HER2+ Gastric Cancer: Optimal Treatment Approaches

Daniel Catenacci, MD:For HER2-positive patients, we test at the beginning when they’re first diagnosed in the stage 4 setting, and the positivity rates are about 10% to 15% of gastric-esophageal cancer. In that setting, they would get chemotherapy plus trastuzumab. The standard TOGA study, which is now several years old, published in 2010, was the landmark study that compared chemotherapy with cisplatin and 5-FU, or capecitabine, physician’s choice, to trastuzumab with that regimen. It was a positive study and became the standard of care for those patients.

Because FOLFOX chemotherapy—which is still fluoropyrimidine plus platinum—is a preferred regimen, it’s considered better tolerated and less toxic than cisplatin versus oxaliplatin; many of us who treat this disease will replace the cisplatin with oxaliplatin and treat with FOLFOX plus trastuzumab. So, that’s a very standard approach to do in a HER2-positive patient.

For HER2-positive patients in the second-line setting, this is a difficult situation at the moment. There have been a number of studies that have assessed what to do at that point in patients in the second-line setting after progression on first-line fluoropyrimidine and platinum plus trastuzumab. Unfortunately, two large phase III studies have been negative. One assessing the utility of lapatinib, in the second-line setting, and one assessing the utility of TDM1 in the second-line setting compared to standard controls of paclitaxel or paclitaxel/docetaxel in the latter study. Unfortunately, they were both negative.

The issue there is that patients that were diagnosed as HER2-positive are considered HER2-positive throughout the course of their treatment through various lines of therapy. What we’re now finding is that patients, if they repeat a biopsy at the time of starting second-line therapy, their biopsy no longer is HER2-amplified. That occurs in a range, depending on what studies you’re being referenced to. From 30%, up to even 70% or 80%, of cases are evolving to become HER2-negative. So, in the setting of assessing what to do in a HER2-positive patient in the second-line setting, the notion now to check to ensure that a patient is still HER2-positive, has retained HER2-amplification, those patients potentially could still benefit from continued anti-HER2 therapy.

On the other hand, patients who are now HER2-negative, you can imagine probably don’t derive much benefit from anti-HER2 therapy. In that setting, they should be treated with a standard second-line regimen like a paclitaxel or FOLFIRI plus ramucirumab.

Transcript edited for clarity.

A 61-Year-Old Woman With Stage 4 Gastric Cancer

November 2017

• A 61-year-old Hispanic woman presents to her PCP complaining of unexplained weight loss (15 lbs over 6 months), intermittent abdominal pain, fatigue, and recent onset of vomiting
• BMI: 23
• PE: negative for ascites
• Notable laboratory findings:
  • HB: 11.2 g/dL
  • LFT: WNL
  • GFR: 100
  • CEA, 18.4 ng/mL
  • AFP, CA 19-9, and CA 125: WNL
• Upper gastric endoscopy: suspicious 7.2-cm ulcerative lesion involving the pyloric region
• Endoscopic ultrasound: suspicious lymph node
• Biopsy: confirmed poorly differentiated, gastric adenocarcinoma, diffuse histologic subtype; positive lymph node
• Molecular testing: HER2(-), MSI-stable, PD-L1 expression 0%
• CT of chest, abdomen, and pelvis: showed diffuse invasion of the gastric wall and visceral peritoneum, lymph node involvement, 1 hepatic lesion
• Staging: stage IV gastric adenocarcinoma, unresectable
• ECOG PS 0

January 2018

• The patient was started on fluorouracil and oxaliplatin (FOLFOX)
• Follow up CT at 3 months showed a response to systemic therapy

July 2018

• Patient reports increasing nausea, fatigue, and shortness of breath
• CT imaging at 7 months shows metastatic spread to multiple suprapyloric nodes and a new liver lesion
• LFT: mildly elevated; GFR: WNL; HB: 10.8 g/dL
• ECOG PS 1
• Patient is motivated to try another systemic therapy
• Treatment with paclitaxel/ramucirumab is planned