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

Summary

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.

Introduction

Breast cancers that overexpress the human epidermal growth factor receptor 2 (HER2 or ERBB2) oncogene are treated with drugs that target the HER2 pathway. Trastuzumab, a humanised monoclonal antibody against HER2, has transformed the natural history of this disease, with recent therapeutic advances such as pertuzumab and trastuzumab emtansine (T-DM1) and neratinib further improving overall survival for patients with this breast cancer subtype.1, 2, 3 Although overall survival for most patients with early-stage disease is impressive,⁴ a few patients still relapse and others still present with incurable stage 4 disease. Hence, further research to improve overall survival in patients with advanced disease is still warranted in this disease subtype.

Research in context

Evidence before this study

We searched PubMed for clinical trials or studies published in English between Jan 1, 2010, and June 1, 2018, assessing checkpoint blockade and HER2-directed therapy in patients with advanced HER2-positive breast cancer, using the search terms “HER2 positive”, “breast”, “checkpoint blockade”, and “trastuzumab”. To the best of our knowledge, this is the first report of the anti-tumour activity and safety of an anti-programmed cell death protein 1 (PD-1) antibody in combination with trastuzumab in the treatment of patients with advanced HER2-positive breast cancer resistant to previous trastuzumab containing therapies. A previous study examined a programmed cell death 1 ligand 1 (PD-L1) inhibitor without trastuzumab and reported no objective responses.

Added value of this study

In this single-arm, multicentre study, pembrolizumab combined with trastuzumab was well tolerated by patients with documented progression and resistance to trastuzumab and trastuzumab-combination therapies, and had durable anti-tumour activity, especially in those patients with PD-L1-positive tumours and tumour-infiltrating lymphocytes assessed by biopsy of metastatic lesions.

Implications of all the available evidence

Our results suggest that immune-mediated mechanisms of trastuzumab resistance are important in patients with HER2-positive breast cancer. Targeting the PD-1 pathway with pembrolizumab in combination with anti-HER2 drugs could prove to be an effective treatment option, particularly in patients who test positive for immune infiltrates. Our data support further development of this treatment approach for patients with HER2-positive breast cancer in large randomised clinical trials.

Substantial quantities of lymphocytic infiltrate have been observed in primary HER2-positive tumours, with increasing amounts associated with achieving a pathological complete response and having improved disease-free survival and overall survival.⁵ Trastuzumab has been shown to have immune mechanisms of action involving innate and adaptive immunity.6, 7 Preclinical studies have suggested that the combination of trastuzumab with drugs targeting immune checkpoints could overcome trastuzumab resistance.⁸ High expression of programmed cell death protein 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1), and other checkpoint molecules have been observed in tumour-infiltrating lymphocytes in this setting.8, 9 Hence, we hypothesised that drugs targeting the PD-1 pathway could be active in patients with HER2-positive breast cancer and trastuzumab-resistant disease.

Pembrolizumab is an anti-PD-1 antibody with robust anti-tumour activity as a monotherapy in multiple settings and an acceptable safety profile, with US Food and Drug Administration (FDA) approval in several solid tumour types. The use of drugs targeting the PD-1 pathway in breast cancer is thus far limited because of the absence of supporting studies10, 11, 12 and the fact that the anti-tumour activity of these checkpoint inhibitors seems somewhat modest in comparison with that seen in more immunogenic tumour types.

We did a combined phase 1b dose-escalation and phase 2 study to determine the safety and anti-tumour activity of pembrolizumab plus trastuzumab in patients with trastuzumab-resistant, HER2-overexpressing, advanced breast cancer. A signal of activity would support the concept that upregulation of checkpoint molecules and subsequent immune evasion might be mechanisms of trastuzumab resistance. A previous phase 1 study¹¹ reported no objective responses in 26 patients with HER2-positive breast cancer unselected for PD-L1 status treated with the PD-L1 inhibitor avelumab as monotherapy. To the best of our knowledge, this is the first report of a clinical trial investigating PD-1 inhibition with trastuzumab in this subtype of breast cancer.