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Lancet Oncol. 2019 Mar;20(3):371-382. doi: 10.1016/S1470-2045(18)30812-X. Epub 2019 Feb 11.

Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial.

Author information

1
Division of Research and Clinical Medicine, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia. Electronic address: sherene.loi@petermac.org.
2
IBCSG Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
3
Institute Jules Bordet, Brussels, Belgium.
4
Centre Léon Bérard, Lyon, France.
5
Westmead Hospital and the University of Sydney, Sydney, NSW, Australia.
6
University of Milano, Milan, Italy; IEO, European Institute of Oncology IRCCS, Milan, Italy.
7
Institut de Cancérologie de l'Ouest, Saint-Herblain, Nantes, France.
8
Ospedale di Prato-AUSL Toscana Centro, Prato, Italy.
9
Institut Bergonié Comprehensive Cancer Center, Université de Bordeaux, Bordeaux, France.
10
International Breast Cancer Study Group, CHU Liège, Liège University, Liège, Belgium.
11
Medical University of Vienna, Vienna, Austria.
12
University Hospital Inselspital, Bern, Switzerland; International Breast Cancer Study Group Coordinating Center, Bern, Switzerland.
13
International Breast Cancer Study Group Coordinating Center, Bern, Switzerland; International Breast Cancer Study Group and Central Pathology Office, Bern, Switzerland.
14
International Breast Cancer Study Group Coordinating Center, Bern, Switzerland.
15
QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
16
International Breast Cancer Study Group and Ospedale di Prato-AUSL Toscana Centro, Prato, Italy.
17
International Breast Cancer Study Group and Division of Medical Senology, IEO, European Institute of Oncology IRCCS, Milan, Italy.
18
University of Milano, Milan, Italy; IEO, European Institute of Oncology IRCCS, Milan, Italy; International Breast Cancer Study Group and Central Pathology Office, Bern, Switzerland.
19
IBCSG Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
20
Institut Gustave Roussy, Université Paris Sud, INSERM U981, Villejuif, France.

Abstract

BACKGROUND:

HER2-positive breast cancers usually contain large amounts of T-cell infiltrate. We hypothesised that trastuzumab resistance in HER2-positive breast cancer could be mediated by immune mechanisms. We assessed the safety and anti-tumour activity of pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, added to trastuzumab in trastuzumab-resistant, advanced HER2-positive breast cancer.

METHODS:

We did this single-arm, multicentre, phase 1b-2 trial in 11 centres based in five countries. Eligible participants were women aged 18 years or older, who had advanced, histologically confirmed, HER2-positive breast cancer; documented progression during previous trastuzumab-based therapy; an Eastern Cooperative Oncology Group performance status of 0 or 1; and a formalin-fixed, paraffin-embedded metastatic tumour biopsy for central assessment of programmed cell death 1 ligand 1 (PD-L1) status. In phase 1b, we enrolled patients with PD-L1-positive tumours in a 3 + 3 dose-escalation of intravenous pembrolizumab (2 mg/kg and 10 mg/kg, every 3 weeks) plus 6 mg/kg of intravenous trastuzumab. The primary endpoint of the phase 1b study was the incidence of dose-limiting toxicity and recommended phase 2 dose; however, a protocol amendment on Aug 28, 2015, stipulated a flat dose of pembrolizumab of 200 mg every 3 weeks in all Merck-sponsored trials. In phase 2, patients with PD-L1-positive and PD-L1-negative tumours were enrolled in parallel cohorts and received the flat dose of pembrolizumab plus standard trastuzumab. The primary endpoint of the phase 2 study was the proportion of PD-L1-positive patients achieving an objective response. This trial is registered in ClinicalTrials.gov, number NCT02129556, and with EudraCT, number 2013-004770-10, and is closed.

FINDINGS:

Between Feb 2, 2015, and April 5, 2017, six patients were enrolled in phase 1b (n=3 received 2 mg/kg pembrolizumab, n=3 received 10 mg/kg pembrolizumab) and 52 patients in phase 2 (n=40 had PD-L1-positive tumours, n=12 had PD-L1-negative tumours). The data cutoff for this analysis was Aug 7, 2017. During phase 1b, there were no dose-limiting toxicities in the dose cohorts tested. Median follow-up for the phase 2 cohort was 13·6 months (IQR 11·6-18·4) for patients with PD-L1-positive tumours, and 12·2 months (7·9-12·2) for patients with PD-L1-negative tumours. Six (15%, 90% CI 7-29) of 40 PD-L1-positive patients achieved an objective response. There were no objective responders among the PD-L1-negative patients. The most common treatment-related adverse event of any grade was fatigue (12 [21%] of 58 patients). Grade 3-5 adverse events occurred in 29 (50%) of patients, treatment-related grade 3-5 adverse events occurred in 17 (29%), and serious adverse events occurred in 29 (50%) patients. The most commonly occurring serious adverse events were dyspnoea (n=3 [5%]), pneumonitis (n=3 [5%]), pericardial effusion (n=2 [3%]), and upper respiratory infection (n=2 [3%]). There was one treatment-related death due to Lambert-Eaton syndrome in a PD-L1-negative patient during phase 2.

INTERPRETATION:

Pembrolizumab plus trastuzumab was safe and showed activity and durable clinical benefit in patients with PD-L1-positive, trastuzumab-resistant, advanced, HER2-positive breast cancer. Further studies in this breast cancer subtype should focus on a PD-L1-positive population and be done in less heavily pretreated patients.

FUNDING:

Merck, International Breast Cancer Study Group.

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