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HER2 ADCs in GI, GU, and GYN
HER2: Biology, Testing, and ADC-Based Treatment in Gastrointestinal, Genitourinary, and Gynecologic Malignancies

Released: August 25, 2025

Catherine Fahey
Catherine Fahey, MD, PhD
Alexandra Leary
Alexandra Leary, MD, PhD
Zev A. Wainberg
Zev A. Wainberg, MD
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Key Takeaways
  • Completing HER2 testing at the time of diagnosis of advanced/metastatic GI, GU, and GYN malignancies is essential for therapy and future clinical trial enrollment.
  • Treatment with trastuzumab deruxtecan (T-DXd) across multiple tumor types and HER2 overexpression (IHC 2+/ISH+ and/or IHC 3+) can result in objective and durable responses.
  • Preparing for adverse event (AE) management during ADC therapy can help optimize outcomes for patients by identifying AEs early and preemptively considering dose holds and adjustments as needed.

Introduction
The development of HER2-targeted therapy was one of the initial targeted treatments for cancer and has dramatically changed the treatment landscape. Initially, HER2-targeted antibodies demonstrated improved outcomes in patients with certain types of cancer that had HER2 amplification (eg, breast and gastrointestinal [GI] cancers). More recently, novel HER2-targeted antibody–drug conjugates (ADCs) have expanded into breast cancer, lung cancer, and other solid tumor types, including gastric and gastroesophageal, colorectal, bladder, biliary tract, and endometrial cancers.

ADCs combine the targeting precision of monoclonal antibodies with the cytotoxicity of chemotherapy and are now approved in multiple tumor types. HER2-targeted ADCs are options for many patients with GI, genitourinary (GU), and gynecologic (GYN) cancers with HER2 alterations, including overexpression, amplification, or activating mutations. This commentary offers key actionable clinical pearls for the use of HER2-targeted ADCs in patients with GI, GU, and GYN malignancies. For additional information, please listen to our podcasts and review the detailed Medical Minute text modules, found here.

Understanding HER2 Scoring Principles
Results from accurate HER2 testing determine whether patients with GI, GU, or GYN cancers are eligible for HER2-targeted treatment, including with HER2-targeted ADCs. Classic HER2 testing criteria and ASCO/CAP HER2 testing guidelines define HER2-positive disease as immunohistochemistry (IHC) 3+ or IHC 2+ with in situ hybridization (ISH) amplification, whereas IHC 2+ with ISH negative and IHC 0/1+ indicate HER2-negative scoring. However, different HER2 testing guidelines have been necessary for gastric cancer, colorectal cancer, and other GI cancers. We now have a fairly uniform recognition of what is considered HER2-positive in breast cancer as well as in gastric and gastroesophageal junction (GEJ) tumor samples, but we still do not know the best guidelines to use in all solid tumors, and guidelines on HER2-low and HER2-ultralow cancers continue to evolve. Regardless of testing methodology, the presence of HER2 IHC 3+ is an indication for HER2-targeted therapy across all solid cancers.

Beyond HER2 protein overexpression, next-generation sequencing can identify HER2-activating mutations. Sequencing results may indicate eligibility for clinical trial enrollment and potential future options for treatment. In general, HER2 testing may be initiated when next-generation sequencing panels are ordered at metastatic presentation or progression, often as part of broader biomarker profiling. 

In clinical practice, two scoring pitfalls may occur, which require vigilance: (1) Institutions may apply breast vs gastric scoring schemas inconsistently and (2) preanalytical/analytical variables (antibodies, tissue handling, reporting) can shift calls at the margin. These variables make close collaboration with pathology essential to harmonize criteria.

Application of HER2 With Treatment Guidelines

Tumor-Agnostic Indication
On April 5, 2024, the FDA granted accelerated approval to trastuzumab deruxtecan (T-DXd) for previously treated, unresectable/metastatic HER2-positive (IHC 3+) solid tumors, supported by DESTINY-PanTumor02. In this trial, patients with locally advanced, unresectable, or metastatic solid tumors and HER2 expression (IHC 3+ or 2+) were enrolled and receive T-DXd. Among all patients, the objective response rate (ORR) was 37.1% (n = 99; 95% CI: 31.3%-43.2%) and was 61.3% in those with IHC 3+ disease (n = 75; 95% CI: 49.4%-72.4%). The median duration of response was 11.3 months (95% CI: 9.6-17.8) in the overall patient population and 22.1 months (95% CI: 9.6-not reached) in patients with IHC 3+ expression.

GYN Cancers
In the DESTINY-PanTumor02 trial, patients with GYN malignancies achieved the highest ORRs across all studied tumor types (57.5% for endometrial, 50.0% for cervical, 45.0% for ovarian), with even higher ORRs in just those patients with IHC 3+ disease (84.6% for endometrial, 75% for cervical, 63.6% for ovarian). These data support incorporating early and routine HER2 testing at diagnosis of endometrial, cervical, and ovarian cancers.

GU Cancers
Urothelial carcinoma demonstrates HER2 overexpression in 15% to 20% of patients. In DESTINY-PanTumor02, 16 of 41 patients (39%) with bladder cancer had HER2 IHC 3+ status tumors. The ORR for all enrolled patients with bladder cancer was 39.0% (95% CI: 24.2%-55.5%) and 56.3% (n = 16; 95% CI: 29.9%-80.2%) for patients with HER2 IHC 3+. Results further stress the importance of baseline HER2 testing for patients with urothelial cancer at diagnosis alongside PD-L1/FGFR3. Another HER2-targeted ADC, disitamab vedotin, is also under active investigation for HER2-overexpressing cancers, including urothelial cancer.

GI Cancers
In current clinical practice, HER2-targeted ADCs are options for many patients with GI cancers, based on a few trials including DESTINY-PanTumor02, DESTINY‑Gastric01, DESTINY‑Gastric02, DESTINY-CRC01, and DESTINY-CRC02. Data from the DESTINY‑Gastric01 and DESTINY‑Gastric02 trials led to the FDA approval of T-DXd for patients with locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH positive) gastric or GEJ cancers who have previously received a trastuzumab-based regimen. More recently, the randomized phase III DESTINY-Gastric04 trial established T-DXd as a new standard over ramucirumab plus paclitaxel as second-line therapy for HER2-positive gastric cancer or GEJ adenocarcinoma, with improvement in ORR from 29.1% to 44.3% and median overall survival (OS) from 11.4 months to 14.7 months (HR: 0.70; 95% CI: 0.55-0.90; P = .004).

For biliary tract cancer, DESTINY-PanTumor02 demonstrated an ORR of 22.0% in the overall population, with a median PFS of 4.6 months and median OS of 7.0 months. In the cohort of patients with biliary tract cancer and HER2 IHC 3+, the ORR was 56.3%, with a median PFS of 7.4 months and a median OS of 12.4 months. These data support consideration of T-DXd for this patient population after standard options have been exhausted.

The DESTINY‑CRC01 trial evaluated T‑DXd 6.4 mg/kg in heavily pretreated HER2‑positive metastatic colorectal cancer. In cohort A (HER2 positive, IHC 3+ or IHC 2+/ISH+), the confirmed ORR was 45.3%, with a median PFS of 6.9 months and median OS of 15.5 months. Subgroup analysis showed an ORR of 57.5% in IHC 3+ tumors. The DESTINY-CRC02 trial assessed T-DXd at 5.4 mg/kg and 6.4 mg/kg in patients with HER2-positive metastatic colorectal cancer. This trial demonstrated that the lower dose offered the optimal balance of efficacy and tolerability, with an ORR of 37.8% at 5.4 mg/kg and 27.5% at 6.4 mg/kg. Among patients with IHC 3+ tumors, ORR was 46.9% in the 5.4-mg/kg arm and 29.4% in the 6.4-mg/kg arm.  

Management of Adverse Events
Since ADCs are linked to cytotoxic compounds, they carry payload-specific risks that require anticipatory vigilance and subsequent adverse event (AE) management. Some AEs associated with ADCs, like cytopenias, anemias, diarrhea, nausea, and alopecia, are already familiar to oncologists treating patients with cancer and may require dose reductions. Other AEs, like interstitial lung disease (ILD), are specific to certain ADCs.

The toxicity profile for each ADC is mainly driven by the payload used: For T-DXd, with a topoisomerase I inhibitor payload, and for disitamab vedotin, with a monomethyl auristatin E payload, the key toxicities differ. For T-DXd, ILD/pneumonitis and decreased ejection fraction have been observed in a small percentage of patients enrolled in the DESTINY clinical trials. For T-DXd, recommendations emphasize proactive radiographic monitoring and early workup to catch asymptomatic pneumonitis or ILD. In patients with suspected, asymptomatic (grade 1) ILD, T-DXd should be held while symptoms are assessed, a CT scan is completed for confirmation of ILD, and alternate causes such as infection or pneumonia (eg, with blood cultures, bronchoscopy) are ruled out. For management of confirmed grade 1 ILD/pneumonitis, T-DXd should be held and corticosteroids (prednisolone 0.5 mg/kg/day) may be considered. T-DXd can be restarted if symptoms resolve within ≤28 days of onset. For those in whom ILD persists past 28 days from onset, treatment should be restarted only with caution after full resolution and at a reduced dose. However, if grade 1 ILD has not resolved within 49 days from last infusion, as well as for any grades 2-4 ILD, T-DXd should be discontinued and systemic corticosteroid treatment (eg, prednisolone ≥1 mg/kg/day or equivalent for ≥14 days, followed by taper for ≥4 weeks) should be started immediately.

For vedotin-based ADCs, the concerns with treatment-related AEs include gastrointestinal events, cytopenias, peripheral neuropathy, and skin events (eg, rash). Healthcare professionals should be prepared to hold the drug and evaluate the patient for safe administration. For more details on AEs with HER2-targeted ADCs, please listen to the podcast, found here.

Summary
Operational protocols that standardize early HER2 testing are necessary for incorporating HER2-targeted ADC treatment options into the clinical practice. This is essential given the outcomes achieved using T-DXd in various solid tumors, including GI, GU, and GYN malignancies. With an approved tumor-agnostic indication, broad testing for HER2 alterations is clinically justified.

Your Thoughts
How are your teams operationalizing HER2 testing (schema, reflex ISH, and timing)? Have you incorporated HER2-targeted ADCs for your patients with GI, GU, and GYN malignancies?

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