First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: an open-label, single-arm, phase 2 trial

Summary

Background

Addition of trastuzumab to first-line chemotherapy improves overall survival in patients with HER2-positive metastatic gastric cancer. We assessed the safety and activity of pembrolizumab in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic oesophagogastric (gastric, oesophageal, or gastroesophageal junction) cancer.

Methods

This study was an investigator-initiated, open-label, non-randomised, single-arm, single centre, phase 2 trial in patients aged 18 years or older with HER2-positive metastatic oesophagogastric cancer. Eligible patients had measurable or evaluable non-measurable disease, Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and left ventricular ejection fraction of at least 53%. Patients were eligible to receive an initial induction cycle of 200 mg flat dose of intravenous pembrolizumab and 8 mg/kg loading dose of intravenous trastuzumab. For subsequent cycles, patients received 130 mg/m² of intravenous oxaliplatin or 80 mg/m² of cisplatin on day 1, 850 mg/m² of oral capecitabine twice a day for 2 weeks followed by 1 week off (or intravenous 5-fluorouracil, 800 mg/m² per day on days 1–5), and a 200 mg flat dose of intravenous pembrolizumab, and 6 mg/kg of trastuzumab, administered on day 1 of each 3-week cycle. The primary endpoint was 6-month progression-free survival, defined as the proportion of patients alive and free of progression at 6 months, assessed in patients who received at least one dose of trastuzumab and pembrolizumab. The regimen would be considered worthy of further investigation if 26 or more of 37 patients were progression-free at 6 months. This trial is registered with ClinicalTrials.gov, NCT02954536, and is ongoing, but closed to enrolment.

Findings

Between Nov 11, 2016, and Jan 23, 2019, 37 patients were enrolled. At the time of data cutoff on Aug 6, 2019, median follow-up among survivors was 13·0 months (IQR 11·7–23·5). The primary endpoint was achieved; 26 (70%; 95% CI 54–83) of 37 patients were progression-free at 6 months. The most common treatment-related adverse event of any grade was neuropathy, which was reported in 36 (97%) of 37 patients. The most common grade 3 or 4 adverse events were lymphocytopenia (seven [19%] patients with grade 3 and two [5%] with grade 4), grade 3 decreased electrolytes (six [16%] patients), and grade 3 anaemia (four [11%] patients). Serious adverse events occurred in two patients patients (both grade 3 nephritis leading to treatment discontinuation). Four patients discontinued pembrolizumab because of immune-related adverse events. There were no treatment-related deaths.

Interpretation

Pembrolizumab can be safely combined with trastuzumab and chemotherapy and has promising activity in HER2-positive metastatic oesophagogastric cancer. A randomised phase 3 clinical trial assessing the efficacy and safety of pembrolizumab versus placebo in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic oesophagogastric cancer is underway.

Funding

Merck & Co.

Introduction

With an estimated 1·5 million new diagnoses in 2018, oesophagogastric (gastric, oesophageal, or gastro-oesophageal junction) cancer represents the fifth most common cancer worldwide and the third leading cause of cancer-related death.¹ Moreover, the incidence of gastrooesophageal junction cancer is increasing rapidly in western countries, particularly among young individuals.² About a third of oesophagogastric tumours are characterised by chromosomal instability and aberrant activation of HER1–4.3, 4, 5 In patients whose cancers harbour HER2 (also known as ERBB2) amplification or HER2 protein overexpression, the combination of the anti-HER2 antibody trastuzumab with cytotoxic chemotherapy (a fluoropyrimidine and platinum) is the recommended first-line therapy. Patients treated with this combination have a median overall survival of 13·8 months (95% CI 12–16) and an overall response rate of 47%.⁶

Research in context

Evidence before this study

We searched PubMed from inception until Jan 6, 2020, for clinical trials published in English assessing trastuzumab or pembrolizumab in oesophagogastric (or gastric, oesophageal, or gastro-oesophageal junction) cancer, using the search terms “trastuzumab” and “gastric cancer OR esophageal cancer,” then repeating the search by substituting “pembrolizumab” for “trastuzumab”. Following the results of the ToGA trial in 2010, trastuzumab plus fluoropyrimidine and platinum chemotherapy became the standard of care for HER2-positive metastatic oesophagogastric cancer. In the KEYNOTE-059 trial, pembrolizumab induced responses in patients with previously treated, PD-L1-positive metastatic oesophagogastric cancer. However, KEYNOTE-062 found no survival advantage for the combination of pembrolizumab and chemotherapy relative to first-line chemotherapy. To inform our investigation of molecular and genetic correlates of response, we also searched for predictors of response and resistance to trastuzumab by adding the term “biomarker” to the search. Resistance has been associated with activation of the receptor tyrosine kinase/KRAS and PI3K pathways, while greater response correlates with degree of HER2 (also known as ERBB2) amplification in tumour and circulating tumour DNA.

Added value of this study

To our knowledge, this is the first study to evaluate the synergistic potential of pembrolizumab, trastuzumab, and chemotherapy for previously untreated metastatic oesophagogastric cancer. We also explored potential molecular determinants of response to inform future studies to identify subsets of patients most likely to benefit from this combination.

Implications of all the available evidence

The results of this study suggest that the addition of pembrolizumab to trastuzumab and chemotherapy is safe and active in treating metastatic oesophagogastric cancer. The efficacy of this combination is being evaluated in the randomised double-blind phase 3 KEYNOTE 811 trial (NCT03615326).

Pembrolizumab, an anti-PD-1 antibody, has been shown to induce responses in 23% of patients with PD-L1-positive (combined positive score ≥1) metastatic oesophagogastric cancer in the third-line setting.⁷ However, combining pembrolizumab with chemotherapy did not improve survival relative to first-line chemotherapy in patients with HER2-negative, PD-L1-positive metastatic oesophagogastric cancer.⁸

Preclinical and clinical evidence support combining pembrolizumab with trastuzumab and cytotoxic chemotherapy to treat HER2-positive cancers. The combination can induce durable clinical responses in a subset of patients with trastuzumab-refractory HER2-positive metastatic breast cancer.⁹ Although the mechanistic basis for synergy between anti-HER2 and anti-PD-1-based therapies has not been definitively established, possible contributors have been identified. Analysis of tumour samples from patients treated with trastuzumab shows upregulation of PD-1 and enhanced gene expression signatures of immune infiltration,¹⁰ which could increase the efficacy of pembrolizumab. Similarly, trastuzumab increases PD-L1 expression in a mouse model of breast cancer.¹¹ In addition, administration of trastuzumab with pembrolizumab can augment HER2-specific T-cell responses, promote T cell and dendritic cell trafficking, and induce expansion of peripheral memory T cells.12, 13, 14

To determine whether pembrolizumab can be safely combined with trastuzumab and chemotherapy, and whether the combination is sufficiently active to warrant comparison to the existing standard of care, we did a phase 2 trial to define the activity of pembrolizumab, trastuzumab, a fluoropyrimidine and platinum as first-line therapy in patients with HER2-positive metastatic oesophagogastric cancer. Tumour and blood samples were collected before treatment to confirm HER2 status and identify molecular determinants of response.