LEO

Lapatinib in Early Oesophago-gastric Cancer

Research summary

7-20% of gastric or oesophageal adenocarcinomas are known to over-express HER-2. Our data suggests that in vitro molecular over-expression of HER-2 is associated with the ligand independent constitutive phosphorylation of both HER-2 and EGFR resulting in the formation of EGFR-HER-2 heterodimers and increased activity of the downstream MAPK and AKT pathways. We have also demonstrated the presence of HER-2 and EGFR constitutive phosphorylation in patients with HER-2 amplified tumours. When oesophageal cell lines with HER-2 amplification are treated with lapatinib the activity of HER-2, EGFR, MAPK and AKT is silenced; proliferation is profoundly inhibited and apoptosis dramatically induced. These observations provide evidence for a role of HER-2 in oncogenic maintenance and support a therapeutic role for its inhibition in oesophageal adenocarcinoma with HER-2 over-expression.

HER-2 targeted therapy in patients with HER-2 over-expressing breast tumours results in clinical responses in over 40% of patients. Responses correlate with reduced tumour cyclin D expression, an increase in cleaved caspase 3 and an increase in apoptosis after treatment; however there are currently no markers or assays which will predict prior to therapy which patients out of the HER-2 over-expressing cohort will respond. This would be important if HER-2 targeted therapy is to be used more broadly in epithelial cancers as part of a personalised regimen.

This is a multicentre open label trial of lapatinib alone and in combination with oxaliplatin and capecitabine in early HER-2 overexpressing oesophago-gastric cancer. In this trial patients with HER-2 overexpressing early oesophago-gastric carcinoma will be recruited and lapatinib will be added to a standard chemotherapy regimen prior to surgery. All patients entered on the trial will receive a 10 day induction treatment with single agent lapatinib with pre and post treatment biopsy and FDG-PET scan. They will then be treated with combination oxaliplatin, capecitabine and lapatinib therapy for 3 cycles. Provided there are no contraindications they will then proceed to curative surgery. The primary objective of this study is to demonstrate relationship between molecular response in biopsies taken pre treatment and treated with lapatinib ex vivo and molecular response in a biopsy taken after 10 days of oral lapatinib.

Main inclusion criteria

  1. Histologically confirmed gastric or oesophageal adenocarcinoma

  2. HER-2 3+ on IHC OR HER-2 2+ on IHC but shown to have HER-2 amplification by FISH

  3. Decision to treat with curative intent

  4. Deemed to require chemotherapy prior to surgery using standard management algorithms

  5. Ability to swallow oral medication

  6. Baseline 18FDG PET/CT scan showing no evidence of distant metastases

  7. Adequate haematological parameters: ANC ≥ 1.0 x 109/L; WBC ≥ 3.0 x 109/L; Plt ≥ 100 x 109/L; haemoglobin (Hb) ≥ 9g/dL (can be post-transfusion)

  8. Adequate renal function (Measured or calculated creatinine clearance ≥ 60 ml/min- if calculated the Cockcroft-Gault equation (Appendix A) to be used.

  9. Adequate liver function: serum Bilirubin ≤ 1.5 x ULN; ALT/AST ≤ 1.5 x ULN; ALP ≤ 2.5 x ULN

  10. Age >18 years

  11. Women of child bearing potential using medically approved contraception. (Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential)

  12. Male patients using barrier contraceptives during the trial and for 6 months after the completion of the trial

Main exclusion criteria

  1. Advanced disease not amenable to surgery

  2. Abnormal Cardiac function (LVEF below normal as measured by echocardiogram or MUGA scan)

  3. History of clinically significant cardiac disease e.g. symptomatic coronary artery disease, uncontrolled cardiac dysrhythmia or myocardial infarction within the last 12 months)

  4. History of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest CT scan.

  5. Known peripheral neuropathy >Grade 1 (absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible)

  6. Inability to give informed consent

  7. Hypersensitivity to lapatinib or oxaliplatin or capecitabine

  8. Prior treatment with chemotherapy or lapatinib or other specific anticancer therapy

  9. Squamous cell carcinomas, unclear differentiation type, sarcomas, carcinoid or GIST

  10. Known positive tests for human immunodeficiency virus (HIV) infection, hepatitis C virus, acute or chronic active hepatitis B infection

  11. Pregnancy/breastfeeding

  12. Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)

  13. Treatment with another investigational agent within 30 days of commencing study treatment

  14. Known or suspected dihydropyrimidine dehydrogenase deficiency (DPD)

  15. Galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption

Chief investigator

Dr Hugo Ford

Contact details

Cancer Theme Email: [email protected]