Editor’s Note: At the 2025 Annual Meeting of the American Association for Cancer Research (AACR), the China-developed HER2-directed antibody-drug conjugate (ADC) Trastuzumab rezetecan(SHR-A1811) made a striking appearance with new data from the HORIZON-Lung study: an objective response rate (ORR) of 74.5%, a median progression-free survival (PFS) of 11.5 months, and an interstitial lung disease (ILD) incidence of just 8.5%—setting new records among global studies in this space.With its well-balanced profile of “high efficacy and low toxicity,” SHR-A1811 is redefining the treatment standard for HER2-mutant non-small cell lung cancer (NSCLC) and marks a pivotal shift for Chinese innovative drugs from “follower” to “front-runner.” We invited leading principal investigator Professor Shun Lu to unpack the scientific rationale and clinical value behind these groundbreaking results.
Q1: At the AACR Annual Meeting held in Chicago, your study HORIZON-Lung brought exciting updates in the treatment of HER2-mutant NSCLC. The new data show an objective response rate (ORR) of 74.5% and a median progression-free survival (mPFS) of 11.5 months. Could you share your insights on the significance of these results for the treatment landscape of HER2-mutant NSCLC?
Prof. Shun Lu: I was very pleased to share the latest findings from the HORIZON-Lung study with colleagues from around the world at the AACR Annual Meeting. In patients with previously treated advanced or metastatic HER2-mutant NSCLC, treatment with (SHR-A1811) achieved an ORR of 74.5% (per IRC assessment) after a median follow-up of 14.2 months—surpassing the previously reported 73.4% published in The Lancet Oncology and setting a new benchmark globally for this class of therapies [¹,²].
These results firmly establish SHR-A1811 as a preferred option for second-line treatment in HER2-mutant NSCLC. Subgroup analyses revealed particularly encouraging outcomes in patients with baseline brain metastases, where the ORR reached 87.5%, offering a potent new therapeutic option for this challenging population. Even patients who had received prior anti-HER2 tyrosine kinase inhibitors (TKIs) responded well, with an ORR of 81.8%, indicating that SHR-A1811 can still provide significant clinical benefit after TKI failure.
Additionally, the median time to response (TTR) was only 1.4 months, and the median reduction in the sum of diameters (SoD) of target lesions reached 54%, demonstrating the rapid and substantial tumor-shrinking capability of SHR-A1811 [¹].
The median progression-free survival (mPFS) reached 11.5 months, with a 12-month PFS rate of 48.6%. Subgroup analysis showed that patients with baseline brain metastases also achieved a median PFS of 11.3 months, demonstrating that SHR-A1811 offers durable tumor control in this challenging population. Among patients who had previously received anti-HER2 TKI therapy, the median PFS was 9.7 months.
At the time of this data analysis, although the median follow-up duration had reached 14.2 months, the median overall survival (OS) was still not mature. The 12-month OS rate was 88.2%.
Compared to the DESTINY-Lung05 study of the imported HER2-directed ADC DS-8201 in Chinese patients, the HORIZON-Lung study featured a longer median follow-up duration (14.2 months vs. 9.8 months), a higher objective response rate (IRC-assessed ORR: 74.5% vs. 58.3%), and more durable disease control, indicating a more robust efficacy profile (median PFS per IRC: 11.5 months vs. not reached; median PFS per investigator: 12.5 months vs. 10.8 months) [¹,¹⁶].
These outstanding efficacy results have filled a critical gap in anti-HER2 treatment options for Chinese patients with advanced HER2-mutant NSCLC. I believe SHR-A1811 will become a valuable tool for clinicians and deliver long-term survival benefits to patients.
Q2: In this data update, SHR-A1811 demonstrated a treatment discontinuation rate due to adverse events of only 2.1% and an ILD incidence of just 8.5%, which is significantly lower than that of comparable agents. What key drug design features do you believe contribute to its favorable safety profile?
Prof. Shun Lu: With extended follow-up, patients are typically exposed to treatment for longer periods, which often leads to the emergence of more adverse events. However, in the HORIZON-Lung study, as the median follow-up extended from 8.7 months to 14.2 months, we observed no significant changes or increases in the spectrum or incidence of adverse events associated with SHR-A1811. This highlights the drug’s remarkable and consistent safety profile.
From a drug development and design perspective, there are three key factors that enable SHR-A1811 to achieve its “high efficacy with low toxicity” profile:
First, in terms of the cytotoxic payload, the molecule incorporates the more potent exatecan derivative R-ZZ108, a next-generation topoisomerase I inhibitor. Compared to DXd, it exhibits a lower IC50 (indicating higher cytotoxic potency), along with greater lipophilicity and membrane permeability. These properties enhance its potential for a stronger bystander killing effect.
Second, the drug-to-antibody ratio (DAR) is another key highlight in the design. DAR refers to the average number of payload molecules attached to a single monoclonal antibody. For SHR-A1811, the DAR is 6, compared to 8 for DS-8201. Preclinical studies have shown that at equivalent doses, SHR-A1811 achieves comparable bystander and antitumor effects to DS-8201. The design choice of a DAR of 6 effectively reduces the total amount of cytotoxic payload introduced into the body, better aligning with the chemotherapy tolerance threshold observed in Asian populations. This balance ensures strong efficacy while improving safety by lowering the risk of adverse events [³,⁴].
Lastly, SHR-A1811 incorporates an innovative chiral cyclopropyl structure at the linkage site between the payload and the linker. This significantly enhances the stability of the payload-linker conjugate in plasma. The 21-day in-plasma payload release rate is less than 1%, lower than the 1.2%–3.9% observed with DS-8201, indicating a more stable structure. This prevents uncontrolled release of the toxin in circulation, further contributing to the drug’s favorable safety profile [³–⁵].
The unique structural design of SHR-A1811 lays the foundation for its hallmark “high efficacy and low toxicity” profile, with an ORR of 74.5% and a median PFS of 11.5 months. More importantly, its safety advantages are clearly evident. Despite a longer follow-up period (14.2 months for SHR-A1811 vs. 15.8 months in the 5.4 mg/kg cohort of DS-8201), the treatment discontinuation rate due to adverse events was only 2.1%, significantly lower than the 14.9% reported in the DESTINY-Lung02 trial. The incidence of interstitial lung disease (ILD) was also notably lower at just 8.5%, with only one case of grade 3 ILD, compared to 14.9% in DESTINY-Lung02.
In short, the clinical data reinforce the rationale behind its development. SHR-A1811 is poised to become a new “high efficacy, low toxicity” treatment option for Chinese patients with HER2-mutant NSCLC [¹,²,⁶].
Q3: Based on the current data, do you believe SHR-A1811 has the potential to redefine the treatment landscape for HER2-mutant NSCLC in the second-line setting? What are the next steps in clinical research?
Prof. Shun Lu: The answer is clear. The HORIZON-Lung study has already demonstrated results far superior to traditional second-line therapies, where ORRs are typically below 30% and median PFS is under 6 months. SHR-A1811 has delivered substantial benefits for patients with HER2-mutant NSCLC. Based on this study [⁷–¹¹], the drug has been granted priority review by the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) and is expected to be approved soon, benefiting patients across China with advanced HER2-mutant NSCLC [¹²].
Furthermore, the principle of “the better drug should be used earlier” holds true. SHR-A1811 offers rapid onset, strong response, and prolonged survival. I believe it has the potential not only to reshape second-line therapy but also to bring long-term benefits in the frontline setting. Currently, we have launched a multicenter Phase III clinical trial (NCT06430437) comparing SHR-A1811 with platinum-based chemotherapy plus immunotherapy as first-line treatment in HER2-mutant NSCLC. We look forward to presenting these results at future international conferences.
In addition, there are two other types of HER2 alterations beyond mutations—HER2 amplification and HER2 overexpression—both associated with poor prognosis. HER2 amplification is seen in approximately 2.4% to 20% of NSCLC cases [¹³,¹⁵], while HER2 overexpression occurs in around 6% to 35% [¹⁴]. These patients also represent a significant unmet clinical need. We are currently conducting a Phase II trial to explore the potential of SHR-A1811, either as monotherapy or in combination with immunotherapy, in these subpopulations.
Q4: China’s homegrown ADCs are rapidly emerging. How do you see SHR-A1811 influencing the global landscape of lung cancer treatment?
Prof. Shun Lu: At this year’s AACR Annual Meeting, ADCs were clearly in the spotlight as a leading therapeutic modality. Among the many ADC breakthroughs presented, Chinese-developed ADCs accounted for nearly half, underscoring China’s growing strength in this field.
SHR-A1811’s global impact on lung cancer treatment can be viewed on two levels. First, from a scientific perspective: as a domestically developed agent by Hengrui, SHR-A1811 validates the combination strategy of enhanced payload (R-Zetecan/DXh) and optimized DAR as a viable path to creating high-efficacy, low-toxicity ADCs. This sets a new paradigm not just for China, but for global ADC development.
Second, on the clinical research front: based on the breakthrough data from the HORIZON-Lung study, SHR-A1811 is on the brink of approval and will offer an innovative treatment for previously treated patients with advanced or metastatic HER2-mutant NSCLC. Moreover, our ongoing studies in the frontline HER2-mutant population and HER2-amplified/overexpressed cohorts aim to extend these benefits to a broader patient population. Our goal is to provide more effective, safer, and accessible therapeutic options from China.
Of course, an equally critical next step is how we strategically expand international multicenter studies—so that high-quality domestic innovations can truly serve global patients. The vision is clear: to move from Chinese breakthroughs to global leadership. I look forward to seeing SHR-A1811 expand its impact in the global lung cancer arena, and I hope Chinese ADCs can transition from making their mark to leading the field—ushering in a new era of ADC therapies made in China, benefiting the world.
References
[1] Lu S, et al. AACR 2025 [2] Li Z, Wang Y, Sun YP, Si W, Lu S. Trastuzumab rezetecan, a HER2-directed antibody–drug conjugate, in patients with advanced HER2-mutant non-small-cell lung cancer (HORIZON-Lung): phase 2 results from a multicentre, single-arm study. The Lancet Oncology 2025.
[3] Ting. Z, et al. 2023 AACR LB031
[4] Ting. Z, et al. Research Square: doi.org/10.21203/rs.3.rs-3770094/v1
[5] Ogitani Y, et al. Clin Cancer Res (2016) 22 (20): 5097–5108.
[6] Pasi A. Janne, et al. 2024ASCO Poster 8543
[7] Cooper AJ,et al. J Clin Oncol. 2022 Mar 1;40(7):693-697. [8] Mazieres J, et al. Annals of Oncology 27: 281–286, 2016 [9] Shepherd FA, et al. J Clin Oncol18:2095-2103, 2000. [10] Ioannis A Vathiotis et al.Cancers (Basel). 2023 Feb 17;15(4):1286. [11] Chu X, Qiang H, Xie M, et al. Cancer Immunol Immunother. 2022;71(7):1625-1631 [12] www.nmpa.gov.cn [13] Pollock NI, Grandis JR, Cin Cancer Res 2015;21:526-33; [14] Iqbal N, Iqbal N, Mol Biol Int 2014; 2014:852748 [15] Shiwang Wen et al. Oncologist. 2019 Nov;24(11):e1070-e1081 [16] Ying Cheng, et al. 2024 AACR. CT248
Expert Profile
- Tenured Professor at Shanghai Chest Hospital, Shanghai JiaoTong University School of Medicine
- Director of the Shanghai Pulmonary Oncology Clinical Medical Center
- Doctoral Supervisor; Full Professor (Level II)
- National Health Commission Outstanding Young and Middle-Aged Expert
- Leading Talent of Shanghai; Distinguished Academic Leader of Shanghai
- Recipient of the State Council Special Allowance
- Director of the Collaborative Innovation Center for Clinical Research and Translational Medicine in Biopharmaceuticals (Jointly supported by the Ministry of Education and the City of Shanghai)
- Named to the 2024 Clarivate Highly Cited Researchers List
- Honorary Chair of the Lung Cancer Committee, Chinese Anti-Cancer Association
- Executive Council Member of the Chinese Society of Clinical Oncology (CSCO); Vice Chair of the Hisco Foundation
- Former Chair, DIA China Advisory Council
- Former Chair, Shanghai Medical Association Oncology Branch
- Standing Member, Chinese Medical Association Oncology Branch; Chair, Lung Cancer Expert Committee
- President, Oncology Branch of the Shanghai Medical Doctor Association; Head of Specialist Training
- Associate Editor of Journal of Thoracic Oncology and Lung Cancer, official journals of the International Association for the Study of Lung Cancer (IASLC)
As Principal Investigator, Professor Lu has led major national and international projects, including:
- National Key R&D Program for Chronic Diseases
- National Major New Drug Innovation Program
- Two sub-projects under the 863 High-Tech Program
- National Natural Science Foundation of China key and general grants
He is the first recipient of numerous prestigious awards, including:
- First Prize, Shanghai Science and Technology Progress Award
- First Prize, Chinese Anti-Cancer Association Science and Technology Award
- Second Prize, Chinese Medical Science and Technology Award
- Second Prize, Huaxia Medical Science and Technology Award
- First Prize, Shanghai Medical Science and Technology Award
- 2021 President’s Award, Shanghai Jiao Tong University
- WuXi AppTec Life Chemistry Research Award
- 2024 DIA Global Inspire Award
- “Compassionate Healer” Award – Outstanding Specialty Physician of Shanghai
