Manish A. Shah, MD, director of the Gastrointestinal Oncology Program within the Division of Hematology and Medical Oncology and the Center for Advanced Digestive Care at Weill Cornell Medical College/ NewYork-Presbyterian Hospital, discusses the updated results of the phase 2 DESTINY-Gastric01 study with fam-trastuzumab deruxtecan-nxki (Enhertu) in HER2-expressing advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma.

The DESTINY-Gastric01 study was quite exciting, says Shah. This was a phase 2 study of the novel antibody-drug conjugate trastuzumab deruxtecan in HER2-positive gastric cancer. It was a 2:1 randomization where patients received either trastuzumab deruxtecan or physician’s choice of standard chemotherapy. 

The overall response rate was 51.3% in patients who received trastuzumab deruxtecan and a significant improvement in overall survival, with a 12-month OS rate of 52.1%. The median overall survival in the trastuzumab deruxtecan arm was 12.5 months versus 8.4 months in the chemotherapy arm (HR, 0.59; 95% CI, 0.39-0.88; 

Based on those findings, there is a lot of excitement about this drug and a global follow-up study is being conducted now, concludes Shah.

Videos

Manish A. Shah, MD, discusses the exciting updated results of the phase 2 DESTINY-Gastric01 study with fam-trastuzumab deruxtecan-nxki in HER2-expressing advanced gastric or gastroesophageal junction adenocarcinoma.

Dr. Shah on Updated Results With Trastuzumab Deruxtecan in DESTINY-Gastric01

Manish A. Shah, MD, Bartlett Family Associate Professor Gastrointestinal Oncology and associate professor of medicine at Weill Cornell Medical College, Cornell University, and associate attending physician at NewYork-Presbyterian Hospital, discusses biomarkers of response to immunotherapy in gastric/gastroesophageal junction (GEJ) cancer.

Mismatch repair deficiency (dMMR) status can inform whether a patient is likely to respond to immunotherapy, explains Shah.

Combined positive score (CPS) also serves as a marker of response to immunotherapy, says Shah.

CPS may indicate which patients will benefit from immunotherapy in the third-line setting, concludes Shah.

Manish A. Shah, MD, discusses biomarkers of response to immunotherapy gastric/gastroesophageal cancer.

Dr. Shah on Biomarkers of Response to Immunotherapy in Gastric/GEJ Cancer

Manish A. Shah, MD, Bartlett Family Associate Professor Gastrointestinal Oncology and associate professor of medicine at Weill Cornell Medical College and associate attending physician at NewYork-Presbyterian Hospital, discusses an optimal sequencing strategy in gastroesophageal cancer.

Findings from pivotal studies in this space have resulted in a clear sequencing strategy for patients with gastroesophageal cancer, explains Shah.

Patients with HER2-positive disease should receive chemotherapy in combination with trastuzumab (Herceptin) in the frontline setting.

There are some data suggesting that adding immunotherapy to first-line chemotherapy and trastuzumab may be superior to chemotherapy and trastuzumab alone, says Shah. However, that combination is still being investigated.

In the second-line setting, paclitaxel plus ramucirumab (Cyramza) is a common treatment regimen that does not require the presence of a specific target, says Shah.

Patients who are PD-L1&shy;—positive and who have a combined positive score ≥1 should be considered for immunotherapy in the third-line setting, explains Shah.

In patients who are mismatch repair deficient, immunotherapy should be moved earlier into the second- or first-line settings, concludes Shah.

Manish A. Shah, MD, discusses an optimal sequencing strategy in gastroesophageal cancer.

Dr. Shah on Optimal Sequencing in Gastroesophageal Cancer

Manish A. Shah, MD, Bartlett Family Associate Professor Gastrointestinal Oncology and associate professor of medicine at Weill Cornell Medical College, Cornell University, and associate attending physician at NewYork-Presbyterian Hospital, discusses the role of immunotherapy in gastroesophageal cancer.

Immunotherapy was originally developed for the advanced setting, specifically for use in third-line and beyond, and it demonstrated activity in some patients with gastroesophageal cancer, says Shah. The patients who reacted positively to immunotherapy experienced immense benefit.

Immunotherapy has since moved to the second-line setting, the first-line setting, and now, the locally advanced setting. Some data in the second-line setting suggest that immunotherapy is not superior to chemotherapy. In the first-line setting, the addition of immunotherapy to chemotherapy has not been found to be superior to chemotherapy alone, according to Shah. Some patients with gastroesophageal cancer benefit from immunotherapy, but there is currently no method to identify who these patients are, adds Shah.

Some patients with gastric cancer experience a large burden of disease and are symptomatic. Starting with chemotherapy is the best approach for those patients, unless a specific target, such as mismatch repair deficiency, is detected, says Shah. If such a target is present, up-front immunotherapy should be considered, concludes Shah.

Manish A. Shah, MD, discusses the role of immunotherapy in gastroesophageal cancer.

Dr. Shah on the Role of Immunotherapy in Gastroesophageal Cancer

Manish A. Shah, MD, Bartlett Family Associate Professor Gastrointestinal Oncology and associate professor of medicine at Weill Cornell Medical College and associate attending physician at NewYork-Presbyterian Hospital, discusses ongoing efforts to improve the benefit of immunotherapy in gastric and gastroesophageal junction (GEJ) cancer.

Immunotherapy has been shown to have efficacy in select patients with gastric/GEJ cancers, specifically those with PD-L1—positive tumors. Although high PD-L1 expression may increase the likelihood of benefit from immunotherapy, only about 10% to 15% of all PD-L1-expressing patients will respond to this approach. 

Chemotherapy has demonstrated efficacy when given early on in the treatment of patients with advanced, symptomatic disease; however, long-duration chemotherapy can be associated with myelosuppression, says Shah.

To avoid myelosuppression, investigators are combining short-course chemotherapy with pembrolizumab (Keytruda) in patients with untreated gastric/GEJ cancer in the ongoing phase III KEYNOTE-585 trial. The role of radiation will also be investigated in this trial with intent to enhance immune response to immunotherapy, concludes Shah.

Manish A. Shah, MD, discusses ongoing efforts to improve immunotherapy in gastric and gastroesophageal junction cancer.
 

Dr. Shah on Improving the Benefit of Immunotherapy in Gastric/GEJ Cancer

Manish A. Shah, MD, Bartlett Family Associate Professor Gastrointestinal Oncology at Weill Cornell Medical College and associate attending physician at NewYork-Presbyterian Hospital, discusses biomarkers in gastric and gastroesophageal junction (GEJ) cancer.

One of the key biomarkers being explored in gastric/GEJ cancer is Claudin 18.2, which binds cells together, explains Shah. When cancers develop, they lose their cell interaction, exposing the protein. An antibody against Claudin 18.2, called IMAB362, binds to Claudin 18.2 and activates an immune response, according to Shah. This antibody is now being evaluated in 2 registrational studies.

There is also potential to target biomarkers with antibody-drug conjugates, says Shah. Ado-trastuzumab emtansine (T-DM1; Kadcyla) is approved for use in breast cancer and has also shown activity in HER2-overexpressing tumors in gastric cancer; however, there is not much activity in HER2 low-expressing tumors. Instead, a new compound called [fam-] trastuzumab deruxtecan (DS-8201) might be more effective, concludes Shah.

Manish A. Shah, MD, discusses biomarkers in gastric and gastroesophageal junction cancer.

Dr. Shah on Biomarkers in Gastric/GEJ Cancer

Manish A. Shah, MD, Bartlett Family Associate Professor Gastrointestinal Oncology at Weill Cornell Medical College and associate attending physician at NewYork-Presbyterian Hospital, discusses the use of trastuzumab (Herceptin) biosimilars in gastric cancer.

The trastuzumab biosimilar goes after a proven target, Shah explains . It is already known that inhibiting HER2 signaling with trastuzumab is effective in gastric and gastroesophageal junction tumors that overexpress HER2. A biosimilar will do the same thing at a reduced cost, which helps patients avoid financial toxicity, says Shah.

Additionally, there is a biosimilar available for bevacizumab (Avastin) for colorectal cancer. Across gastrointestinal malignancies, biosimilars are going to have an important impact, concludes Shah.

Manish A. Shah, MD, discusses the use of trastuzumab biosimilars in gastric cancer.

Dr. Shah on the Trastuzumab Biosimilar in Gastric Cancer

Manish A. Shah, MD, director of gastrointestinal oncology and chief of Solid Tumor Service at Weill Cornell Medicine/NewYork-Presbyterian Hospital, discusses the BRIGHTER study in patients with gastric and gastroesophageal junction (GEJ) adenocarcinoma.

BRIGHTER is a phase III clinical trial that examined the role of the stem cell inhibitor napabucasin in patients with gastric and GEJ cancers. The aim was to target STAT3 in hopes of blocking cancer stem cell self-renewal. Patients randomized to the napabucasin arm received 480 mg twice daily. Paclitaxel was administered in the standard dose of 80 mg/mg

Although the study was negative, Shah says that a biomarker analysis is being done in a subset of patients with overexpression of the STAT3 target to see if they benefited from napabucasin. Currently, there are no data in colon cancer, where the phosphorylated STAT3 group did benefit from napabucasin, Shah explains.

There is an ongoing study in the second-line evaluating chemotherapy with or without napabucasin in patients with colon cancer. Shah says that he hopes to get some data in gastric cancer that will parallel that.

Manish A. Shah, MD, director of gastrointestinal oncology and chief of Solid Tumor Service at Weill Cornell Medicine/NewYork-Presbyterian Hospital, discusses the BRIGHTER study in patients with gastric and gastroesophageal junction (GEJ) adenocarcinoma.
 

Dr. Shah Discusses the BRIGHTER Study in Gastric Cancer

Manish A. Shah, MD, director of gastrointestinal oncology and chief of Solid Tumor Service at Weill Cornell Medicine/NewYork-Presbyterian Hospital, discusses challenges with immunotherapy in esophageal cancer.

Modest activity has been observed with immunotherapy in patients with esophageal cancer. The FDA approved pembrolizumab (Keytruda) for the treatment of patients with PD-L1—positive recurrent or advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma who have received 2 or more lines of chemotherapy in September 2017. Nivolumab (Opdivo) has also demonstrated strong clinical activity in patients with gastric and GEJ adenocarcinoma.

Shah says that although there has been success, the mechanism of resistance is still not known. It is unknown whether it could be increased regulatory T cells that are inhibitory, lack of antigen-presenting cells, or not enough cytotoxic T cells. More studies need to be done to understand what the mechanism of resistance is. Once that is accomplished, then immunotherapy can be augmented with another drug to overcome the resistance, or the mechanism or resistance can give an idea of how to better select patients, Shah says.

Manish A. Shah, MD, director of gastrointestinal oncology and chief of Solid Tumor Service at Weill Cornell Medicine/NewYork-Presbyterian Hospital, discusses challenges with immunotherapy in esophageal cancer.
 

Dr. Shah Discusses Challenges With Immunotherapy in Esophageal Cancer

Manish A. Shah, MD, director of gastrointestinal oncology and chief of Solid Tumor Service at Weill Cornell Medicine/NewYork-Presbyterian Hospital, highlights immunotherapy for esophageal cancer.

In general, the prognosis is not very optimistic for patients with metastatic disease—a significant amount will die within 1 year. There are very few targeted therapies in esophageal cancer, and most patients do not receive treatment after second-line therapy, Shah says.

However, recent data suggest that the PD-1 inhibitor pembrolizumab (Keytruda) can have modest efficacy in the third-line setting for patients with adenocarcinoma and squamous cell carcinoma. The most compelling aspect of the findings, Shah adds, was the durability of the responses. Patients who responded to immunotherapy could have increased overall survival of up to 1 year or longer.

Data from the phase Ib KEYNOTE-28 trial indicate that pembrolizumab induced an overall response rate of 30% (95% CI, 13%-53%) in patients with PD-L1—positive advanced esophageal carcinoma.