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Spotlight

This roundtable series presents physicians' views on how to treat a patient with locally advanced or metastatic HER2-positive gastric cancer, as discussed by participants at virtual live events.

Using Antibody-Drug Conjugates in Later-Line HER2+ Gastric Cancer

John L. Marshall, MD, chief of the division of hematology/oncology at Medstar Georgetown University Hospital, professor of medicine and oncology at Lombardi Comprehensive Cancer Center at Georgetown University, and director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancer, discusses the situations where patients could benefit from fam-trastuzumab deruxtecan-nxki (Enhertu) as second-line treatment for locally advanced or metastatic HER2-positive gastric cancer.

Trastuzumab deruxtecan was approved based on the DESTINY-Gastric01 study (NCT03329690) in patients who previously received trastuzumab (Herceptin). In this trial, there was an objective response rate (ORR) of 51% versus 14% with paclitaxel or irinotecan chemotherapy. This shows it can provide better efficacy for patients than recommended second-line chemotherapy options, though it has a unique adverse event profile including risk of interstitial lung disease that must be managed, according to Marshall.

Marshall says that when using this agent following first-line trastuzumab, physicians must decide whether testing for HER2 expression again is needed since it was not required in the trial. Repeating HER2 testing is difficult since it requires another biopsy, though some liquid biopsies could identify HER2 status more quickly and easily. Overall, he says it is better to re-test if possible when considering treatment with a second HER2-targeted agent, but trastuzumab deruxtecan is otherwise a good option.

 You now have a new tool in the toolbox for the treatment of HER2-positive gastric and gastroesophageal junction cancers. We didn't have that before. So if you were going to give HER2-targeted therapy in [the] first line, you only had your other chemotherapy options. And now you've got into second-line [a] HER2-positive option with trastuzumab deruxtecan. So if you're looking at the patient in front of you and trying to decide, “Do I go with taxane, or irinotecan, or other of the guideline-suggested chemotherapies in second and third line,” you know you've got this compound in hand. [It has a] higher response rate, [and] yes, some toxicity that goes with that. So, in a patient who's not faring well [and] needs a response, this is clearly a good choice in that patient population.

 One of the controversies that comes up with this agent is: Do you need to repeat HER2 testing in the second line? It wasn't required as part of this clinical trial, and, of course, in other diseases, you do repeat HER2 testing. So I think the answer is best to do it if you can. But it's not easy to do repeat biopsies and repeat HER2 testing. Some liquid biopsies may be able to help you with that. But it's not a requirement in going forward into second line. So if I've got a patient in front of me needs a response needs it in second line, I think the [trastuzumab deruxtecan] angle is a very legitimate choice in that second-line space.

John L. Marshall, MD, discusses the situations where patients could benefit from fam-trastuzumab deruxtecan-nxki as second-line treatment for locally advanced or metastatic HER2-positive gastric cancer.

The Role of HER2-Targeted Therapy for Gastric Cancer

John L. Marshall, MD, professor of medical oncology, chief of hematology-oncology, and director of the Otto J Ruesch Center for the Cure of Gastrointestinal Cancers at Lombardi Comprehensive Cancer Center at Georgetown University, discusses of the adverse event (AE) profile of fam-trastuzumab deruxtecan-nxki (Enhertu) in patients with locally advanced or metastatic HER2-positive gastric cancer.

Trastuzumab deruxtecan has shown efficacy in patients with HER2-positive breast cancer, and the DESTINY-Gastric01 study (NCT03329690) demonstrated its efficacy in patients with pretreated HER2-positive gastric and colorectal cancers as well. However, AEs were noted in the trial, such as some that are characteristic of chemotherapy, Marshall says. These AEs included myelosuppression, nausea, and diarrhea. The most common grade 3 or higher AE was neutropenia at 51% in the trastuzumab deruxtecan group versus 24% of those receiving physician’s choice of therapy.

An uncommon but significant treatment-related AE observed in the trial was interstitial lung disease, which was reported in 12 out of 125 patients (10%) treated with trastuzumab deruxtecan, with a median time to first onset of 84.5 days (range, 36 to 638). There were 9 cases of grade 1 or 2 interstitial lung disease and 3 cases of grade 3 or 4. Eight cases were resolved or were resolving at the time of analysis. In the DESTINY-Breast01 trial, (NCT03248492), 2 fatalities were associated with interstitial lung disease.

Marshall says physicians should monitor lung scans for asymptomatic signs of interstitial lung disease in all patients receiving trastuzumab deruxtecan since this can be a progressive toxicity.

 It's working quite well, in HER2-positive gastrointestinal cancers, both gastric [and] colorectal; we already knew it was working in breast cancer. But it is a drug that has some [AEs]. It is chemotherapy, and so you get chemotherapy kinds of [AEs]: myelosuppression, nausea, diarrhea, that you can see with chemotherapy, but it has an unusual [AE] that we have to be aware of, and this is interstitial lung disease or pulmonary fibrosis. And we're seeing this more with immuno-type therapies. But this one's a little different. It actually occurs in as many as 10% of patients in some level.

So you might come across it in a scan, an asymptomatic pattern on the lungs, for example, when the patient's not having shortness of breath or cough, but the reason we need to understand this is [because] this can become a more progressive toxicity, and some fatalities have been reported. So as we think about targeted therapies, this does have some of those elements, but it also has the elements of chemotherapy, and this interstitial lung disease, which we must be aware of and must monitor for in all of our patients.

John L. Marshall, MD, discusses of the adverse event profile of fam-trastuzumab deruxtecan-nxki in patients with locally advanced or metastatic HER2-positive gastric cancer.

Monitoring AEs of Trastuzumab Deruxtecan in HER2+ Gastric Cancer

Bassel El-Rayes, MD, director of the division of hematology and oncology, vice chair of clinical research, and professor of hematology and medical oncology at the University of Alabama at Birmingham, discusses how he approaches second-line therapy for patients with HER2-positive gastric cancer.

According to El-Rayes, the choice of second-line therapy for gastric cancer depends on the first-line therapy given, as well as whether the patient is HER2-positive. Other considerations include performance status, organ function, and other patient characteristics.

If a patient is HER2-positive, El-Rayes would use trastuzumab (Herceptin) plus a platinum-based agent such as cisplatin, 5FU [fluorouracil], or FOLFOX [leucovorin calcium, fluorouracil, and oxaliplatin] as frontline therapy. Following progression, the antibody-drug conjugate trastuzumab deruxtecan (Enhertu) may be given in the second line for patients who have previously received trastuzumab.

El-Rayes says trastuzumab deruxtecan may offer advantages in disease control and survival over second-line chemotherapy options due to being an HER2-targeted agent. In the DESTINY-Gastric01 study (NCT03329690), it demonstrated improved efficacy and median overall survival benefit of 12.5 versus 8.4 months for physician’s choice of irinotecan or paclitaxel chemotherapy for patients with HER2-positive advanced gastric cancer.

 The things that affect the second-line therapy in patients with gastric cancer that are HER2-positive, as of course the choice of therapy in the front line, and the overall medical condition of the patient performance status, organ function, things of that nature.

 In my practice, when I approach patients with gastric cancer, one of the first things I look at is if they are HER2-positive. If they are HER2-positive, then [in the] frontline setting, I'm using trastuzumab plus a platinum-based tablet, like cisplatin, 5FU, or FOLFOX, or something of that nature. At the time of progression, I'm usually shifting over to trastuzumab deruxtecan, rather than going to another second-line chemotherapy like [paclitaxel] or ramicirumab. I feel like targeting the HER2 in the second-line setting provides advantage in terms of disease control and survivorship.

Bassel El-Rayes, MD, discusses how he approaches second-line therapy for patients with HER2-positive gastric cancer. 

Choosing Second-Line Therapy for HER2+ Gastric Cancer

John Marshall, MD, clinical director of oncology and chief of the division of hematology-oncology for Georgetown University Hospital, and associate director for clinical care of the Lombardi Comprehensive Cancer Center, discusses the DESTINY-Gastric01 study (NCT03329690) of fam-trastuzumab deruxtecan-nxki (Enhertu) in patients with locally advanced or metastatic HER2-positive gastric cancer.

HER2-targeted agents have been investigated in breast, gastric, and colon cancer, and are being tested in other solid tumors currently. According to Marshall, HER2-targeted therapies are likely to be effective across disease types.

Trastuzumab deruxtecan is an antibody-drug conjugate that combines the monoclonal antibody trastuzumab with a topoisomerase inhibitor that binds to the cancer and delivers a chemotherapeutic agent. It was used successfully in patients with HER2-positive metastatic breast cancer in the DESTINY-Breast01 trial (NCT03248492), Marshall says.

In the phase 2 DESTINY-Gastric01 trial, 188 patients with advanced HER2-positive upper gastrointestinal [GI] cancers who had received at least 2 prior therapies, including trastuzumab, were randomized 2:1 to receive trastuzumab deruxtecan or physician’s choice of irinotecan or paclitaxel chemotherapy. Patients receiving trastuzumab deruxtecan had an objective response rate (ORR) of 51% versus 14% with chemotherapy. Median overall survival (OS) was 12.5 months versus 8.4 months, while progression-free survival was 5.6 months versus 3.5 months.

Based on the efficacy results, trastuzumab was approved as second-line and later therapy for patients with HER2-positive locally advanced or metastatic gastric cancer.

 We have been targeting HER2 for a long time, really led by the breast cancer teams, gastric cancer, now colon cancer has come behind. But we are now testing lots of cancers for HER2 positivity because the therapies do seem to work one disease to the next. In breast cancer, they had already figured out novel ways to target the HER2 pathway and receptor in through lines of therapy.

One of those is a novel therapy, a sort of loaded antibody, if you will, trastuzumab deruxtecan. This is essentially trastuzumab with a topoisomerase inhibitor attached to it. So the principle here is the antibody comes and binds to the receptor, probably has a pathway targeting piece to it as well, but brings along a very potent chemotherapeutic agent to the cancer cell and delivers that successfully. And we'd already seen this compound work in metastatic breast cancer.

 And the [DESTINY-Gastric01] study, it's a clinical trial looking in second- and third-line HER2-positive upper GI cancers where half the patients were randomized to receive chemotherapy of choice. The other half were given the single-agent trastuzumab deruxtecan, and the results were quite positive. They had a higher ORR, a higher PFS, [and] a higher OS in this space, which subsequently led to the approval of this drug, also known as Enhertu, in second- and subsequent-line therapy, [in] gastric cancer that is HER2-positive.

John Marshall, MD, discusses the DESTINY-Gastric01 study of fam-trastuzumab deruxtecan-nxki in patients with locally advanced or metastatic HER2-positive gastric cancer.