities were mostly “mild”, although 15.6% of the group experienced grade 3 or more severe side effects and there was one treatment-related death from disseminated intravascular coagulation and grade 4 blood fibrinogen decline.

The overall response rate was 18.5% of the 27 patients evaluated for efficacy, with complete response, partial response and stable disease reported in 3.7%, 14.8% and 25.9%, respectively, and an overall disease control rate for 24 weeks or longer of 25.9%.

The median time to response was 17.9 weeks, and median duration of response was not yet reached, ranging from 15.0 to over 47.3 weeks, report Rita Nanda, from the University of Chicago in Illinois, USA, and co-authors.

Median progression-free and overall survival (PFS; OS) were 1.9 months and 11.2 months, respectively, with corresponding 6-month rates of 24.4% and 66.7%.

“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 TNBC”, the team concludes.

“A single-agent phase II study examining a 200-mg dose given once every 3 weeks is ongoing.”

A second KEYNOTE-012 report, published in The Lancet Oncology describes the outcome of 39 patients with recurrent or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until disease progression.

Safety analysis recorded six grade 3 or 4 side effects in five patients, including two cases of grade 3 fatigue, but no treatment-related deaths.

Eight (22%) of the 36 patients evaluated by RECIST v1.1 had a response to treatment, all of which were partial, after a median of 8 weeks. The median duration of response was 40 weeks and at time of analysis four of the patients with a response remained free from progression or need for further anticancer treatment.

Median PFS was 1.9 months, with 26% of patients achieving this at 6 months, while median OS was 11.4 months with a 6-month rate of 66%.

“[O]ur results support the importance of the PD-1 pathway in gastric cancer”, write Kei Muro, from Aichi Cancer Center in Nagoya, Japan, and co-authors.

“These data show that pembrolizumab can be safely given to patients with PD-L1-positive advanced gastric cancer and provides sustained antitumour activity”, they say, adding that pembrolizumab is now under investigation for advanced gastric and gastro-oesophageal cancer in the phase II KEYNOTE-059 study and the phase III KEYNOTE-061 and -062 trials.

The authors of an accompanying comment caution that the interaction between pembrolizumab and prior treatments is “unclear” and that the metrics for defining success of immunotherapy treatments in gastric cancer requires “careful consideration”, noting that by “statistical definition KEYNOTE-012 is a negative trial”.

“Neither do the unremarkable progression-free survival results account for the substantial overall survival benefit for patients who responded to treatment”, write Elizabeth Smyth and David Cunningham, from the Royal Marsden Hospital in Sutton, UK.

Nevertheless, they conclude that KEYNOTE-012 results are an “encouraging first step towards the development of a therapy that can result in long-term remission for a disease that, for most patients, currently has no realistic hope for a cure.”


Nanda R, Chow LQM, Dees EC, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: Phase Ib KEYNOTE-012 study. J Clin Oncol 2016; Advance online publication 2 May. doi: 10.1200/JCO.2015.64.8931

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 2016; Advance online publication 3 May. doi:

Smyth EC, Cunningham D. Encouraging results for PD-1 inhibition in gastric cancer. Lancet Oncol 2016; Advance online publication 3 May. DOI:

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