The development of HER2-targeted therapies has dramatically changed the treatment landscape for many patients with cancer. Initially, HER2-targeted antibodies demonstrated improved outcomes in patients with breast cancer and HER2 amplification. More recently, novel HER2-targeted strategies using ADCs have also expanded into other solid tumor types, including gastric and gastroesophageal junction (GEJ), colorectal, bladder, biliary tract, and endometrial cancers.

As a class, HER2-targeted therapies can be used to interrupt oncogenic ERBB signaling in cancer with HER2 alterations (eg, protein overexpression, gene amplification, or gene mutations). There are a few different types of HER2-targeted therapy, including nonselective (pan-HER) tyrosine kinase inhibitors (TKIs), selective TKIs, antibody therapy, and ADCs. Nonselective TKIs inhibit the intracellular kinase domains of multiple ERBB receptors (EGFR/HER1, HER2, HER3, HER4), broadly suppressing phosphorylation cascades. Selective HER2 TKIs preferentially block the HER2 kinase domain, limiting off-target EGFR effects while disrupting HER2-driven pathways. Monoclonal antibodies to HER2 bind the extracellular receptor to prevent dimerization and signaling and can recruit immune effector functions such as antibody-dependent cellular cytotoxicity. ADCs pair an anti-HER2 antibody with a cytotoxic payload. After receptor binding and endocytosis, the payload is released intracellularly to induce tumor-cell death.

In this module, we will be focusing on HER2-targeted ADCs, as this treatment class has been shown to have the most significant efficacy in various solid tumors.

ADCs are engineered therapeutics designed for targeted chemotherapy delivery. They consist of a monoclonal antibody targeting a tumor-associated antigen, such as HER2, linked to a potent cytotoxic payload via a specialized chemical linker. Following binding to the HER2 receptor on a cancer cell, the ADC-receptor complex is internalized into the cell. Within the lysosome, the linker is cleaved, releasing the cytotoxic payload. This release mechanism not only kills the target cell but can also induce a "bystander effect," where the payload diffuses out to kill adjacent tumor cells that may not express the target antigen, while largely sparing other healthy tissues throughout the body.¹ Key characteristics, including linker stability, the class of payload (eg, topoisomerase I inhibitors vs microtubule disruptors), and the drug-to-antibody ratio, are critical determinants of an ADC's efficacy, distribution, and safety profile.²

There are currently 3 different HER2 ADCs that are approved worldwide, including trastuzumab emtansine (T-DM1) for HER2-positive breast cancer; T-DXd for HER2-positive breast cancer, HER2-low and HER2-ultralow breast cancer, HER2-positive gastric or GEJ adenocarcinoma, HER2-positive solid tumors, and HER2-mutated NSCLC; and disitamab vedotin which is approved in China for HER2-positive gastric cancer, HER2-positive urothelial cancer (UC), and HER2-positive breast cancer.

In this module, we will talk about current clinical trial data for patients with GU, GI, and GYN cancer.

On April 5, 2024, T-DXd was granted accelerated approval by the FDA for adults with unresectable or metastatic HER2-positive (IHC3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options, based in part on data from the phase II DESTINY-PanTumor02 trial.

DESTINY-PanTumor02 is an open-label, multicenter, phase II trial that enrolled 267 patients with locally advanced, unresectable, or metastatic solid tumors and HER2 expression (IHC 3+ or 2+)—including endometrial, cervical, ovarian, bladder, biliary tract, and pancreatic cancers or those with other solid tumors excluding breast, colorectal, gastric, and non-small-cell lung cancers (NSCLC)—with disease progression after 1 or more prior treatment or with no satisfactory alternatives. Patients received T-DXd at a dose of 5.4 mg/kg once every 3 weeks. Treatment with T-DXd continued until documented disease progression (RECIST 1.1), withdrawal of consent, or when discontinuation criteria were met.

The primary endpoint of this trial was investigator-assessed confirmed ORR. Secondary endpoints included DoR, disease control rate, PFS, OS, and safety.

In the DESTINY-PanTumor02 trial, the confirmed ORR across all patients was 37.1%. In the cohort with high HER2 expression (IHC 3+), the ORR was 61.3%. Responses were durable, with a median DoR of 11.3 months in the overall population and 22.1 months in the IHC 3+ group.³

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). Patients with bladder cancer achieved an ORR of 39.0% overall, with an ORR of 56.3% in the IHC 3+ cohort. Patients with biliary tract cancer (BTC) achieved an ORR of 22.0%, but those with IHC 3+ had similar ORR to the bladder cancer cohort, at 56.3%.

These ORR data suggested promising efficacy with T-DXd across in patients with HER2-expressing solid tumors.

In addition to efficacy, it is important to consider safety data. In all 267 treated patients with various malignancies in DESTINY-PanTumor02, most experienced a drug-related treatment-emergent adverse event (AE) (84%) and 39% had a grade ≥3 event. Interstitial lung disease (ILD)/pneumonitis is an established risk with T-DXd and was observed in 20 patients (7.5%). Most of these were low-grade events, but there was 1 death (0.4%) related to ILD/pneumonitis.

In addition to ILD, a small number of patients may experience cardiac AEs. In this trial, 2.6% of patients experienced ejection fraction decrease and 1 patient experienced cardiac failure.

The most common AEs with T-DXd are more easily managed and include GI toxicity and cytopenias. More specifically, nausea, fatigue, neutropenia, anemia, and diarrhea were the most common AEs and were reported in ≥25% of patients.

DESTINY‑PanTumor01, a phase II basket study, evaluated T‑DXd 5.4 mg/kg in patients with heavily pretreated solid tumors harboring activating HER2 mutations. Independent central review confirmed an ORR of 29.4% with 2 patients achieving a complete response. Overall, responses were durable, with the median DoR not reached. Median PFS was 5.4 months, and median OS was 10.9 months. Grade ≥3 treatment‑emergent AEs occurred in 51% of patients, with adjudicated drug‑related ILD/pneumonitis reported in 11% of patients, including 2 grade 5 fatalities.

These results underscore that T‑DXd can achieve meaningful antitumor activity across HER2‑mutated solid tumors and support ongoing tumor‑agnostic development.⁴ Based on these data and additional data from the pivotal DESTINY-Lung01 trial which demonstrated significant efficacy with T-DXd 6.4 mg/kg every 3 weeks in patients with HER2-mutant NSCLC, T-DXd was granted accelerated approval for adults with metastatic NSCLC with a HER2 mutation who have received a prior systemic therapy.

Although the approval of T-DXd in HER2-mutant NSCLC is another large step forward, more data are needed to understand optimal use of T-DXd in other solid tumors with HER2 mutations. For now, we will go into a more in-depth analysis of HER2-targeted ADCs for patients with GYN, GU, and GI malignancies.

The phase II DESTINY‑PanTumor02 trial evaluated T‑DXd in patients with endometrial, cervical, and ovarian cancers expressing HER2. In endometrial cancers, HER2 overexpression (IHC 3+) is most frequently seen in the aggressive uterine serous subtype, occurring in approximately 15%-30% of cases.⁵ Within the trial’s endometrial cohort, T‑DXd achieved an objective response rate (ORR) of 57.5% overall and an impressive 84.6% in the IHC 3+ subgroup. In the overall cohort of patients with endometrial cancer, the median PFS and OS were 11.1 months and 26.0 months, respectively, and median DoR was not reached.³ These results underscore the potential benefit of T‑DXd for HER2‑expressing endometrial cancers, particularly in tumors with IHC 3+ expression.

In the cervical cohort, the ORR was 50% overall, rising to 75% among patients with HER2 IHC 3+ expression. The median DoR was 14.2 months, median PFS was 7 months, and median OS reached 13.6 months for the whole cohort. OS was not reached for the IHC 3+ subgroup.³ These findings reinforce T‑DXd as a promising therapeutic option for advanced cervical cancer. HER2 overexpression is less common in ovarian cancer, especially in high‑grade serous tumors, but it can be enriched in mucinous subtypes.⁶

In DESTINY‑PanTumor02, the overall ovarian cancer cohort had an ORR of 45.0%, with patients harboring HER2 IHC 3+ tumors achieving an ORR of 63.6%.³ Median PFS and OS were 5.9 months and 13.2 months overall, and 12.5 months and 20.0 months in the IHC 3+ subgroup. Median DoR was 11.3 months for the overall cohort and extended to 22.1 months for the IHC 3+ cohort.^6,7 These outcomes highlight T‑DXd as a promising treatment for HER2‑positive ovarian cancer, particularly in tumors with high HER2 expression.

Approximately 15% of metastatic UCs overexpress HER2 (IHC 3+ or IHC 2+ and in situ hybridization [ISH]/fluorescence in situ hybridization+), while roughly half of tumors fall into the HER2‑low category (IHC 1+ or IHC 2+/ISH-).¹²

Within the bladder cancer cohort of the DESTINY‑PanTumor02 trial, T‑DXd achieved an ORR of 39%. Responses were most pronounced in patients with HER2 IHC 3+ tumors who had a 56% ORR, whereas those with IHC 2+ expression had a 35% ORR. The median PFS was 6.9 months, the median OS was 13.4 months, and median DoR across the cohort was 8.7 months.³ 

These results suggest encouraging clinical activity with T‑DXd in patients with HER2‑expressing UC after progression on previous therapy, with particularly robust benefit observed in tumors with IHC 3+ expression.

Another HER2-targeted ADC, disitamab vedotin, is being assessed in patients with HER2-positive UC. A combined analysis of 2 open-label, multicenter, single-arm phase II clinical trials evaluated the efficacy and safety of disitamab vedotin in patients with HER2-positive (IHC 3+ or 2+) locally advanced or metastatic UC. Patients with bladder cancer who had progression after 1 or more previous line of systemic chemotherapy were enrolled and received disitamab vedotin 2 mg/kg intravenously every 2 weeks. The primary endpoint of this trial was ORR assessed by blinded independent review committee. Although these were 2 separate trials, they were designed relatively similarly and were pooled for analysis. The ORR with disitamab vedotin was 50.5%, with a median DoR of 7.3 months. The median PFS was 5.9 months, and the median OS was 14.2 months.¹³

There is an ongoing open-label, multicenter, multicohort phase II trial exploring disitamab vedotin with or without pembrolizumab in patients with HER2-expressing locally advanced/metastatic UC (NCT04879329). Early data from cohort C reported an ORR of 61.1% with disitamab vedotin plus pembrolizumab, suggesting promising activity.¹⁴

Further, the phase II RC48-C017 trial is evaluating neoadjuvant disitamab vedotin in combination with the PD-1 inhibitor toripalimab in muscle-invasive bladder cancer with HER2 expression IHC ≥1+ (n = 47). In this combination regimen, pathologic complete response rate was 63.6%, and 84.6% in those with HER2 IHC 3+ disease, highlighting the promise of ADC/immunotherapy combinations in the perioperative setting.¹⁵

Currently, disitamab vedotin has an approval by China’s National Medical Products Administration for patients with HER2-overexpressing locally advanced or metastatic urothelium carcinoma previously treated with platinum-based chemotherapies, as well as in HER2-overexpressing locally advanced or metastatic gastric carcinoma after 2 or more lines of systemic chemotherapy, and HER2-positive advanced breast cancer with liver metastasis after treatment with trastuzumab and taxanes.

In GI cancers, we have considerable data supporting the use of HER2 testing and HER2-based therapy. The incidence of HER2 alterations in GI cancers ranges from approximately 15%-25% in esophagogastric cancers to approximately 3%-10% for colorectal cancer (CRC), GI neuroendocrine cancer, and pancreatic cancer. The rate of various HER2 alterations can vary even within a specific GI tumor type. For example, in BTC, HER2 gene amplifications occur in approximately 5%-15% of BTCs while protein overexpression occurs in approximately 20%.¹⁷

In current clinical practice, HER2-targeted ADCs are options for many patients with GI cancers. T-DXd can be considered as a biomarker-directed treatment option for patients who have BTC with progressive disease after primary treatment (based on DESTINY-PanTumor02) or as second-line and later therapy for CRC (based on DESTINY-CRC01 and DESTINY-CRC02) under the tumor agnostic FDA accelerated approval of T-DXd for unresectable or metastatic HER2‑positive (IHC 3+) tumors after prior systemic treatment and no alternative treatment options. T-DXd is also FDA approved for locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH positive) gastric or GEJ cancer after a prior trastuzumab-based regimen based on the DESTINY-Gastric01 trial.¹⁸ Next, we will go into some detail about each of these studies.

In DESTINY‑PanTumor02, T‑DXd 5.4 mg/kg was evaluated in a cohort of patients with BTC. The investigator‑assessed ORR was 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 BTC 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.³ 

These results supported the tumor‑agnostic approval of T‑DXd for previously treated metastatic HER2‑positive (IHC 3+) solid tumors and suggest a role for T-DXd in patients with HER2+ BTC.¹⁹

In metastatic colorectal cancer (mCRC), approximately 2%-5% of tumors harbor HER2 amplification. Data suggest that HER2‑positive metastatic CRC represents a distinct subset of patients with mostly left-sided or distal cancer as well as a higher incidence of lung or brain metastases. In patients with HER2-amplified and RAS/BRAF wild-type metastatic CRC, the initial treatment is typically trastuzumab plus either pertuzumab, lapatinib, or tucatinib.

Subsequently, the phase II HERACLES-B trial evaluated T-DM1 in refractory HER2-positive mCRC, but yielded a low response rate of 5.6%.²⁰

However, the DESTINY‑CRC01 trial evaluated T‑DXd 6.4 mg/kg in heavily pretreated HER2‑positive mCRC. 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 ORR 57.5% in IHC 3+ tumors.^21,22

The DESTINY-CRC02 trial assessed T-Dxd at 5.4 mg/kg and 6.4 mg/kg in patients with HER2-positive mCRC. 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 vs 29.4% in the 6.4 mg/kg arm. The median PFS was 5.8 months vs 5.5 months and the median DoR was 5.5 months in both arms. Median OS was 13.4 months in the 5.4 mg/kg arm and not yet reached in the 6.4 mg/kg arm.¹⁸

Data from DESTINY-CRC02 and DESTINY-PanTumor02 have led to the recommendation to consider T-DXd as an option for second-line therapy (or beyond) for patients with HER2‑positive CRC.²³

Numerous studies have evaluated anti-HER2 therapies in gastric and GEJ cancers, including the phase II DESTINY‑Gastric01 and DESTINY‑Gastric02 trials.

The randomized phase II DESTINY‑Gastric01 study evaluated T-DXd vs investigator’s choice of chemotherapy in patients of Asian descent with HER2-positive recurrent gastric and GEJ cancers after 2 previous treatments. This trial reported an ORR of 51% with T‑DXd vs 14% with chemotherapy (HR: 0.59; P <.0001), a median PFS of 5.6 with T-DXd vs 3.5 months with chemotherapy (HR: 0.47), and a median OS of 12.5 with T-DXd vs 8.4 months with chemotherapy (HR: 0.60).²⁴

The phase II DESTINY-Gastric02 trial enrolled patients from Western countries who had unresectable or metastatic HER2-positive gastric or GEJ cancer (on postprogression biopsy) and progression on or after first-line treatment with trastuzumab. This trial reported an ORR of 42%, a median PFS of 5.6 months, and median OS of 12.1 months.²⁵

Taken together, these data 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 received a prior trastuzumab-based regimen.

More recently, the phase III DESTINY‑Gastric04 trial compared T‑DXd 6.4 mg/kg every 3 weeks with ramucirumab plus paclitaxel as second‑line therapy for HER2‑positive gastric/GEJ cancer. T‑DXd significantly improved outcomes with median OS 14.7 months vs 11.4 months, median PFS 6.7 months vs 5.6 months, and ORR 44.3% vs 29.1%; median DoR was 7.4 months vs 5.3 months. These data established T‑DXd as the new standard second‑line therapy for HER2‑positive gastric/GEJ cancer.²⁶

The paradigm-shifting success of T-DXd in HER2-low (IHC 1+ or 2+/ISH-) breast cancer has spurred additional investigation into its activity in other HER2-low solid tumors, including GI, GU, and GYN malignancies.²⁷ For example, exploratory results from the DESTINY-Gastric01 trial suggested a potential benefit of T-DXd in patients with HER2-low gastric cancer. Preliminary results from these cohorts suggested potential activity in this population.²⁸ Future research will elucidate optimal sequencing and combination strategies to expand the benefit of ADCs.