Trastuzumab Deruxtecan for HER2+ Gastric Cancer

EP: 1.Patient Case With HER2+ Gastric Carcinoma

EP: 2.Molecular Testing for Gastric Carcinoma

EP: 3.Treatment Options for Gastric Carcinoma

EP: 4.The DESTINY-Gastric01 Trial and Mechanisms of Resistance in Gastric Carcinoma

EP: 5.Future Directions and Unmet Needs for Gastric Carcinoma

Now Viewing

EP: 6.Trastuzumab Deruxtecan for HER2+ Gastric Cancer

Bassel El-Rayes, MD: We are excited that the FDA recently approved trastuzumab deruxtecan for HER2+ [human epidermal growth factor receptor-2 positive] metastatic gastric and gastroesophageal cancer for patients who have progressed on a prior trastuzumab-based regimen. This was mainly based on the results of the DESTINY-Gastric01 trial, which compared trastuzumab deruxtecan to chemotherapy of choice by investigator. That trial showed significant improvement in terms of outcome in favor of trastuzumab deruxtecan in this population again. The trial included patients who had received 2 or more lines of therapy, but the approval from the FDA spans patients who have received prior trastuzumab without specification of the line of therapy, so it could be used in the second-line setting and beyond.

Our traditional approach for patients with HER2+ gastric or gastroesophageal junction tumors that are stage IV disease is to use trastuzumab plus a platinum-based therapy in the frontline setting. This is based on the ToGA trial. At the time of progression, we have traditionally treated patients similarly to the way we treat all other patients with gastric cancer using ramucirumab and paclitaxel. This approach in the second-line setting was heavily based on the fact that targeting the HER2 pathway in the second-line setting and beyond in gastric cancer had not been successful previously. Now with the results of the DESTINY-Gastric01 trial, we have an approach to target the HER2 pathway beyond the first-line setting. In my practice [at the Winship Cancer Institute of Emory University], I have tended to move trastuzumab deruxtecan to the second-line setting in patients who have failed frontline HER2-based therapy like trastuzumab plus a platinum regimen. This trial says that, in the second-line setting, you either continue to target the HER2/neu pathway, or you could use ramucirumab and Taxol [paclitaxel]. If you choose to use ramucirumab and Taxol [paclitaxel], then you should consider the trastuzumab deruxtecan in the third-line setting. As I said, in my practice, I feel like continuous targeting of the HER2 pathway in the second-line setting makes sense in this disease.

In my experience using this agent in the second- or third-line settings, it is an effective agent. It is relatively safe, and the adverse effects are relatively well controlled. The results of the DESTINY-Gastric01 trial, alongside my personal experience, indicate that this approach has a higher chance of disease control than using standard chemotherapy that is not directed against the HER2 pathway.

The main advice I would give regarding using trastuzumab deruxtecan in the second-line setting—this would apply also for using it beyond the second-line setting—is that one has to be careful about the adverse effect profile. Many of the adverse effects are adverse effects that we are used to managing such as problems with blood counts. Markers in cardiac function are also something we are used to doing with the trastuzumab use in breast cancer and gastric cancer. However, the adverse effect that is a bit unique for this drug is interstitial lung disease. We have to be aware of this potential adverse effect and be cognizant of it, and if patient presents with respiratory symptoms, we need to consider interstitial lung disease within the differential diagnosis because this is a known adverse effect of the drug. That adverse effect is not common, but we have to be aware and alert of it, and when patients present with symptoms, we need to consider it in our differential diagnosis and not directly assume that this is a viral or bacterial pneumonia but also consider interstitial lung disease from the therapy in the differential diagnosis. The last point I would say about the dose of the drug that is approved in gastric cancer is that it is different than the dose that is traditionally used in breast cancer. That is another thing that we have to keep in mind as we start using this drug more commonly in this clinical setting.

Transcript edited for clarity.

Case: A 66-Year Old Male With HER2+ Gastric Cancer

Initial presentation

• A 66-year-old man complains of a 4-month history of decreased appetite and diffuse abdominal pain
• PMH: DM, medically controlled; colonoscopy at age 55 was unremarkable; no personal or family history of cancer
• PE: bloating; abdominal pain on deep palpation; otherwise unremarkable
  

Clinical Workup

• Labs: Hb 9.5 g/dL, plt 104 x 109/L; other lab values WNL
• Endoscopy with biopsy: showed well differentiated papillary adenocarcinoma with invasion into the lamina propria
• EUS: irregular borders on extraluminal surfaces with hyperechogenic spots
• Abdominal/pelvic CT confirmed a 5.1 cm lesion with indistinct margins in the antrum of the stomach
• Stage IV gastric adenocarcinoma; ECOG 1
• IHC score for HER2 expression 3+
• Biomarker testing: PD-L1 0%, NTRK -
• MSI by PCR/MMR by IHC: stable

Treatment

• He was started on FOLFOX + trastuzumab
  • Well tolerated for 5 cycles
  • Imaging showed 3 new small pulmonary lesions
• Treatment changed to docetaxel + ramucirumab
  • Treatment was well tolerated for 4 cycles when he developed neutropenia
• Patient was started on trastuzumab deruxtecan; repeat HER2 expression score was not indicated