Manish A. Shah, MD, discusses the emerging agent zolbetuximab and the antibody-drug conjugate trastuzumab deruxtecan as treatment options for patients with gastric and GEJ cancers.
Manish A. Shah, MD, the Bartlett Family Associate Professor of Gastrointestinal Oncology, associate professor of medicine at Weill Cornell Medical College, and associate attending physician at NewYork-Presbyterian Hospital
Manish A. Shah, MD
The GLOW and DESTINY-Gastric01 trials showcase 2 novel agents coming down the pipeline in the treatment paradigm for patients with gastric cancers, according to Manish A. Shah, MD.
The ongoing phase 3 GLOW study is enrolling patients with claudin 18.2 (CLDN18.2)-positive/her2-negative locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.1 Patients are randomly assigned 1:1 to receive either zolbetuximab plus capecitabine and oxaliplatin (CAPOX) or placebo plus CAPOX. The primary objective of the study is progression-free survival (PFS). Secondary endpoints include response, overall survival (OS), and the safety/tolerability.
The phase 2 DESTINY-Gastric01 study enrolled patients with HER2-overexpressing advanced gastric or GEJ adenocarcinoma who have progressed on 2 prior treatment regimens. Patients were randomized to either fam-trastuzumab deruxtecan-nxki (Enhertu) or physician’s choice of standard chemotherapy. Results showed that trastuzumab deruxtecan resulted in a median OS of 12.5 months (95% CI, 9.6-14.3) versus 8.4 months (95% CI, 6.9-10.7) in the physician’s choice arm (HR, 0.59; 95% CI, 0.39-0.88; P = .0097). The median PFS was 5.6 versus 3.5 months, respectively (HR, 0.47; 95% CI, 0.31-0.71; P = .0003).2
In an interview with OncLive, Shah, associate professor of medicine at Weill Cornell Medical College, Cornell University, and associate attending physician at NewYork-Presbyterian Hospital, discussed the emerging agent zolbetuximab and the antibody-drug conjugate trastuzumab deruxtecan as treatment options for patients with gastric and GEJ cancers.
OncLive: You are the first author on the phase 3 GLOW study which treated patients with CAPOX plus either zolbetuximab or placebo. What was the rationale for exploring this regimen?
Shah: This was a 3-drug regimen. The standard chemotherapy is CAPOX. That is the standard doublet regimen we use in gastric and GEJ tumors. [Patients with] tumors that are HER2-negative and CLDN18.2-positive should be eligible for the GLOW study. They would receive either CAPOX with zolbetuximab or CAPOX with a placebo.
Zolbetuximab is a new monoclonal antibody inhibitor of CLDN18.2, which is important in the tight junctions between cells. As the cancer develops, these tight junctions open up and reveal the CLDN18.2 receptor. By revealing the CLDN18.2 receptor, an antibody can then bind to it and activate immunity against the cancer cell itself. The idea is to examine CAPOX with this monoclonal antibody that binds the claudin 18.2 versus placebo. It is an international study open across the United States, Europe, and Asia, and I am one of the global principal investigators.
What methods were used to identify the patient population?
It is standard screening procedures, which include imaging studies, such as a CAT scan, blood work, history, and physical. The important part is that we examined the tumor tissue by immunohistochemistry to examine the overexpression of claudin 18.2. The study is focused on the high claudin 18.2 expression and HER2-negative tumors. We expect about 30% of patients who have gastric cancer would be eligible based on those criteria.
What findings have you come across thus far?
The study just recently opened and, unfortunately, things were on a bit of a hiatus because of the COVID-19 pandemic but we are resuming activities. There was an earlier phase 2 study that examined zolbetuximab with FOLFOX chemotherapy and, prior to that, there was another study of zolbetuximab with epirubicin, cisplatin, and 5-fluorouracil. The data are quite encouraging. Based on those phase 2 data where we see improvement in both PFS and OS, we are really hopeful that this study has activity.
What is the safety profile of the regimen in this patient population?
CLDN18.2 is naturally expressed on the epithelial line. Patients commonly have nausea and vomiting with the administration of the drug. We think that it is an on-target effect. We have learned how to give the drug in a safe way. The initial dose is given over a longer infusion to allow patients to tolerate it better. That is the main safety profile. We have also seen some increase in myelosuppression but, in general, when combined with chemotherapy, it is well tolerated.
What are the next steps with this research and unanswered questions?
The activity of the zolbetuximab antibody in high CLDN18.2 expressors by itself is being evaluated. As I mentioned, it activates the immune response by binding through receptors, so we are interested in its activity when combined with a checkpoint inhibitor. We need to examine its first-line efficacy both with capecitabine and oxaliplatin. That is the GLOW study that we talked about. It is also being combined with FOLFOX which is the phase 3 SPOTLIGHT study, and it is also being examined in a more advanced-line setting.
Moving on to the phase 2 DESTINY-Gastric01 study. Could you provide a brief overview?
The DESTINY-Gastric01 study was quite exciting. This was a phase 2 study of the novel antibody-drug conjugate trastuzumab deruxtecan in HER2-positive gastric cancer. It was a randomized study, 2:1 randomization, to receive trastuzumab deruxtecan versus chemotherapy. There was a significant response rate of 50% in patients who received trastuzumab deruxtecan and a significant improvement in survival. Based on that, there is quite a significant excitement about this drug. A global follow-up study is being conducted now.
Trastuzumab deruxtecan was recently granted an orphan drug designation for patients with HER2-positive metastatic gastric or gastroesophageal cancer. If it is approved down the line, what would the implications be?
We are very excited about this drug. If it is approved down the line, then it opens up the door for treating patients for HER2-positive disease in the advanced-line setting. We know in gastric cancer that HER2-positive disease is not the same as it is in breast cancer. In breast cancer, the idea is to always block HER2 signaling throughout many lines of therapy. You see patients on trastuzumab deruxtecan for first-, second-, or third-line therapy, and other drugs, such as lapatinib (Tykerb), TDM-1 (ado-trastuzumab emtansine; Kadcyla), and pertuzumab (Perjeta), work in breast cancer.
In gastric cancer, it has been demonstrated that blocking HER2 signaling with trastuzumab (Herceptin) in the first-line setting has proven benefit—that is based on the ToGA study. We know that based on other studies that lapatinib and continuing trastuzumab beyond progression are not active. We think the reason why that is the case is that there is probably more heterogeneity in HER2 signaling in gastric cancer. Also, it has been demonstrated from baseline to after first-line and after second-line that the HER2 signal is lost. Now, targeting HER2-positive disease in the advanced-line setting, second- and third-line, with trastuzumab deruxtecan, is quite exciting. It opens up new doors for us.
What are the next steps to this research and unanswered questions you hope to address?
Similar to zolbetuximab, there is a lot of excitement to using the antibody-drug conjugates in combination with checkpoint inhibitors. That is something that will be pursued in the future. Additionally, we need to understand how to use this drug with chemotherapy, which we think might be better in the first-line setting. One of the current concerns about trastuzumab deruxtecan is the rate of interstitial lung disease or pneumonitis. There are some patients who have died from that disease, but the better we learn how to use the drug and the more acutely we are aware of this toxicity, we will find it to be quite tolerable.
Is there anything else from this study that you would like to highlight?
Trastuzumab deruxtecan has been examined in colorectal cancer as well as in breast cancer. In both of those diseases, the drug also demonstrated benefit. Clearly, this drug has significant activity and it is something to look out for in the future.
What is your take-home message from this research?
Both of these drugs that we have talked about are novel agents that attack targets on gastric and GEJ tumors. That is the future of drug development in this disease. It is to identify novel targets and attack them as these drugs do. We will have more of these types of drugs and novel targets being developed which is exciting for patients as well as researchers.
Beyond this work, what are some of the other research efforts that are being made in this space that you are excited about?
There is a lot of work being done on trying to improve the efficacy of immune checkpoint inhibition and identifying targets better. One of the exciting things that are being developed is the novel way to augment the efficacy of checkpoint inhibition in tumors that are mismatch repair deficient. As you know, 15% to 20% of gastric tumors have a microsatellite instability-high phenotype. This type of strategy might be appropriate for that group of patients.