Journal article
Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial.
- Loi S Division of Research and Clinical Medicine, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia. Electronic address: sherene.loi@petermac.org.
- Giobbie-Hurder A IBCSG Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Gombos A Institute Jules Bordet, Brussels, Belgium.
- Bachelot T Centre Léon Bérard, Lyon, France.
- Hui R Westmead Hospital and the University of Sydney, Sydney, NSW, Australia.
- Curigliano G University of Milano, Milan, Italy; IEO, European Institute of Oncology IRCCS, Milan, Italy.
- Campone M Institut de Cancérologie de l'Ouest, Saint-Herblain, Nantes, France.
- Biganzoli L Ospedale di Prato-AUSL Toscana Centro, Prato, Italy.
- Bonnefoi H Institut Bergonié Comprehensive Cancer Center, Université de Bordeaux, Bordeaux, France.
- Jerusalem G International Breast Cancer Study Group, CHU Liège, Liège University, Liège, Belgium.
- Bartsch R Medical University of Vienna, Vienna, Austria.
- Rabaglio-Poretti M University Hospital Inselspital, Bern, Switzerland; International Breast Cancer Study Group Coordinating Center, Bern, Switzerland.
- Kammler R International Breast Cancer Study Group Coordinating Center, Bern, Switzerland; International Breast Cancer Study Group and Central Pathology Office, Bern, Switzerland.
- Maibach R International Breast Cancer Study Group Coordinating Center, Bern, Switzerland.
- Smyth MJ QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
- Di Leo A International Breast Cancer Study Group and Ospedale di Prato-AUSL Toscana Centro, Prato, Italy.
- Colleoni M International Breast Cancer Study Group and Division of Medical Senology, IEO, European Institute of Oncology IRCCS, Milan, Italy.
- Viale G University of Milano, Milan, Italy; IEO, European Institute of Oncology IRCCS, Milan, Italy; International Breast Cancer Study Group and Central Pathology Office, Bern, Switzerland.
- Regan MM IBCSG Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
- André F Institut Gustave Roussy, Université Paris Sud, INSERM U981, Villejuif, France.
- 2019-02-16
Published in:
- The Lancet. Oncology. - 2019
Adolescent
Adult
Aged
Antibodies, Monoclonal, Humanized
B7-H1 Antigen
Breast Neoplasms
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Female
Humans
Middle Aged
Programmed Cell Death 1 Receptor
Receptor, ErbB-2
Trastuzumab
Treatment Outcome
English
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.
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.
- Language
-
- English
- Open access status
- closed
- Identifiers
-
- DOI 10.1016/S1470-2045(18)30812-X
- PMID 30765258
- Persistent URL
- https://sonar.ch/global/documents/178815
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