In May 2025, China’s NMPA approved SHR-A1811 for adult patients with unresectable locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring activating HER2 (ERBB2) mutations who have received at least one prior systemic therapy.

It is Hengrui’s first approved ADC and the world’s 19th commercially launched antibody–drug conjugate therapy.

Its direct comparator is Trastuzumab Deruxtecan (Enhertu, DS-8201), the most successful ADC globally.

Co-developed by AstraZeneca and Daiichi Sankyo, DS-8201 is a third-generation HER2 ADC. Since its launch in 2019, it has secured approvals across HER2-positive breast cancer, HER2-low breast cancer, and HER2-mutant NSCLC, demonstrating markedly superior efficacy over older HER2 ADCs such as T-DM1 (Kadcyla).

In 2025, DS-8201 achieved global sales exceeding USD 4.982 billion, firmly cementing its title as the King of ADCs. By comparison, T-DM1 recorded approximately USD 2.45 billion in sales, with the performance gap widening further from 2024.

SHR-A1811 differs fundamentally from DS-8201 in linker and payload design. Its proprietary linker incorporates a unique structure with two key advantages:

1. Enhanced payload lipophilicity for stronger bystander killing effects.
2. Increased steric hindrance to improve circulatory stability and minimize premature payload shedding—the primary cause of traditional ADC safety risks.

In molecular configuration, DS-8201 features a drug-to-antibody ratio (DAR) of 8, meaning each antibody carries 8 DXd payload molecules. SHR-A1811 adopts a DAR of 6, reducing total payload exposure by roughly 25% at equivalent doses, inherently offering greater safety potential.

Before Hengrui’s bold move, most domestic head-to-head ADC trials targeted T-DM1. By directly benchmarking DS-8201, Hengrui demonstrates unprecedented confidence and ambition.

Zhang Lianshan emphasized:

“To prove you are Best-in-Class, you must compare against the gold-standard benchmark. Indirect cross‑trial comparisons offer insights, yet they lack true impartiality.”

Hengrui is challenging DS-8201 in one of its most groundbreaking indications.

At the 2022 ASCO Annual Meeting, pivotal Phase III data confirmed that DS-8201 significantly prolonged PFS and overall survival versus conventional chemotherapy in HER2-low breast cancer patients.

In August 2022, the FDA approved DS-8201 for unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH‑) breast cancer following prior systemic therapy. China’s NMPA granted matching approval in July 2023.

This approval redefined traditional HER2 diagnostic boundaries and drastically expanded eligible patient populations. Analyst Andrew Berens forecasts that DS-8201 could generate USD 4.6 billion solely from HER2-low breast cancer indications by 2030.

Head-to-head randomized controlled trials represent the gold standard for clinical validation. In recent years, Chinese developers have launched increasingly bold head-to-head studies against top-tier global therapies.

Proving Best-in-Class requires direct comparison against the current standard of care—not outdated comparators.

Take osimertinib as an example. In 2017, the NCCN Guidelines recommended osimertinib as first-line therapy for EGFR-mutant NSCLC. In 2018, FDA approval followed the landmark FLAURA Phase III trial, which reduced the risk of disease progression or death by 54% and extended median PFS from 10.2 months to 18.9 months versus erlotinib or gefitinib.

Despite this milestone, many domestic third-generation EGFR-TKIs continued to compare against older first/second-generation drugs instead of osimertinib. Professor Zhou Caicun from Shanghai East Hospital pointed out:

“Without choosing osimertinib as the optimal control, these candidates merely become followers rather than true innovators.”

In March 2025, Tongyao Kang Pharmaceuticals announced that its core asset TY‑9591 (aidotinib) achieved statistically significant intracranial objective response rate (iORR) in a pivotal Phase II head-to-head trial versus osimertinib for EGFR-mutant NSCLC with brain metastases, delivering meaningful clinical benefits. It became the first Chinese novel drug to demonstrate superiority over osimertinib in a head-to-head setting.

While debates persist regarding additional endpoints, TY‑9591 clearly signals China’s growing confidence in pursuing Best-in-Class status.

This shift mirrors the broader evolution of China’s head-to-head trials—from superficial comparisons to genuine high-stakes competition. Similar breakthroughs are unfolding across therapeutic areas.

Brukinsa (zanubrutinib) by BeiGene pioneered this strategy. The global Phase III ALPINE trial (2022) reported an ORR of 80.4% for zanubrutinib versus 72.9% for ibrutinib in relapsed/refractory CLL/SLL. At 24 months, investigator-assessed PFS reached 78.4% versus 65.9%.

Fueled by this clinical victory, zanubrutinib exceeded USD 1.3 billion in global sales in 2023, becoming China’s first blockbuster novel drug to surpass the billion-dollar threshold.

Among recent high-profile head-to-head studies, Akeso Biopharma’s PD‑1/VEGF bispecific antibody ivonescimab versus pembrolizumab (Keytruda) stands out.

At the 2024 WCLC Congress, pivotal Phase III data showed a median PFS of 11.14 months with ivonescimab versus 5.82 months with Keytruda in PD-L1-positive NSCLC, reducing the risk of progression or death by 49%.

This marked the world’s first Phase III head-to-head superiority over Keytruda. Despite ongoing discussions over overall survival outcomes, ivonescimab is widely tipped to become China’s next billion-dollar molecule. In January 2026, Summit Therapeutics, Akeso’s overseas partner, submitted the BLA to the FDA, with approval expected in 2026.

Notably, head-to-head trials are not mandatory for every developer.

Zhang Lianshan commented:

“Drugs with robust inherent safety and efficacy data can succeed independently in the marketplace. Head-to-head trials demand massive resource investment—and resources are always limited. Ultimately, it is a strategic market decision, not an absolute requirement.”

Legend Biotech’s BCMA CAR‑T therapy ciltacabtagene autoleucel (Carvykti) exemplifies an alternative pathway. Without head-to-head CAR‑T comparisons, it achieved remarkable commercial growth supported by solid clinical evidence. In 2025, annual revenue reached USD 1.887 billion, surging nearly 96% year-on-year, securing its position as the world’s top-selling CAR‑T product.

Regulatory landscapes are evolving rapidly. In late 2025, Dr. Vinay Prasad, then Director of the FDA’s Center for Biologics Evaluation and Research (CBER), proposed that future CAR‑T approvals would require randomized controlled superiority trials against existing standards of care.

This regulatory shift prompted several companies to initiate head-to-head CAR‑T studies, though subsequent personnel changes at the FDA introduced uncertainty around final implementation.

For Chinese developers planning global launches, close monitoring of regulatory trends remains critical. Decisions on conducting head-to-head trials must integrate scientific rationale with target-market approval requirements.

Ultimately, head-to-head trials embody a core mindset: refusing to shy away from comparisons and daring to challenge global leaders. The true strength of China’s landmark new drugs lies not in pipeline scale, but in the courage to compete at the highest level—and courage itself represents the first victory. Time will validate the rest.