Strategic Value Assessment of Kelun Biotech's Focus on HER2 ADC Drug Resistance Scenarios

Based on the collected information, I now provide you with a systematic and comprehensive analysis report.

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HER2-targeted antibody-drug conjugates (ADCs) have become one of the most commercially valuable and technologically challenging tracks in breast cancer treatment. Since the launch of Enhertu (trastuzumab deruxtecan, T-DXd), this drug has redefined the treatment standard for HER2-positive breast cancer with its breakthrough efficacy, and successfully expanded its indications to the HER2-low expression field, forming a comprehensive replacement trend for traditional HER2-targeted therapies [1][2].

From a global competitive landscape perspective, the current HER2 ADC market exhibits the following characteristics:

Drug	Developer	Toxin Type	DAR	Approved Indications	Features
Enhertu	Daiichi Sankyo/AstraZeneca	Dxd (Topoisomerase I inhibitor)	8	HER2+ breast cancer, HER2-low expression breast cancer, gastric cancer, lung cancer	Leading efficacy, higher ILD risk
T-DM1	Roche	DM1 (Microtubule inhibitor)	3.5	Second-line HER2+ breast cancer	Good safety but limited efficacy
Disitamab Vedotin	Rongchang Biotech	MMAE (Microtubule inhibitor)	4	Gastric cancer, urothelial carcinoma	Differentiated indication layout
A166	Kelun Biotech	Duo-5 (MMAF derivative)	2	Second-line HER2+ breast cancer	Potentially optimal safety

Enhertu has established significant advantages in clinical efficacy through its unique molecular design (high DAR value of 8, potent topoisomerase I inhibitor Dxd, and prominent bystander effect). In the DESTINY-Breast03 study, Enhertu demonstrated overwhelming efficacy advantages over T-DM1, with a median PFS of 28.8 months, becoming the new standard for second-line treatment of HER2-positive breast cancer [1].

However, Enhertu still faces several challenges in clinical application:

• Safety Risks
  : The incidence of interstitial lung disease (ILD) is approximately 2.9%-8.8%, and some patients discontinue treatment due to severe toxicity [3][4]
• Drug Resistance Issue
  : With the popularization of Enhertu in first-line treatment, treatment options after resistance will become an increasingly urgent clinical need
• Administration Restrictions
  : Has embryonic toxicity, contraindicated in pregnant patients

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Kelun Biotech’s Botuzumab (A166, trade name: Shutailai®) was approved for marketing by China’s NMPA on October 17, 2025, as the first domestic ADC drug approved for second-line treatment of HER2-positive breast cancer [5][6].

Component	A166 Design	Comparison with Enhertu
Antibody	Trastuzumab	Identical
Toxin	Duo-5 (MMAF derivative, microtubule inhibitor)	Enhertu uses Dxd (topoisomerase I inhibitor)
Linker	Protease-cleavable linker	Both are cleavable designs
DAR	2	Enhertu is 8
Conjugation Method	Random lysine conjugation	Site-specific cysteine conjugation

A166 adopts a

strategy, which stands in sharp contrast to Enhertu’s high DAR, potent toxin strategy. The core consideration behind this design trade-off is balancing efficacy and safety [3][4].

Efficacy Endpoint	A166	T-DM1	Magnitude of Advantage
Median PFS	11.1 months	4.4 months	152% increase
Objective Response Rate (ORR)	76.9%	53.0%	23.9 percentage points increase
Complete Response Rate	Approximately 2.5%	0%	-

This study enrolled patients with HER2-positive unresectable or metastatic breast cancer who had previously received trastuzumab and taxane-based therapy. The results showed that A166 achieved improvements in the primary endpoint PFS that were both statistically and clinically significant [5][6].

In heavily pretreated HER2+ breast cancer patients (4.8mg/kg dose group):

• ORR reached
  73.9%
• Median PFS was
  12.3 months
• Disease Control Rate (DCR) was 100%

Notably, the median number of prior anti-HER2 treatment lines for enrolled patients reached

, 94.8% received HER2-targeted TKI therapy, and 20.7% received other HER2-ADC therapies, indicating that A166 still demonstrates strong efficacy in later-line patients [7][8].

The most prominent differentiated advantage of A166 lies in its

:

Safety Endpoint	A166	Enhertu	SHR-A1811
Grade ≥3 Adverse Reactions	49.4%	67.5%	50%
Serious Adverse Reactions	4.9%	37.5%	-
Interstitial Lung Disease (ILD)	0%	2.9%-8.8%	-
Discontinuation Due to Adverse Reactions	5.7%	12.5%	-

A 0% ILD incidence is A166’s most notable safety advantage, which holds important clinical significance for breast cancer patients requiring long-term treatment [3][4][7].

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As Enhertu has become the standard second-line treatment for HER2-positive breast cancer globally, treatment options after resistance are becoming an increasingly urgent unmet clinical need. According to the latest research presented at the 2025 ASCO Annual Meeting, ADC resistance mechanisms mainly include [9]:

1. High Expression of Drug Efflux Transporters
   : High expression of ABCB1 and ABCC1 is significantly associated with shorter treatment duration of T-DXd
2. Changes in Target Antigen Expression
   : Changes in ERBB2 amplification status affect ADC efficacy
3. Alterations in Intracellular Drug Metabolic Pathways
   : Lysosomal dysfunction, internalization impairment

• Median time to next treatment (TTNT) for ERBB2-amplified patients receiving T-DXd reached 22.5 months
• Median TTNT for the non-amplified group was only 6.4 months
• Patients with high ABCB1 expression had a 30% increased risk of death (HR=1.30, p=0.002)

In the face of Enhertu’s strong advancement in first-line therapies, Kelun Biotech has adopted a differentiated strategy of

[1][2]:

1. Clear Indication Positioning
   : Position A166 as a “backup option” after resistance to mainstream drugs such as Enhertu
2. Launch Specialized Clinical Studies
   : An open-label, multi-center Phase II clinical study has been initiated for HER2+ unresectable or metastatic breast cancer patients who have received topoisomerase inhibitor ADC therapy
3. Multi-Cancer Expansion
   : In addition to breast cancer, indications for gastric cancer, non-small cell lung cancer, colorectal cancer, etc., are under development

This strategic layout reflects Kelun Biotech’s

of the competitive landscape in the HER2 ADC track:

• In the first-line market where Enhertu has built strong barriers, the commercial certainty of direct competition is low
• Differentiated resistance backup scenarios have clearer commercial value
• Form a synergistic rather than competitive market pattern with its own and similar products

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The fundamental difference between A166 and Enhertu in the selection of cytotoxic drugs provides a theoretical basis for overcoming drug resistance:

Feature	A166 (MMAF)	Enhertu (Dxd)
Drug Type	Microtubule inhibitor	Topoisomerase I inhibitor
Mechanism of Action	Inhibits microtubule polymerization, blocks mitosis	Induces DNA double-strand breaks
Cross-Resistance Risk	Theoretically low	Theoretically low
Bystander Effect	Exists	Potent

According to research, due to different mechanisms of action, the

, which provides scientific support for the application of A166 after Enhertu resistance [9].

A166’s zero ILD incidence is particularly important for patients requiring subsequent treatment:

• Enhertu treatment-related ILD risk limits patients’ long-term medication and treatment options
• A166’s safety profile makes it more suitable as a subsequent treatment option
• A lower rate of serious adverse reactions helps maintain patients’ quality of life

The Phase I study included 20.7% of patients who had previously received HER2-ADC therapy, and A166 still demonstrated efficacy in this subgroup, suggesting its application potential in ADC-pretreated patients [7][8].

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• With the popularization of Enhertu globally, the post-resistance treatment market will continue to expand
• The base of HER2-positive breast cancer patients is stable, with approximately 200,000 new cases each year
• HER2-positive breast cancer patients in China account for approximately 20%-25% of all breast cancer patients

Enterprise	Product	Strategic Positioning	Differentiated Advantage
Kelun Biotech	A166	Focus on drug resistance scenarios	Zero ILD safety
Baili Tianheng	T-Bren	Directly compete with Enhertu	Cross-cancer layout
Rongchang Biotech	Disitamab Vedotin	Differentiated indications	Gastric cancer, urothelial carcinoma
Hengrui Medicine	SHR-A1811	Multi-indication expansion	Combination regimen development

Kelun Biotech has reached a strategic cooperation with Merck, licensing SKB264 (global rights excluding Greater China), SKB315 (global rights), and seven preclinical ADC assets to Merck, with a total transaction value of up to

[3][4]. This cooperation not only validates the technological value of Kelun Biotech’s ADC platform but also lays a foundation for the international development of A166.

Kelun Biotech’s ADC pipeline layout exhibits good synergy:

• SKB264
  (TROP2 ADC): Targets indications such as TNBC, NSCLC, etc.
• A166
  (HER2 ADC): Focuses on breast cancer drug resistance scenarios
• SKB315
  (CLDN18.2 ADC): Targets solid tumors such as gastric cancer

A multi-target layout can form synergies in treatment strategies, providing sequential treatment options for patients.

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• Phase II Clinical Results in Drug Resistance Scenarios
  : Still need verification from Phase III studies with larger sample sizes
• Long-Term Safety Data
  : Need longer-term follow-up data
• Biomarker Screening
  : How to accurately identify the patient population that can benefit most from A166

• Enhertu Indication Advancement
  : If Enhertu achieves breakthroughs in neoadjuvant/adjuvant therapy, the characteristics of drug-resistant populations may change
• Competition from Other ADCs
  : Competitive pressure from products such as Hengrui’s SHR-A1811 and Baili Tianheng’s T-Bren
• Technology Iteration Risk
  : Potential impact from new ADC technologies (such as bispecific antibody ADCs)

• Medical Insurance Negotiation Pressure
  : Balancing innovative drug pricing and medical insurance access
• Production Capacity Supply
  : Complexity of ADC drug production
• Academic Promotion
  : Clinical concept education for drug resistance scenarios

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Based on the above analysis, Kelun Biotech’s focus on HER2 ADC drug resistance scenarios has the following strategic value:

Dimension	Assessment	Rating
Scientific Basis	Mechanistic differences between MMAF and Dxd, theoretically avoid cross-resistance	★★★★☆
Clinical Data	Excellent Phase III head-to-head data, significant safety advantages	★★★★★
Strategic Positioning	Clear differentiated competition strategy, avoids direct conflict with Enhertu	★★★★★
Market Space	Real and continuously growing demand for drug resistance treatment	★★★★☆
Execution Capability	Merck cooperation validates platform value, leading R&D progress	★★★★★

1. Complete Registration Clinical Studies in Drug Resistance Scenarios
   : Need to initiate and complete Phase III clinical studies for ADC-pretreated patients
2. Establish an Accurate Patient Stratification System
   : Screen the most beneficial population based on biomarkers (such as ABCB1 expression, ERBB2 amplification status)
3. Form a Clear Clinical Positioning
   : Establish the status of “A166 after Enhertu progression” in treatment guidelines
4. Continuous Academic Promotion
   : Establish clinical awareness through clinical data release and academic cooperation

Kelun Biotech’s “focus on drug resistance scenarios” strategy reflects a profound understanding of the competitive landscape of China’s innovative drugs. In the first-line market where Enhertu has established strong barriers, this

has high commercial certainty. A166’s zero ILD safety profile provides a unique value proposition for its application in drug resistance scenarios.

It is recommended to pay attention to the following catalysts:

• Release of Phase II/III clinical data in drug resistance scenarios
• Results of medical insurance negotiations
• Progress of international clinical studies
• Follow-up advancement of cooperation with Merck

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[1] China Pharmaceutical Innovation and Research Development Association - HER2 ADC Track: Survival of Domestic Players? (https://www.phirda.com/artilce_41347.html)

[2] Tencent News - HER2 ADC Track: Survival of Domestic Players? (https://news.qq.com/rain/a/20260112A01DTT00)

[3] SPD Bank International - Kelun Biotech (6990.HK): ADC Leader on the Verge of Commercialization, Promising Future (https://www.spdbi.com/)

[4] Industrial Securities - ADC Pioneer Goes Global, Innovative Platform Has Great Potential (https://pdf.dfcfw.com/pdf/H3_AP202312041613222468_1.pdf)

[5] Smart Pharma Circle - Kelun Biotech’s Innovative Drug Botuzumab Approved (https://synapse.zhihuiya.com/blog/)

[6] Cancer-Free Home - Another Domestic HER2 ADC New Drug Approved (https://m.tumormed.com/aizhengzhiliao/7814.html)

[7] Kelun Biotech Official Website - News Center (http://www.kelun-biotech.com/newsCenter.aspx)

[8] NPJ Breast Cancer - Phase I study of A166 (https://www.nature.com/)

[9] 2025 ASCO Annual Meeting - ADC Continues to Lead Cancer Treatment (https://zh.tri-apex.com/info/insight/720.html)

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Report Compiled by: Jinling AI Financial Analysis Team
Data Cut-Off Date: January 14, 2026