Editor's Note: Numerous anti-HER2 antibody–drug conjugates (ADCs) are now available in clinical practice. Based on their payload mechanisms, they can be broadly classified into topoisomerase I inhibitor (TOP1i)-based ADCs and microtubule inhibitor-based ADCs. These two classes differ in their mechanisms of action, resistance profiles, and risks of cross-resistance. Bodutuzumab, a microtubule inhibitor-based ADC featuring the novel payload Duostatin-5 and a distinctive mechanism of action, has demonstrated differentiated advantages in patients who have progressed after tyrosine kinase inhibitor (TKI) therapy or who have received or developed resistance to TOP1i-based ADCs. In the KL166-III-06 study, a head-to-head comparison of bodutuzumab with trastuzumab emtansine (T-DM1) also demonstrated significant improvements in progression-free survival (PFS) and objective response rate (ORR), with adverse events that were manageable, preventable, and reversible.Against this background, Oncology Frontier invited Professor Lu Gan of the First Affiliated Hospital of Chongqing Medical University, Professor Huihui Li of Shandong Cancer Hospital, and Professor Jian Huang of the Second Affiliated Hospital of Zhejiang University School of Medicine to discuss treatment selection with ADCs in HER2-positive advanced breast cancer, the clinical positioning of bodutuzumab, treatment sequencing after resistance, and safety management. They also shared their perspectives on future research directions.
01. Mechanistic Differences and the Distinctive Advantages of Bodutuzumab
Oncology Frontier: Numerous anti-HER2 ADCs are currently available. Based on their payload mechanisms, they can broadly be divided into microtubule inhibitor-based ADCs and TOP1i-based ADCs. Only three microtubule inhibitor-based ADCs have been approved, while most agents in development belong to the TOP1i class. From the perspectives of pharmacological mechanisms and clinical practice, what are the key differences between these two classes? Among the three approved microtubule inhibitor-based ADCs, what distinguishes bodutuzumab?
Professor Lu Gan:
ADCs consist of three components: an antibody, a linker, and a cytotoxic payload. Current anti-HER2 ADCs can be broadly divided into two major categories: microtubule inhibitor-based ADCs and TOP1i-based ADCs. The most important difference between these two classes lies in their payloads.
TOP1i-based ADCs, including trastuzumab deruxtecan (T-DXd) and ruikang trastuzumab, use topoisomerase I inhibitors as their payloads. Microtubule inhibitor-based ADCs, including trastuzumab emtansine (T-DM1), disitamab vedotin (RC48), and bodutuzumab (A166), use microtubule inhibitors as their payloads.
There are currently three principal approved microtubule inhibitor-based anti-HER2 ADCs.
The first is T-DM1, the first ADC introduced into breast cancer treatment. The EMILIA study established its role in second-line treatment of HER2-positive advanced breast cancer.
The second is RC48. The RC48-C006 study investigated the efficacy and safety of disitamab vedotin versus lapatinib plus capecitabine in patients with HER2-positive advanced or metastatic breast cancer. Based on this study, its approved breast cancer indication covers patients with HER2-positive advanced breast cancer and liver metastases who have previously received trastuzumab, or its biosimilar, and a taxane. Its approved indication therefore covers a relatively restricted population, primarily patients with liver metastases.
The third is bodutuzumab. The KL166-III-06 study evaluated its efficacy and safety versus T-DM1 in patients with HER2-positive unresectable or metastatic breast cancer who had previously received trastuzumab and a taxane. Following the positive results, bodutuzumab was approved for adults with unresectable or metastatic HER2-positive breast cancer who have received at least one prior anti-HER2 treatment.
The pivotal KL166-III-06 study compared bodutuzumab with T-DM1, a well-established standard second-line treatment, in terms of efficacy and safety. The results demonstrated favorable efficacy and safety with bodutuzumab. Median PFS assessed by blinded independent central review (BICR) was 11.1 months versus 4.4 months, respectively (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.30–0.51), while the ORR was 76.9% versus 53.0%.
Regarding safety, bodutuzumab was associated with lower hematologic, hepatic, pulmonary, and gastrointestinal toxicity than T-DM1. The incidence of interstitial lung disease (ILD)/pneumonitis was only 1.1%, and no patients discontinued treatment because of adverse events.
The key to bodutuzumab’s efficacy in second-line and later-line treatment lies largely in its payload, Duostatin-5. Duostatin-5 is a derivative of monomethyl auristatin F (MMAF) and a novel microtubule inhibitor with improved efficacy compared with earlier microtubule inhibitor payloads. In addition, its drug-to-antibody ratio (DAR) is approximately 2. Its high homogeneity, good plasma stability, and low level of free payload contribute to favorable therapeutic efficacy and a lower incidence of adverse reactions.
Based on its approved indication and efficacy data, bodutuzumab has been recommended in the 2026 edition of the CSCO Breast Cancer Diagnosis and Treatment Guidelines and the 2026 Concise Edition of the CBCS & CSOBO Breast Cancer Diagnosis and Treatment Guidelines and Standards. Overall, compared with the other two approved microtubule inhibitor-based ADCs, bodutuzumab offers distinct advantages in indication coverage, efficacy, safety, and guideline recommendations.
02. Interpreting the KL166-III-06 Results and Their Clinical Significance
Oncology Frontier: The KL166-III-06 study showed that bodutuzumab significantly outperformed T-DM1, with a BICR-assessed median PFS of 11.1 versus 4.4 months (HR, 0.39; 95% CI, 0.30–0.51), an ORR of 76.9% versus 53.0%, and a median duration of response (DoR) of 12.2 versus 5.7 months. As the first phase III study since DESTINY-Breast03 (DB-03) to once again directly compare an ADC with T-DM1, how do you interpret these findings? What is their significance for breast cancer treatment?
Professor Huihui Li:
Professor Gan has clearly explained the distinctive advantages of bodutuzumab from the perspectives of mechanism of action and drug structure. I will focus on the KL166-III-06 results and their implications for breast cancer treatment.
KL166-III-06 is another phase III study to directly compare an ADC with T-DM1 following DB-03. The results showed substantial improvement in outcomes among previously treated patients with HER2-positive breast cancer receiving bodutuzumab compared with T-DM1. BICR-assessed median PFS was 11.1 versus 4.4 months (HR, 0.39; 95% CI, 0.30–0.51). The ORR increased to 76.9% versus 53.0%, and median DoR improved to 12.2 versus 5.7 months.
The overall survival (OS) data remain immature, but the HR was 0.62, and the 12-month OS rates were 90.6% versus 85.0%, suggesting a favorable trend.
In subgroup analyses, the HR among patients previously treated with TKIs was 0.36, compared with 0.41 among TKI-naive patients. This suggests that patients previously exposed to TKIs also benefited, with a numerically greater treatment effect. Consistent benefits were also observed among patients who had received at least two prior lines of therapy, those with visceral metastases, and those previously treated with pertuzumab.
In terms of safety, bodutuzumab was associated with lower hematologic and hepatic toxicity than T-DM1. The incidence of ILD/pneumonitis was 1.1%, and all cases were grade 2 or lower. No additive adverse effects were observed with sequential use.
I would interpret the clinical significance of this study from several perspectives.
First, it is another phase III head-to-head comparison against T-DM1 following DB-03. DB-03 compared T-DXd with T-DM1, whereas KL166-III-06 compared bodutuzumab, a microtubule inhibitor-based ADC, with T-DM1. This demonstrates that microtubule inhibitor-based ADCs can also outperform T-DM1.
Second, the enrolled population closely reflects clinical practice in China: 53.4% had previously received at least two lines of anti-HER2 therapy, 59.5% had received TKIs, 46.0% had received pertuzumab, and 73.4% had visceral metastases.
Despite extensive prior treatment, bodutuzumab achieved a median PFS of 11.1 months, representing a clinically meaningful outcome. It offers a new and potent treatment option for Chinese patients with HER2-positive advanced breast cancer receiving second-line or later-line therapy. Its value may be particularly pronounced in patients whose disease has progressed after TKI treatment.
From a safety perspective, hematologic, hepatic, pulmonary, and gastrointestinal toxicities were relatively low. Although ocular adverse events were notable, they were generally manageable.
03. Positioning Bodutuzumab After TKI Resistance and Individualizing Treatment Selection
Oncology Frontier: Pyrotinib has become one of the main treatment options for HER2-positive advanced breast cancer in China. Selecting subsequent therapy after TKI failure remains challenging, particularly because the populations enrolled in clinical trials often differ from those encountered in practice. In KL166-III-06, 53.4% of patients had received at least two prior lines of anti-HER2 treatment, 55.9% had previously received pyrotinib, and one patient in each treatment group had previously received T-DXd. These patients also demonstrated favorable outcomes with bodutuzumab. In light of related studies, how would you assess the clinical positioning of bodutuzumab? How do you select treatments in clinical practice based on prior drug exposure and resistance mechanisms?
Professor Jian Huang:
For patients with HER2-positive breast cancer, determining the next treatment after resistance to TKIs or large-molecule monoclonal antibodies remains a difficult clinical problem that warrants further discussion.
Available evidence suggests that novel ADCs offer a new treatment option for these patients. Based on their targets, novel ADCs can be divided into HER2-targeting ADCs, TROP2-targeting ADCs, and other categories. Anti-HER2 ADCs can be further classified according to their payloads into TOP1 inhibitor-based and microtubule inhibitor-based agents.
A comparison of studies involving microtubule inhibitor-based ADCs is informative. In EMILIA, the control regimen was lapatinib plus capecitabine, so no patients in the study had previously received a TKI. The RC48-C006 study primarily enrolled patients with HER2-positive breast cancer and liver metastases and did not include patients previously treated with TKIs. Consequently, among currently approved microtubule inhibitor-based anti-HER2 ADCs, bodutuzumab has the strongest evidence in patients with TKI-resistant disease.
Based on KL166-III-06, bodutuzumab has demonstrated favorable treatment outcomes, particularly in patients whose disease has progressed after TKI therapy, making it an important treatment option for this population.
In clinical practice, I consider several factors when selecting treatment.
First, prior drug exposure. This includes the duration of treatment, the drugs previously used, and whether resistance has developed. If a patient has not developed resistance and recurrence occurs only after a prolonged period of treatment, it may still be reasonable to continue using the original agent.
Second, resistance mechanisms. Treatment selection may differ for patients with HER2 mutations, BRCA mutations, or other relevant molecular alterations.
Third, the ADC payload. Sequential use of drugs with the same payload should generally be avoided when possible. Strategies involving the same target but a different payload, or a different target and a different payload, may help improve treatment efficacy.
Fourth, metastatic sites and patient tolerability. For patients with extensive metastases or poor treatment tolerance, an ADC with a more favorable safety profile should be considered. Patients with pre-existing eye disease may benefit from agents associated with fewer ocular adverse events, thereby reducing the risk of worsening ocular conditions. Hepatic toxicity, pulmonary toxicity, and potential effects on brain function must also be taken into account.
Managing ADC-related adverse events is therefore just as important as optimizing efficacy and overall safety.
In summary, when both TKI therapy and large-molecule monoclonal antibody treatment have failed, an ADC such as bodutuzumab may be considered as a subsequent treatment option.
04. Sequential Treatment with the Same Target but a Different Payload After TOP1i-Based ADC Resistance
Oncology Frontier: As TOP1i-based HER2 ADCs such as T-DXd move into earlier lines of treatment, more patients will face the challenge of selecting subsequent therapy after developing resistance to TOP1i-based ADCs. From the perspective of sequential treatment using the same target but a different payload, what advantages might microtubule inhibitor-based HER2 ADCs such as bodutuzumab offer in patients previously treated with or resistant to TOP1i-based ADCs?
Professor Lu Gan:
As TOP1i-based anti-HER2 ADCs such as T-DXd move into earlier lines of treatment, selecting subsequent therapy after resistance to these agents is indeed becoming an increasingly important clinical challenge.
Mechanistically, resistance to TOP1i-based ADCs can arise through several pathways, including loss or alteration of the antibody target and payload-related resistance. Payload-related mechanisms may play a more dominant role. Therefore, sequentially switching to an ADC with a different target but the same payload may carry a relatively high risk of cross-resistance.
This is where the strategy of maintaining the same target while changing the payload becomes particularly important. Bodutuzumab is a representative option for this approach: it retains trastuzumab as the antibody component but uses the microtubule inhibitor Duostatin-5 as its payload.
Microtubule inhibitors and TOP1 inhibitors act through different mechanisms. TOP1 mutations do not directly affect the activity of microtubule inhibitor payloads, so the risk of cross-resistance may be lower.
From a clinical strategy perspective, for patients whose tumors remain HER2-positive after developing resistance to a TOP1i-based ADC, subsequent treatment should prioritize an ADC with a different payload when appropriate. Microtubule inhibitor-based anti-HER2 ADCs are potential options. Bodutuzumab has demonstrated favorable results in PFS, ORR, and adverse-event outcomes and has been included in treatment guidelines, making it an option worth prioritizing for suitable patients.
05. Preventing and Managing Ocular Adverse Events Associated with Bodutuzumab
Oncology Frontier: Safety data from KL166-III-06 show that ocular events were a notable part of the adverse-event profile of bodutuzumab. However, most ocular adverse events resolved with protocol-based management, and no patients discontinued treatment because of adverse reactions. Based on your clinical experience, how would you establish a pathway for screening, prevention, grading, management, and ophthalmology referral? Which patients require particular caution or early intervention?
Professor Huihui Li:
Ocular events are indeed prominent among the adverse reactions associated with bodutuzumab. Common events include corneal disorders, dry eye, and blurred vision. The median time to onset of grade ≥3 adverse events was approximately 46–47 days, so particular attention is needed during the first four treatment cycles.
With protocol-based management, most patients recovered to grade 2 or lower. The median recovery time was approximately 16 days. No patients discontinued treatment because of adverse events, and no patients experienced treatment interruption or serious adverse events attributable to ocular toxicity. Overall, although ocular adverse events occur relatively frequently, they are generally preventable, manageable, and reversible.
I would organize clinical management into four steps.
Step 1: Screening. At baseline, assess best-corrected visual acuity, perform corneal fluorescein staining and slit-lamp examinations, and evaluate for dry eye. Close monitoring is particularly important during the first four cycles, with ophthalmologic follow-up every cycle or every two cycles.
Step 2: Prevention. Initiate lubricating eye drops or ophthalmic ointments in advance, advise patients to avoid contact lenses, reinforce eye hygiene, and provide patient education. Patients should promptly report dry eyes, foreign-body sensation, photophobia, or blurred vision.
Step 3: Grade-based management.
- Grade 1: Use artificial tears and lubricating eye drops, continue treatment, and monitor closely.
- Grade 2: Intensify the use of lubricating eye drops and ointments, consider dose adjustment or temporary treatment interruption, and request an ophthalmology consultation.
- Grade 3: Withhold treatment and refer the patient to ophthalmology. Topical corticosteroids, antibiotics, or corneal-healing treatments may be used as appropriate. Bodutuzumab may be resumed once the adverse event has improved to grade 2 or lower, with dose reduction if necessary.
Step 4: Ophthalmology referral. Establish a fast-track referral pathway to ensure timely specialist assessment, particularly for severe or persistent symptoms that do not improve with initial management.
Patients who require particular caution or early intervention include those with a history of severe corneal epithelial disease, dry eye, corneal surgery, autoimmune disease, diabetes, or advanced age, as well as long-term contact lens users and patients who may have difficulty adhering to ophthalmologic follow-up.
06. The Potential Role of Bodutuzumab in Patients with Brain or Visceral Metastases
Oncology Frontier: In KL166-III-06, the incidence of new brain metastases was 9.2% with bodutuzumab and 11.7% with T-DM1. Median PFS among these patients was 13.8 and 7.6 months, respectively. Approximately 73% of enrolled patients had visceral metastases. How might these data influence your treatment decisions for patients with HER2-positive advanced breast cancer and brain, liver, or lung metastases? How do you view the potential of bodutuzumab in patients with brain and visceral metastases?
Professor Jian Huang:
Patients with breast cancer may develop visceral and brain metastases during the course of their disease, creating additional treatment challenges. Previous studies have demonstrated some efficacy of T-DM1 in patients with visceral and brain metastases. The emergence of novel ADCs has further changed the treatment landscape.
Based on the available data, novel ADCs, including T-DXd and bodutuzumab, have shown advantages over T-DM1 in reducing the incidence of new brain metastases and prolonging PFS. These agents therefore expand the treatment options available for patients with visceral and brain metastases.
More specifically, KL166-III-06 allowed enrollment of patients with previously treated, clinically stable brain metastases but excluded those with active brain metastases. In clinical practice, patients with active brain metastases should therefore generally receive appropriate local treatment first, with systemic therapy considered once the disease has stabilized.
For patients with stable brain metastases, bodutuzumab is an option worth considering because the study demonstrated favorable findings regarding both the incidence of new brain metastases and PFS.
If an ADC alone does not provide adequate disease control, the combination of an ADC with a TKI could also be explored. The HER2CLIMB-02 study demonstrated that T-DM1 plus tucatinib prolonged PFS compared with T-DM1 alone. This suggests that combining an ADC with a TKI may represent a potential treatment strategy for reducing or controlling brain metastases and improving therapeutic outcomes.
The visceral metastasis subgroup in KL166-III-06 also showed consistent benefit. Bodutuzumab is therefore a promising option for patients with liver or lung metastases.
Overall, I believe bodutuzumab has considerable therapeutic potential in patients with brain and visceral metastases, although further prospective studies are needed to validate these findings.
07. Future Directions for Bodutuzumab
Oncology Frontier: Bodutuzumab has been approved in China for unresectable or metastatic HER2-positive breast cancer in adults who have received at least one prior anti-HER2 treatment. What areas of research do you believe are most important to explore next? What are your expectations for the future development of this agent?
Professor Lu Gan:
Now that bodutuzumab has received approval for its current indication, the first priority should be to evaluate its efficacy and adverse-event profile in broader real-world use.
Future research could explore combination strategies, such as combining bodutuzumab with TKIs or pertuzumab. Combinations with immunotherapy or PARP inhibitors could also be considered.
For patients with triple-positive breast cancer, combination treatment with CDK4/6 inhibitors may be another avenue for investigation. For patients with alterations in the PI3K–AKT–mTOR pathway, the INAVO122 study may provide a reference for exploring combinations with PI3K inhibitors.
These combination strategies may help overcome resistance, prolong the duration of treatment, and delay disease progression.
Of course, we also hope that bodutuzumab will be included in China’s National Reimbursement Drug List as soon as possible, improving access so that more patients can benefit from this treatment.
Professor Jian Huang:
For microtubule inhibitor-based ADCs such as bodutuzumab, important questions remain regarding the selection of subsequent therapies after resistance and the identification of new targets involved in resistance mechanisms.
Potential strategies include changing the payload or changing the target. These approaches may help overcome resistance to existing ADCs and restore treatment sensitivity, but they require a deeper understanding of the relevant targets and resistance pathways.
In addition, a meaningful proportion of patients with HER2-positive breast cancer develop brain metastases or visceral metastases, including liver and lung metastases. Although ADCs can provide therapeutic benefit, their safety profiles must also be carefully considered. We need better ways to balance efficacy and safety and identify the patients most likely to benefit, so that treatment outcomes can be improved while safety management becomes more reliable. These are important areas for future research.
For bodutuzumab, I hope that inclusion in China’s National Reimbursement Drug List will be achieved soon, improving affordability and allowing more patients to access treatment.
Professor Huihui Li:
I agree with both professors. ADCs are being used increasingly widely in clinical practice, but this expansion also brings new challenges. One common question is how to select subsequent treatment after ADC failure, which requires a deeper understanding of resistance mechanisms.
If we can conduct translational research using patient samples to investigate predictive factors for ADC efficacy and the mechanisms of resistance, this could substantially improve individualized treatment decisions, guide ADC selection, and inform the choice of therapy after ADC resistance develops.
In addition, ADCs can produce distinctive adverse effects, placing greater demands on patient management. In real-world practice, we need a widely applicable system for screening, prevention, and grade-based management of ADC-related adverse events, together with clear pathways for timely referral when problems arise.
A multidisciplinary and comprehensive approach to patient management is essential to ensure treatment safety and help patients derive the greatest possible benefit from these therapies.
Professor Lu Gan
Professor Huihui Li
Professor Jian Huang
