At ESMO 2024, HER2-targeting antibody-drug conjugates (ADCs) generate significant attention as potential breakthroughs for HER2-positive cancers, particularly breast cancer, gastric cancer, and urothelial cancers. 

One of the most well-known and established HER2-targeting ADCs is KADCYLA (trastuzumab emtansine), developed by Genentech/Roche. Approved in 2013, KADCYLA did set the benchmark for HER2-targeting ADCs, with roughly 44,000 HER2+ breast cancer incident cases in the US (Delveinsight estimates), it has been a blockbuster backbone ADC in this cancer for over a decade. However, newer-generation HER2-targeting ADCs, ENHERTU (trastuzumab deruxtecan), are raising the bar with enhanced efficacy and broader applicability. Developed by Daiichi Sankyo and AstraZeneca, ENHERTU has become a major competitor to KADCYLA as KADCYLA reaches closer to losing its patent. It is approved for HER2-positive breast cancer in later lines and, more recently, for patients with HER2-low breast cancer, an important distinction as HER2-low was previously an untapped market. ENHERTU'S high drug-to-antibody ratio and potent payload have led to superior outcomes, with significantly better PFS and OS rates compared to KADCYLA. We see Enhertu replacing conventional untargeted chemo for all HER2-expressing cancers, after approval and use set to be expanded in all HER2-expressing cancers.

At ESMO 2024, ENHERTU is expected to feature prominently, with multiple data updates from ongoing trials in breast cancer and HER2-expressing gastric cancers. This would further solidify its position as a leading ADC, particularly as it moves into earlier treatment lines and across different cancer types.

The buzz at ESMO 2024 extends beyond ENHERTU, as new HER2-targeting ADCs aim to challenge the established players, among which are Pfizer’s Disitamab Vedotin, which is set to present data in treatment-naive HER2-expressing, locally advanced or metastatic urothelial carcinoma in combination with pembrolizumab. The drug has already gained approval in China in 2021 for HER2-positive gastric cancer and urothelial carcinoma. Another rising contender is Hangzhou Adcoris Biopharmacy’s ZV0203 in early phase. 

Unveiling the latest in HER2-targeting ADC space

• Abstract Number – LBA21
• Abstract Type – Mini oral session
• Indication – HR+/ HER2- metastatic breast cancer

Title: DESTINY-Breast06 data reveal another potential avenue for ENHERTU in HR+/ HER2-Low Metastatic Breast Cancer, and now in HER2-ultralow patient segment as well

Executive Summary: While results from DESTINY-Breast06 will be unveiled at ESMO 2024, early indications suggest that ENHERTU demonstrates impressive efficacy in both HER2-low and HER2-ultralow patients. 

Main Content –  

It is estimated that approximately 60-65% of HR+/HER2- breast cancers are HER2-low and potentially an additional 25% may be HER2-ultralow. Before the approval of ENHERTU in 2022 based on the DESTINY-Breast04 trial in HER2-low metastatic breast cancer, there were no targeted therapies approved specifically for patients with HER2-low expression. The DESTINY-Breast06 trial goes further by exploring its efficacy in the HER2-ultralow population, potentially broadening the scope of patients who can benefit from this therapy. The emerging notion of "HER2-ultralow" (IHC scores just below 1+ but above 0) raises questions about whether even lower levels of HER2 expression might still be targetable, driving the design of DESTINY-Breast06. 

The findings from DESTINY-Breast06 presented at the 2024 ASCO Annual Meeting showed statistically significant and clinically meaningful improvement in PFS vs investigator’s choice of chemotherapy in pretreated patients with HR+, HER2-low metastatic breast cancer. Notably, the PFS benefit was consistent in patients with HER2-ultralow disease. 

At ESMO 2024, the much-anticipated DESTINY-Breast06 study will be a focal point of discussion, with new insights into the classification of HER2-low and HER2-ultralow status in patients with HR+ metastatic breast cancer. If DESTINY-Breast06 confirms the efficacy of ENHERTU in HER2-ultralow patients, this ADC could become the go-to therapy for a broader range of HER2-expressing breast cancers, reinforcing its dominance in the ADC space.

• Abstract Number – 1967MO
• Abstract Type – Mini oral session
• Indication - Metastatic Urothelial Carcinoma

Title: Race to treat HER2-expressing cancers heats up as disitamab vedotin-pembrolizumab duo shows promise in HER2-positive urothelial carcinoma

Executive Summary: Disitamab Vedotin, an innovative ADC approved in China for HER2-positive cancers, may position it as a competitive force in HER2-positive urothelial carcinoma, with expected results at the ESMO 2024.

Main Content –  

Disitamab Vedotin, an innovative ADC, being developed by RemGen in China, has already gained approval in China in 2021 for HER2-positive gastric cancer and urothelial carcinoma. Currently, at the global level, the drug is undergoing evaluation in various trials, which will determine its potential in markets outside China, including the US and Europe, further intensifying the competition in the ADC market. One of the key differentiators of disitamab vedotin is its ability to target both HER2-positive and HER2-low expressing tumors. ENHERTU has already made headway in this space, but disitamab vedotin's broader binding capacity and innovative linker technology may provide an edge in certain patient populations.

The Phase II study evaluating the efficacy and safety of disitamab vedotin with pembrolizumab in treatment-naive HER2-expressing, locally advanced or metastatic urothelial carcinoma represents a significant exploration of HER2-directed therapies in urothelial carcinoma, a space where options remain limited for HER2-positive patients, making the combination of disitamab vedotin with pembrolizumab particularly intriguing. The rate of HER2 expression varies by the organ of origin of the urothelial carcinoma. For example, 70% of bladder urothelial carcinomas, 29% of ureter urothelial carcinomas, and 64% of renal pelvis urothelial carcinomas are HER2-positive. 

The full presentation of the RC48G001 Cohort C results at the ESMO 2024 is anticipated to provide further insights into the long-term potential of disitamab vedotin and its role in the evolving treatment landscape of urothelial carcinoma.

Top Abstracts for HER2-targeting ADCs