This article has a total of2229words, reading time:3-4 minutes ｜Author: MaxTom

On May 29, 2025, Merck and Daiichi Sankyo jointly announced thevoluntary withdrawal of the market application for the HER3-targeted antibody-drug conjugate (ADC), Patritumab deruxtecan (HER3-DXd), which was originally seeking accelerated approval for the treatment of patients with advanced non-small cell lung cancer (NSCLC) who had received two or more systemic therapies. This event has sparked deep reflections on the future direction ofADC innovative drugs.

HER3-DXd’s setback

HER3-DXd was born with high expectations. It originates from Daiichi Sankyo’s uniqueDXd ADC technology platform, which is considered a benchmark in theADC field, featuring three core innovations.The new topoisomerase I inhibitorDXd is ten times more potent than the commonly used chemotherapy drugSN-38, making it extremely powerful. The peptide linker (GGFG) serves as a cleavable linker that can be specifically cleaved by enzymes within tumor cells, releasing the membrane-permeableDXd to precisely target tumor cells. The high drug-antibody ratio (DAR) design greatly enhances tumor-killing efficiency.

HER3 is expressed in up to75% of patients with EGFR-mutatedNSCLC, and is closely related to resistance toEGFR-TKI. The antibody of HER3-DXd,Patritumab, can block the formation of HER2/HER3 heterodimers, theoretically overcoming the bypass activation resistance problem afterEGFR-TKI treatment. In 2023, based on positive data from theII phase HERTHENA-Lung01 study,Merck was willing to pay$4 billion for its global rights[2] and listedHER3-DXd as the product closest to commercialization in their collaboration pipeline..

However,HER3-DXd‘s regulatory path has been fraught with challenges. In December 2023, a biologics license application (BLA) was submitted to the FDA based onII phase data, receiving priority review status. In June 2024, however, the FDA issued a complete response letter (CRL), but the rejection was due to defects in third-party manufacturing facilities, not the drug data itself. In September 2024, theIII phase HERTHENA-Lung02 study announced it reached the primary endpoint of progression-free survival (PFS), reigniting hopes for market approval. However, by May 2025, with the overall survival data revealed, the application was ultimately withdrawn voluntarily.

At the ASCO annual meeting in 2025, the results ofHERTHENA-Lung02 revealed the key reasons for the withdrawal of the market application.AlthoughPFS achieved statistical significance, the absolute benefit of 0.4 months was considered clinically insignificant. More critically, the overall survival (OS) data did not show significant improvement, and safety issues were prominent, with a thrombocytopenia incidence rate as high as30%, and the risk of interstitial lung disease (ILD) was particularly concerning.

Opportunities for ADC Innovative Drugs

Although the setback ofHER3-DXd is regrettable, it also brings new opportunities for the field ofADC innovative drugs.The challenges faced byHER3-DXd have prompted pharmaceutical companies and researchers to re-examineADC technology.This will drive in-depth research and innovation on key elements such as linkers, payloads, and antibodies.

For example, in terms of linkers, developing new types of linkers that are more stable and can precisely release payloads at tumor sites. For payloads, exploring alternatives with lower toxicity and better efficacy. In antibody design, pursuing higher tumor specificity and affinity. Some pharmaceutical companies have already begun to attempt to develop non-cleavable linkers forADC to reduce off-target toxicity, and the withdrawal ofHER3-DXd may accelerate the maturity and application of such technologies.

HER3-DXd’s failure in lung cancer indications does not mean it has no opportunities in other tumor types or combination therapy regimens. Researchers can reassessHER3’s expression and mechanism of action in other cancer types, exploring the therapeutic potential ofHER3-DXd in head and neck squamous cell carcinoma, gastric cancer, and other tumor types.

At the same time, combination therapy is also an important direction. CombiningHER3-DXd with immune checkpoint inhibitors or other targeted drugs may enhance efficacy through synergistic effects. Studies have shown that in certain cancer models,ADC drugs combined with immunotherapy can activate the immune system and enhance the killing effect on tumor cells.

For other latecomers in theHER3 ADC track and the entireADC field, the withdrawal ofHER3-DXd presents a rare opportunity for overtaking. Ming En Bio has publicly presented data on itsHER3 ADC drug DB-1310 at the ASCO conference, showing better clinical results thanPatritumab deruxtecan based on differentiated antibodies andADC structural design, offering new hope.

Baillie Tianheng’sEGFR/HER3 ADC drugiza-bren (BL-B01D1) has previously shown extraordinary efficacy in treating EGFR-mutated non-small cell lung cancer, and during this ASCO conference, further progress was demonstrated in non-EGFR classic mutation non-small cell lung cancer and small cell lung cancer, injecting new vitality into the development ofHER3 ADC drugs.

Challenges for ADC Innovative Drugs

HER3-DXd’s withdrawal highlights the regulatory agencies’ strict requirements for the efficacy and safety ofADC drugs. In terms of efficacy, it is essential to focus not only on alternative endpoints such asPFS, but also to ensure significant benefits inOS. An analysis of 260 solid tumorIII phase studies shows that the success rate of converting positivePFS to positiveOS is only38%.ADC drugs must be designed more scientifically and rationally in clinical trials to improve the success rate of convertingPFS toOS benefits.

Safety cannot be overlooked either.HER3-DXd’s occurrence of thrombocytopenia andILD and other severe adverse reactions has sounded the alarm for the entireADC field. During the development process, it is necessary to reduce side effects starting from drug structure design. For example, optimizing the combination of linkers and payloads to reduce off-target effects and avoid damage to normal tissue cells.

Developing ADC innovative drugs requires significant investment of time and resources. From target discovery, drug design, clinical trials to approval, each step is filled with uncertainty.HER3-DXd consumed enormous resources from development to the withdrawal of its market application. For pharmaceutical companies, how to allocate resources reasonably during the high-risk development process and balance innovation with risk is an urgent issue to be solved. At the same time, as competition intensifies, the risk of development failure is also increasing, and once a project fails, the initial investment will be wasted.

The ADC field has become a hot track for global pharmaceutical companies to compete. Many companies are laying out their strategies, including industry giants like Daiichi Sankyo and Merck, as well as numerous emerging biotech companies. This fierce market competition requires pharmaceutical companies to possess unique technological advantages, efficient R&D capabilities, and precise market positioning to stand out in the competition.

Conclusion

HER3-DXd’s withdrawal of the market application undoubtedly brings a shock to the field ofADC innovative drugs, but there are also opportunities in the midst of crisis. Through technological iteration, expanding new indications and combination therapies, and the proactive efforts of latecomers,ADC innovative drugs are expected to usher in a new stage of development. Of course, the road ahead is fraught with challenges, including improving efficacy and safety, controlling development costs and risks, and responding to intense market competition, all of which require the joint efforts of pharmaceutical companies, researchers, and regulatory agencies.

In the difficult battle against cancer,ADC innovative drugs are one of the important weapons, and their development is crucial. We hope that the medical community can learn from the experience ofHER3-DXd’s event, seizing opportunities amidst challenges, and continuously promoting the progress ofADC innovative drugs to provide more effective treatment options for cancer patients, writing a new chapter in the fight against cancer.

References:

1. Patritumab Deruxtecan Biologics License Application for Patients with Previously Treated Locally Advanced or Metastatic EGFR-Mutated Non-Small Cell Lung Cancer Voluntarily Withdrawn, May 29, 2025, Daiichi-Sankyo website

2. Daiichi Sankyo and Merck Announce Global Development and Commercialization Collaboration for Three Daiichi Sankyo DXd ADCs, October 19, 2023, Merck website

Written by丨MaxTomOperation丨Yu YuImage source丨Wenxin Yiyan, Health Kaige Research InstituteEdited by丨Xiao Ran, Hong JieThank you for your likes and follows!⭐