Trastuzumab Deruxtecan Brings HER2 Targeted Therapy to 3L HER2+ Advanced Gastric/GEJ Cancers

Yelena Y. Janjigian, MD

Objective responses observed in 51% of patients with HER2-positive advanced gastric cancer gastroesophageal junction (GEJ) adenocarcinoma treated with the antibody-drug conjugate (ADC), trastuzumab deruxtecan-nxki (DS-8201a; Enhertu) occurred in the phase 2 DESTINY-Gastric01study. The study recently led to the FDA approval of the agent in the third-line setting for the patient population. This approval is seen as practice-changing because, for the first time, oncologists can focus on targeting HER2 in later line settings.

“It's important to know that typically in the third line, the cancers are disease refractory, so to see a response rate of 40%, or more is quite impressive and unprecedented,” Yelena Y. Janjigian, MD, told Targeted Oncology.

In the open-label randomized study, DESTINY-Gastric01, treatment with trastuzumab deruxtecan was also notable for achieving significant improvements in progression-free survival and overall survival when compared with physician’s choice of chemotherapy. It was also notable that even though no patients from the United States were included in the study, the results and patient population were impressive enough to be translated to patient population worldwide.

In an interview with Targeted Oncology, Janjigian, medical oncologist and chief of the Gastrointestinal (GI) Oncology Service at Memorial Sloan Kettering Cancer Center, provided important highlights from the DESTINY-Gastric01 trial and explained the overall impact of the FDA approval of trastuzumab deruxtecan for oncologists treating patients with HER2-positive advanced gastric cancer or GEJ cancers.

TARGETED ONCOLOGY: Can you discuss the frequency of HER2 overexpression and positivity in gastric cancer? How often is this being tested, currently?

Janjigian: HER2 expression or amplification occurs in approximately 20% to 30% of esophageal and stomach cancers. Interestingly, we see a higher rate of up to 30% in patients with esophageal adenocarcinoma and GEJ tumors compared to gastric cancer where esophageal cancers more commonly overexpress HER2 gastric cancers where it's about 15% to 20% of the patient population. Trastuzumab, the HER2-directed antibody, is approved in this population in the first-line setting in patients with metastatic HER2-positive esophageal, GEJ, and gastric adenocarcinoma.

What we do see is globally in countries where trastuzumab is not approved, routinely used, or produced, testing is not as commonly done, and it's disappointing because HER2 is 1 of the most validated biomarkers in metastatic disease. However, if patients don't have access to HER2-directed therapies, often the clinicians in those places in the world don't test for HER2. In the United States, however, testing for HER2 was relatively well-accepted for metastatic gastric cancer and GEJ tumors. Esophagus cancers and adenocarcinomas are also HER2 tested and typically in first-line setting at the initial diagnosis of metastatic disease.

TARGETD ONCOLOGY: What led to the investigation of trastuzumab deruxtecan in this patient population, and what was the design of the study?

Janjigian: HER2 has been evaluated as a target in metastatic esophageal and gastric cancer for nearly a decade. We've known that targeting is important for outcomes in the first-line setting. The approval was based on the so-called ToGA study, combining chemotherapy plus trastuzumab in the previously untreated population, but beyond that, the field is stalled. We have not had a single successful positive trial or approval in this disease since the initial trastuzumab approval in this cancer and several factors contributed to that, such as disease heterogeneity, different approaches, and backbone chemotherapy. In other words, these are drugs that you would commonly be unacceptable for use in metastatic breast cancer with HER2 overexpression, such as lapatinib (Tykerb) and TDM1 (Kadcyla), pertuzumab (Perjeta), and so on, have all been tried, but have not shown clear and clinical and statistically significant benefit in this population.

Here we have a new drug on the market, trastuzumab deruxtecan, it's an ADC that has a higher cytotoxic chemotherapy payload than any other ADC that has been studied to date. It has a crosslinker, and 8-molecule payload using irinotecan- or topotecan-like drug for carrying and binding to HER2. [This drug] is particularly attractive in GI tumors, [specifically for] use in gastric cancer. Trastuzumab deruxtecan was used in the third-line setting, after progression of first-line HER2-directed therapy, Then, paclitaxel plus ramucirumab was used as second-line therapy, and then patients were randomized in the third-line setting to receive trastuzumab deruxtecan, or investigators choice of chemotherapy, which is typically taxane, docetaxel, or irinotecan.

The study randomized patients with a primary end point of survival, and also response rate and other biomarkers and end points were explored. The study was published in the New England Journal of Medicine. What’s important to note about this study, is that it was solely conducted in Asia. Patients enrolled on a study were from Japan, Korea, and Taiwan. None of the patients were from United States. There was a clear statistically significant benefit, and the response rate and all the survival end points were met. When you compare trastuzumab deruxtecan to other standard therapies that you would typically use in the third-line setting.

It's important to know that typically in the third line, the cancers are disease refractory, so to see a response rate of 40% or more, is quite impressive and unprecedented. Also, although typically, the FDA would require a study to be largely accrued in the United States, based on the Asia data, and also ongoing phase 2 studies in the United States, which also show promise so far, this is a meaningful impact on patients all over the world.

TARGETED ONCOLOGY: How specifically do these data apply to patients in the United States?

Janijigian: In the third-line setting in the United States, the options for metastatic HER2-positive gastric cancer is very limited. Pembrolizumab is approved for patients with a combined positive score, PD-L1 greater than 1 category, but single-agent responses are not that dramatic, and most patients do not benefit long term. Furthermore, patients who are HER2-positive often do not express PD-L1 in their tumors, and, therefore, pembrolizumab would not even be an option for those patients. Other agents available such as TAS-102 also just show a very modest benefit compared with placebo. The landscape for HER2-positive disease in the third-line setting in United States or anywhere is very bare, and to not offer this drug to our patients, because there's no US data confirming it, would be harsh. These patients have very limited options. It’s true that it's difficult to directly compare and translate the data in Asia, because patients tend to do better stage for stage, and their disease biology and overall functional status is improved. Also, more patients end up getting second-and third-line therapy. That's the unique difference in the patient population. That being said, if you have a patient in United States who's well enough to receive third-line therapy, who's being treated by an experienced clinician, I believe that the data at least in the third-line setting could be translated from Asia to the United States, particularly because, beyond trastuzumab right now we don't have any other targeted agent that would be approved for HER2-positive disease.

TARGETED ONCOLOGY: Can you summarize the overall impact of this FDA approval?

Janjigian: The impact of this approval is that it is great to be able to offer our patients HER2-directed therapy in third-line setting. It’s a game changer for patients and their families because it offers hope that you can target HER2 and something important about tumor biology that is driving their tumor.

I think a bigger impact in some ways is the impact on the research field. To be able to validate and for the first time, targeting HER2 and later lines of therapy is important and has promise. I’ve already seen with the trials that we're doing at Memorial Sloan Kettering Cancer Center, and globally, a new renaissance and enthusiasm for HER2-directed research in GI tumors across the board, but particularly in gastric cancer.

TARGETED ONCOLOGY: What is most important for oncologists to know about the safety profile of this agent?

Janjigian: The safety profile of this agent raises some concern about the possibility of lung toxicity or interstitial pneumonitis, so it's very important to monitor your patients and ask them to report any big symptoms such as cough, dry cough, perhaps dishpan exertion, and so on. Also, mindfully read these reports that may have some vague lung findings. Sometimes, radiologists report nonspecific ground classification or mild inflammatory changes that oncologists should continue to follow. Normally, in an oncology clinic, if we don't have large liver or bone metastases progressing or something big, we tend to minimize these little findings and focus on the big picture, but these are things that patients need to know. Is my cancer getting worse or is it my cancer getting better? But for when you're treating patients with ADCs, in general, but particularly trastuzumab deruxtecan, looking specifically at the lung findings and monitoring them on scans going forward may help our patients feel aware and empowered to monitor their symptoms and to report them. I think this will be critical.

TARGETED ONCOLOGY: Is there anything community oncologist should know about this drug, in general?Is there anything they should know about this patient population?

Janjigian: The patient population in metastatic gastric cancer is interesting. What we do know is with each subsequent line of therapy, at least 20% of patients lose HER2 expression in their tumor at the time of trastuzumab progression. The third-line study that was conducted and led to the FDA approval of trastuzumab deruxtecan in the third-line setting did not mandate biopsies to confirm HER2 expression prior to enrollment. Even with that, the response rate and the survival benefit were clear and very meaningful. What does that mean? It means that it doesn't matter that a patient still has HER2 expression. I believe that if a biopsy is possible, and the patient has a clinical need for a biopsy, it's reasonable to do it and confirm HER2 expression before you treat your patient. Patients with HER2 expression are the most likely to benefit. The risk-benefit ratio is in favor of therapy if the tumor is still HER2-positive.

That being said, there's now emerging data that even patients with low HER2 expression in gastric cancer may also have a response rate benefit, although the response is not as high compared with really high HER2 expressers.

The other factor to really consider is that in gastric cancer, the dose of trastuzumab deruxtecan is higher than the breast cancer dose. That being said, the risk of fatal pulmonary toxicity is low or pretty much non-existent. Part of that is probably due to dose reductions over time and also the amount of the drug that the patients end up getting. Patients that you're considering for treatment after maximum response, or after 3 or 4 months of therapy, where they've already derived benefit and they're doing fine, I would consider a dose reduction because it may improve tolerance and also reduce the risk of pulmonary toxicity further down the line.