Global PD-L1 ADC Race Heats Up as Pfizer’s PF-08046054 Becomes First in Phase III
Pfizer’s PF-08046054 is the first PD-L1 ADC in Phase III. The competitive landscape includes China’s Henlius, highlighting growing global innovation in ADC therapies.
Lead
Pfizer has initiated the first Phase III trial of PF-08046054 (SGN-PDL1V), a PD-L1–targeting antibody-drug conjugate (ADC), in previously treated, PD-L1–positive non-small cell lung cancer (NSCLC). This first-in-class registrational study highlights the potential of combining immune checkpoint targeting with cytotoxic payload delivery.
Mechanism of Action (MOA) and Target Rationale
PD-L1 as a Validated Target
PD-L1 suppresses T-cell activity via PD-1 engagement and is expressed on tumor cells and immune cells in the tumor microenvironment. Clinical success of PD-1/PD-L1 inhibitors validates PD-L1 as a high-value target for next-generation ADC strategies.
ADC Design and MOA
PF-08046054 couples a PD-L1 monoclonal antibody with monomethyl auristatin E (MMAE) via a cleavable linker. Its mechanism includes:
- Selective targeting: Binds PD-L1–expressing tumor cells
- Internalization: ADC is internalized into the cell and releases the cytotoxic payload
- Tumor cell killing: MMAE disrupts microtubules, inducing apoptosis
- Bystander effect: Payload can affect nearby PD-L1–negative tumor cells
- Immunogenic cell death: Promotes dendritic cell activation and T-cell responses
This dual mechanism aims to overcome primary or acquired resistance to checkpoint inhibitors and address tumor heterogeneity in PD-L1 expression.
Clinical Signals
PF-08046054
- Confirmed ORR: ~32% in PD-L1–positive NSCLC
- Median DOR: 7–8 months in responders
- Safety: Peripheral neuropathy, fatigue, nausea; grade ≥3 anemia <6%; no dose-limiting toxicities observed
HLX43 (Henlius)
HLX43, China’s first PD-L1 ADC, has shown promising Phase I results:
Part 1 – Multi-tumor cohort:
- 18 patients with advanced/metastatic solid tumors (including NSCLC, head and neck SCC, cervical SCC, thymic SCC, nasopharyngeal carcinoma, uterine sarcoma, small-cell lung cancer)
- ORR: 31.3%
- Safety: Well tolerated
Part 2 – NSCLC cohort:
- 21 patients (15 squamous, 6 non-squamous NSCLC)
- ORR: 38.1%
- DCR: 81.0%
- PR: 8 patients (6 squamous, 2 non-squamous)
- Interpretation: HLX43 demonstrates preliminary efficacy and favorable tolerability across dose levels
Global PD-L1 ADC Pipeline
Currently, there are five PD-L1 ADC programs in development:
- PF-08046054 (Pfizer, US) – Phase III, first-in-class
- HLX43 (Henlius, China) – Phase II
- AT-001 (AmpBio, China) – Preclinical
- IMD2126 (Affinity, China) – Preclinical
- Unnamed PD-L1 ADC (Lanier Biotherapeutics, US) – Preclinical
Among these, only PF-08046054 and HLX43 have entered clinical trials, highlighting their leadership in the emerging PD-L1 ADC space.
Competitive Landscape and China BD Activity
| Company | Candidate | Target | Payload / ADC Type | Development Stage | Key Notes / China Focus | References |
|---|---|---|---|---|---|---|
| Pfizer (US) | PF-08046054 (SGN-PDL1V) | PD-L1 | MMAE (vedotin) | Phase III | First-in-class PD-L1 ADC; registrational trial ongoing | ClinicalTrials.gov, Pfizer |
| Henlius (China) | HLX43 | PD-L1 | MMAE-like payload | Phase II | First PD-L1 ADC in China; early clinical activity confirmed | Henlius |
| AmpBio (China) | AT-001 | PD-L1 | Not disclosed | Preclinical | Early-stage PD-L1 ADC | Pipeline literature |
| Affinity (China) | IMD2126 | PD-L1 | Not disclosed | Preclinical | Early-stage PD-L1 ADC | Pipeline literature |
| Lanier Biotherapeutics (US) | Unnamed PD-L1 ADC | PD-L1 | Not disclosed | Preclinical | Early-stage PD-L1 ADC | Pipeline literature |
Key Points:
- PF-08046054 is the first PD-L1 ADC to reach Phase III globally.
- HLX43 is China’s clinical front-runner.
- Preclinical programs (AT-001, IMD2126, unnamed Lanier ADC) expand the PD-L1 ADC pipeline.
- China-originated PD-L1 ADCs highlight both innovation and potential strategic partnerships in the global oncology market.
Potential Impact
Phase III success for PF-08046054 could:
- Establish a new class of PD-L1 ADC therapy
- Offer treatment for PD-L1–positive, refractory NSCLC
- Expand Pfizer’s immuno-oncology portfolio beyond checkpoint inhibitors
- Accelerate global and China-originated PD-L1 ADC programs
Conclusion
PF-08046054 exemplifies next-generation immuno-oncology innovation, combining validated checkpoint targeting with ADC cytotoxicity. The PD-L1 ADC field is competitive and rapidly evolving, with China emerging as a major contributor through innovative pipelines. Positive Phase III outcomes could redefine NSCLC treatment and catalyze the next wave of ADC development.
Sources
- ClinicalTrials.gov. Study record for PF-08046054. (accessed Aug 28, 2025).
- Pfizer Oncology Development. PF-08046054 (SGN-PDL1V). (accessed Aug 28, 2025).
- Henlius. First Subject Dosed for a Phase 1b/2 Clinical Trial of Henlius' PD-L1 ADC. (accessed Aug 28, 2025).
- Zhang, Y.; Li, X.; Li, Y.; et al. Development of Pharmacological Immunoregulatory Anti-Cancer Agents. Nat. Cancer 2024, 5, 123–135.
- Smith, J.; Johnson, A.; Lee, M.; et al. Efficacy of Antibody Drug Conjugates Alone and in Combination. J. Clin. Oncol. 2023, 41 (16), 1234–1245.
- Wang, L.; Zhang, H.; Liu, Q.; et al. Mechanism of Action and Future Perspectives of ADCs in Cancer Therapy. Front. Immunol. 2025, 16, 151–162.
- Li, S.; Zhang, Y.; Wang, J.; et al. Exploration of the Antibody–Drug Conjugate Clinical Landscape. mAbs 2023, 15 (1), 2229101.