Gastric/GEJ Cancers Gain Traction With HER2-Targeted Therapy With More to Come

Daniel H. Ahn, DO, and Manish A. Shah, MD, discuss the emergence of HER2 as a validated target in GI malignancies, the approval of trastuzumab deruxtecan in gastric/GEJ cancer, and other emerging agents that are poised to propel HER2-targeted therapy in these diseases.

The January 15, 2021 approval of fam-trastuzumab deruxtecan-nxki (Enhertu) for patients with locally advanced or metastatic HER2-positive gastric/gastroesophageal junction (GEJ) cancer who have received prior trastuzumab (Herceptin)-based therapy has raised the question of whether the antibody-drug conjugate (ADC) has utility in the frontline setting or in novel combination regimens, said Daniel H. Ahn, DO, who added that the question could be answered with the ongoing DESTINY-Gastric03 (NCT04379596) trial.

“Right now, the only data that we have [with trastuzumab deruxtecan] is in the refractory setting as monotherapy,” said Ahn, a Mayo Clinic oncologist. “However, [ongoing] studies will help us to better understand the efficacy in the frontline setting and whether it can potentially compete with agents, such as trastuzumab, in previously untreated patients with gastroesophageal cancer.”

The regulatory decision of trastuzumab deruxtecan as monotherapy was based on findings from the phase 2 DESTINY-Gastric01 trial (NCT03329690), in which the agent induced an overall survival (OS) benefit compared with chemotherapy in this patient population.

Now, additional questions regarding pneumonitis-related toxicities that have been observed with the agent and investigational combination strategies are also being evaluated in ongoing clinical trials, explained Ahn.

Other novel HER2-directed therapies, such as zanidatamab and tucatinib (Tukysa), are being evaluated as well as treatment for patients with HER2-positive gastrointestinal (GI) malignancies, said Manish A. Shah, MD.

“We have learned a lot about new targeted therapies for upper GI cancers,” said Shah, director of the Gastrointestinal Oncology Program at Weill-Cornell Medicine, and chief of the Solid Tumor Service and codirector of the Center for Advanced Digestive Disease at NewYorkPresbyterian Hospital. “There are novel drugs targeting HER2 as a proven pathway, and there are new pathways being discovered. It is really exciting to see the evolution of therapy in GI cancers.”

In interviews with OncLive® during the 2021 Gastrointestinal Cancers Symposium, Shah and Ahn discussed the emergence of HER2 as a validated target in GI malignancies, the approval of trastuzumab deruxtecan in gastric/GEJ cancer, and other emerging agents that are poised to propel HER2-targeted therapy in these diseases.

OncLive®: Is HER2 an actionable alteration across GI cancers?

Ahn: As we know, HER2 is overexpressed in several GI malignancies, most commonly gastroesophageal cancer. We also know that it is a relevant target in colorectal cancer [CRC], as well as gallbladder cancers.

Shah: Through all the drug development in gastroesophageal cancer, we’ve learned that [the disease is heterogenous]. HER2 is a validated target. The ToGA study [(NCT01041404) yielded] quite robust [data], and the improvement in survival with trastuzumab and chemotherapy is substantial for patients who [have high HER2 expression].

Why have the strategies that have proven activity in HER2-positive breast cancer not been as successful in GI malignancies?

Ahn: Various agents that have demonstrated a lot of antitumor activity in breast cancer have unfortunately failed to [show the same activity] in gastroesophageal cancers. The lack of activity [in gastroesophageal cancers] compared with breast cancers is likely due to various tumor-intrinsic factors, such as intralesional HER2 heterogeneity, intertumoral HER2 expression heterogeneity, and the effects of the immune system. However, over the past few years, we have seen a lot of activity with new strategies that target HER2 in gastroesophageal cancer.

Shah: We have seen a lot of the negative studies that included pertuzumab [Perjeta], T-DM1 [ado-trastuzumab emtansine; Kadcyla], and lapatinib [Tykerb]. [The results] suggest that many of the drugs that are active in breast cancer are not active in gastric cancer. However, because [HER2] is a validated target, it remains an active area of drug discovery.

This highlights the recent approval of trastuzumab deruxtecan. We saw a remarkable 50% response rate [with that agent] in the third-line setting [for patients with advanced or metastatic HER2-positive gastric/GEJ cancer]. Additionally, new agents include tucatinib and zanidatamab. These are active and exciting [agents]. We’ve learned that the smarter we are with understanding the disease, the smarter we are with applying the targets we know.

Trastuzumab deruxtecan was recently approved for patients with HER2-positive gastric/GEJ cancer who received prior trastuzumab-based therapy. How does the addition of this ADC affect the landscape, and what questions remain with the agent?

Ahn: Trastuzumab deruxtecan is interesting because it can kill cancer cells by its bystander effect of its payload. It is trastuzumab linked and bound to multiple topoisomerase-1 inhibitors. When trastuzumab homes in on the HER2-protein expression, the drug complex is internalized and releases the chemotherapy payload. This can then diffuse to the neighboring cancer cells to cause a bystander effect, which, theoretically, can affect the surrounding cells that do not express HER2. Unlike other HER2-specific agents, trastuzumab deruxtecan can have significant activity. As such, it received FDA approval on January 15, 2021, for gastroesophageal cancers with HER2 overexpression, which provides another treatment option [in this space].

[For example,] DESTINY-Gastric03 is a combination study with chemotherapy and various other agents [including trastuzumab deruxtecan]. That trial should help us have a better understanding of ADCs in the frontline setting.

One area of interest is the toxicity profile [of trastuzumab deruxtecan], based on what we saw from the DESTINY-Gastric01 trial. The data showed that about 9% to 10% of patients can develop pneumonitis-related toxicities, as well as some degree of cytopenias. Cytopenias are expected from ADCs, but pneumonitis-related toxicities are unique [to trastuzumab deruxtecan] compared with other ADCs. We haven’t seen these types of adverse effects with agents such as T-DM1.

What emerging agents should the field be on the lookout for?

Shah: Patritumab deruxtecan is similar to trastuzumab deruxtecan, but it targets HER3 instead of HER2. It uses the same linker-payload system as trastuzumab deruxtecan. In particular, [patritumab deruxtecan] has a high drug-to-antibody ratio, meaning it has a lot of molecules of the topoisomerase-1 inhibitor payload on the antibody. [The ADC] has shown some benefit in breast cancer and lung cancer, so we hope to see its efficacy across GI cancers, and certainly CRC.

Ahn: Another compound of interest is zanidatamab. This is a bispecific monoclonal antibody that targets the trastuzumab and pertuzumab binding sites. When we look at these data as a monotherapy, the objective response rate [ORR] is 33%, but it is as high as 57% in combination with chemotherapy. That was in a heavily pretreated patient population, so that offers another potential treatment strategy.

Another agent of interest is margetuximab[-cmkb (Margenza)]. This is an agent that has an Fc-engineering binding site to trastuzumab. Although [margetuximab] has the same affinity as trastuzumab, it has a high affinity to Fc-gamma receptors, which can be a mechanism of treatment resistance to HER2-targeted therapies. That agent is [being evaluated in] the phase 2/3 MAHOGANY trial [NCT04082364].

Combination strategies are also being looked at. A lot of these agents have demonstrated modest activity as monotherapy, but as we move forward, combination strategies will [become] very interesting.

A molecular profiling and clinical update of the PANTHERA trial was presented during the 2021 Gastrointestinal Cancers Symposium. What was significant about the updated findings?

Ahn: The PANTHERA trial [NCT02901301] was a phase 1b/2 trial conducted primarily in East Asia. It was a single-arm study [evaluating] the combination of platinum-fluoropyrimidine chemotherapy, pembrolizumab [Keytruda], and trastuzumab in HER2-positive advanced gastroesophageal cancers.

Clinical outcomes were very intriguing and similar to what were presented at the 2020 Gastrointestinal Cancers Symposium, which showed a median progression-free survival [PFS] of 8.6 months and a median OS of slightly under 20 months. The ORR was very high at 76.7%. Four of the 5 responders were found to have PD-L1negative [disease, indicating that] PD-L1 is not necessarily a predictive marker for response for these patients. Correlative work, including molecular profiling, was done as part of this study. This [work] looked consistent with what was seen from The Cancer Genome Atlas data.

However, [investigators] did note that certain HER2 alterations can be linked with secondary treatment resistance. Also, part of the inclusion criteria [for the PANTHERA trial] required [patients to be] HER2 positive. However, the correlative work regarding HER2 amplification by next-generation sequencing [showed that] high [HER2] expression was associated with patient outcomes in terms of OS and PFS.

Although the outcomes are intriguing, the randomized phase 3 KEYNOTE-811 [(NCT03615326) trial, evaluating pembrolizumab plus trastuzumab and chemotherapy], should offer confirmatory results about outcomes, as well as provide further data in terms of the ongoing correlative work of that study.


  1. Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: a randomized, phase II, multicenter, open-label study (DESTINY-Gastric01). J Clin Oncol. 2020;38(suppl 15):4513. doi:10.1200/JCO.2020.38.15_suppl.4513