Targeted Agents Continue to Emerge for HER2+ GI Cancers

After HER2 was established as an actionable target in gastric cancer, its amplification has become a key biomarker of interest for other gastrointestinal cancers.

After HER2 was established as an actionable target in gastric cancer, its amplification has become a key biomarker of interest for other gastrointestinal (GI) cancers. In particular, the phase 2 HERACLES trial (NCT03225937), which showed the efficacy of combining the anti-HER2 agents trastuzumab (Herceptin) and lapatinib (Tykerb) for patients with HER2-positive metastatic colorectal cancer (CRC), led to a restored effort in exploring HER2-targeted agents in GI cancers, according to Andrea Sartore-Bianchi, MD.

Data from the trial showed the combination elicited an objective response rate (ORR) of 30% (95% CI, 14%-50%) in 27 patients with HER2-positive metastatic CRC, including 1 complete response and 7 partial responses.1 Additional research around HER2 amplification in CRC and other GI cancers has stemmed from that study, and more is planned, Sartore-Bianchi added.

“We have a renewed interest in HER2, because thanks to next-generation sequencing, we are now making more diagnoses [of actionable biomarkers] across tumors. As far as GI tumors are concerned, [HER2] is a very relevant target not only gastric cancer, but also in other GI tumors such as CRC and hepatobiliary cancer, for example,” Sartore-Bianchi explained.

In an interview with OncLive® during the 2022 ESMO World Congress on GI Cancer, Sartore-Bianchi, the head of Clinical Molecular Oncology in the Department of Hematology & Oncology at Grande Ospedale Metropolitano Niguarda and Università degli Studi di Milano in Milano, Italy, discussed his presentation from the conference, which focused on the evolution of HER2-targeted therapies in GI cancer and ongoing investigations of other agents for the potential treatment of this subset of patients.2

OncLive®: Could you elaborate on the prevalence of HER2 amplification in patients with GI cancer?

Sartore-Bianchi: We are learning that there are HER2 amplifications across the GI tract, such as in [esophageal and gastric cancer], where we know it is an established target. Amplification [occurs] in the range of 10%-15% [of patients].

There are also scattering amplifications in other portions [of cancers] of the GI tract. For example, in CRC, [HER2 is amplified in] up to 3%-5% of patients. [HER2 amplification can also be seen in] hepatobiliary and small bowel cancer. These are other tumor types where you can use [HER2]-targeted treatment.

How have therapies evolved in terms of targeting HER2 in GI cancer?

There has been an evolution over the years in HER2 targeting. But there is a renewed interest in targeting HER2 in CRC, [which] came from a more rational approach based on preclinical knowledge. For example, in CRC with the [phase 2] HERACLES trial, we based [the rationale] on a patient-derived xenograft model showing that the best strategy here is a double blockade with trastuzumab and lapatinib.

Thanks to advancements in pharmacological options and molecular diagnoses, we are now taking advantage of this knowledge, and we have more potent anti-HER2 strategies.

Are there any intriguing agents under investigation that could continue to change the paradigm for patients with HER2-amplified GI cancers?

Thanks to pharmacological evolution, we now have trials ongoing with other compounds. It will be important to look at the results of [the combination of] trastuzumab and tucatinib [Tukysa] in the [phase 2] MOUNTAINEER trial [(NCT03043313) in patients with HER2-positive CRC].

Also, an important ongoing trial is the [phase 2] DESTINY-CRC02 study [NCT04744831] with fam-trastuzumab deruxtecan-nxki [(Enhertu) in patients with HER2-overexpressing advanced or metastatic CRC]. This trial is interesting because it also included patients with RAS mutations.

What role could trastuzumab deruxtecan potentially play for patients with HER2-positive CRC?

We had results of trastuzumab deruxtecan in CRC from the [phase 2] DESTINY-CRC01 trial [NCT03384940]. A high overall response rate was observed at 45.3% with durable survival variables.

Interestingly, we did not see any efficacy in low [HER2] expressers. Efficacy was confined to [patients with HER2 positivity of 3+ by immunohistochemistry or 2+ by fluorescence in situ hybridization]. There are histotype differences in different tumor types, but it will be important to have confirmation of the data from the DESTINY-CRC02 trial.

What is the importance of genetic testing to identify HER2 and other targetable pathways in patients with GI cancer?

Results from HERACLES and other trials clearly indicated that HER2 is a relevant biomarker that should be tested in GI tumors. An important research question, as it is for any targeted treatment, is how to tackle secondary resistance. We know that at the end, resistance will arise under HER2-targeted treatment.

We have some data coming from HERACLES analyzing the liquid biopsy of patients with secondary mutations. This is an important field of investigation to enhance results that we can obtain with HER2-targeted treatment.


  1. Sartore-Bianchi A, Trusolino L, Martino C, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17(6):738-746. doi:10.1016/S1470-2045(16)00150-9
  2. Sartore-Bianchi A. Targeting the HER-2 pathway in GI cancer. Presented at: 2022 ESMO World Congress on Gastrointestinal Cancer; June 29-July 2, 2022; Barcelona, Spain.