Esophageal cancer is characterized by early and frequent metastasis. Surgery is the primary treatment for early-stage disease, whereas patients with patients with locally advanced disease receive ...perioperative chemotherapy or chemoradiotherapy. Squamous cancers can be treated with primary chemoradiotherapy without surgery, depending on their response to therapy and patient tolerance for subsequent surgery. Chemotherapy with a fluorinated pyrimidine and a platinum agent, followed by later treatment with taxanes and irinotecan, provides some benefit. Agents that inhibit the erb-b2 receptor tyrosine kinase 2 (ERBB2 or HER2), or vascular endothelial growth factor, including trastuzumab, ramucirumab, and apatinib, increase response and survival times. Esophageal adenocarcinomas have mutations in tumor protein p53 and mutations that activate receptor-associated tyrosine kinase, vascular endothelial growth factor, and cell cycle pathways, whereas esophageal squamous tumors have a distinct set of mutations. Esophageal cancers develop systems to evade anti-tumor immune responses, but studies are needed to determine how immune checkpoint modification contributes to esophageal tumor development.
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.
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.
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.
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.
Merck & Co.
Although recent decades have witnessed incremental improvements in the treatment of gastroesophageal junction (GEJ) carcinoma, outcomes remain modest. For locally advanced esophageal cancer, the ...addition of chemotherapy and/or radiation to surgery is considered the standard of care. Chemotherapy remains the primary treatment for metastatic disease and improves survival over best supportive care. However, the prognosis for patients with GEJ cancers, which are treated along the same paradigms as esophageal and gastric carcinomas, remain poor because of the emergence of chemoresistance and limited targeted therapeutic approaches, which include agents that target the HER2 and vascular endothelial growth factor pathways. Evaluation of immune checkpoint inhibitors in the chemorefractory setting have confirmed the activity of immunotherapy in esophagogastric cancer. Ongoing immunotherapeutic strategies are being evaluated in both the locally advanced and metastatic settings. This review focuses on the treatment of locally advanced and metastatic GEJ carcinomas, which encompass all tumors that have an epicenter within 5 cm proximal or distal to the anatomical Z‐line (Siewert classification). Because the vast majority of GEJ tumors are adenocarcinoma, the management of adenocarcinoma is the focus of this review. Evolving approaches and areas of clinical equipoise are discussed.
The management of gastroesophageal junction cancer is complex. Recent advances in positron emission tomography–adapted therapy, molecular targeting, and immuno‐oncology may usher in a new wave of multimodality approaches to enhance patient outcomes.
...for adenocarcinoma of the oesophagus or gastro-oesophageal junction, there is ongoing debate about the use of chemotherapy alone or combined chemoradiotherapy followed by surgery as the most ...effective pre-surgery treatment. Because of the confines of the mediastinum and absence of a peritoneal lining in oesophageal and Siewert type 1 and 2 gastro-oesophageal junction adenocarcinomas, the issues of R0 resection, response to treatment, achievement of a node negative status, and local recurrence become important. Additionally, only 24% of the patients in the CROSS trial had gastro-oesophageal junction cancer, and the outcomes for this important group were not reported. ...from an objective perspective, any clinical decision to administer chemoradiotherapy rather than chemotherapy to a patient with localised adenocarcinoma of the gastro-oesophageal junction is a risky decision. In addition to the surgical mortality that was increased in some trials after chemoradiotherapy (eg, 10% in the POET trial, assessing the addition of radiotherapy to neoadjuvant chemotherapy for patients with adenocarcinoma or the oesophagus), radiotherapy causes long-term complications such as cardiovascular disease and secondary malignancies. ...a compelling justification for opting for a chemoradiotherapy approach over chemotherapy alone is needed. The individual studies contributed a weight of more than 5% of the total population of the meta-analysis were uniformly negative. ...except for one study, individual studies that contributed a relative weight of more than 7% showed a detrimental effect on survival (HR >1) when radiotherapy was added to chemotherapy.
The incidence of esophagogastric cancer is rapidly rising, but only a minority of patients derive durable benefit from current therapies. Chemotherapy as well as anti-HER2 and PD-1 antibodies are ...standard treatments. To identify predictive biomarkers of drug sensitivity and mechanisms of resistance, we implemented prospective tumor sequencing of patients with metastatic esophagogastric cancer. There was no association between homologous recombination deficiency defects and response to platinum-based chemotherapy. Patients with microsatellite instability-high tumors were intrinsically resistant to chemotherapy but more likely to achieve durable responses to immunotherapy. The single Epstein-Barr virus-positive patient achieved a durable, complete response to immunotherapy. The level of
amplification as determined by sequencing was predictive of trastuzumab benefit. Selection for a tumor subclone lacking
amplification, deletion of
exon 16, and comutations in the receptor tyrosine kinase, RAS, and PI3K pathways were associated with intrinsic and/or acquired trastuzumab resistance. Prospective genomic profiling can identify patients most likely to derive durable benefit to immunotherapy and trastuzumab and guide strategies to overcome drug resistance.
Clinical application of multiplex sequencing can identify biomarkers of treatment response to contemporary systemic therapies in metastatic esophagogastric cancer. This large prospective analysis sheds light on the biological complexity and the dynamic nature of therapeutic resistance in metastatic esophagogastric cancers.
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To review recent studies in esophagogastric cancer.
Positive emission tomography (PET) scan in follow-up after curative treatment of esophagogastric cancer did not lead to improved survival. In the ...preoperative treatment of esophagogastric cancer, the addition of the antivascular endothelial growth factor agent bevacizumab to perioperative chemotherapy with combination epirubicin, cisplatinum, and 5-fluorouracil (5-FU; ECF) failed to improve survival compared with chemotherapy alone. In a head-to-head comparison of preoperative chemotherapy for locally advanced gastric and esophagogastric adenocarcinoma, FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) significantly improved overall survival compared with ECF. Assessing response to induction chemotherapy prior to combined preoperative chemoradiotherapy in PET nonresponding patients allowed a change in chemotherapy during subsequent radiotherapy with improved rates of pathologic complete response. In human epidermal growth factor receptor-2-positive advanced esophagogastric adenocarcinoma, second-line treatment with the chemotherapy/trastuzumab drug conjugate emtansine/trastuzumab failed to improve response or overall survival compared with treatment using paclitaxel chemotherapy. The immune checkpoint inhibitor, nivolumab, improved survival in refractory gastric cancer.
Recent studies in gastric cancer clarify the optimal preoperative chemotherapy regimen and the use of PET scan as a response measure of preoperative therapy in esophagogastric cancer, and the role of targeted agents and immune checkpoint inhibitors in metastatic disease.
The practice-changing results from SCOT need to be taken in the context of the IDEA trial, a pooled analysis of more than 10 000 patients enrolled in six global adjuvant therapy trials, including ...SCOT.2 There is consistency in the results of IDEA3 and the individual trials), which supports the adoption of 3 months of capecitabine and oxaliplatin as the preferred adjuvant therapy in patients with low-risk stage III disease.2,4,5 Similar to SCOT, a small difference favouring 6 months of therapy over 3 months in higher risk patients was also seen in IDEA.Al-Batran and colleagues have reported that the addition of docetaxel to infused fluorouracil and oxaliplatin, using the FLOT regimen (fluorouracil, leucovorin, oxaliplatin, and docetaxel) as preoperative therapy, resulted in a significant survival benefit compared with preoperative ECX in patients with gastric and gastro-oesophageal junction cancers.10 If a third chemotherapy agent is to be added to preoperative fluorinated pyrimidine platinum chemotherapy, it should be docetaxel and not epirubicin.The SCOT investigators deserve congratulations for their practice-changing trial that can directly improve the lives of patients receiving adjuvant chemotherapy for stage III colon cancer.
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