Introduction and Scientific Rationale
Programmed death-1 (PD-1) bispecific antibodies are engineered immunoglobulins that simultaneously bind PD-1 on cytotoxic T cells and a second target—most commonly vascular endothelial growth factor (VEGF), cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), or lymphocyte activation gene-3 (LAG-3)—within a single molecular scaffold. The central rationale is that dual-pathway engagement can overcome the inherent limitations of PD-1/PD-L1 monotherapy: inadequate immune priming, immunosuppressive tumor microenvironment remodeling, and limited activity in programmed death-ligand 1 (PD-L1)–low or –negative disease. Compared with sequential or concurrent administration of two separate monoclonal antibodies, the bispecific format offers the theoretical advantages of synchronized pharmacokinetics, a single infusion schedule, and potentially reduced overlapping immune-related adverse events (irAEs) through coordinated dosing of both biologic activities 18.
However, mechanistic elegance does not automatically translate to clinical superiority. As of July 2026, the critical question for oncologists, clinical researchers, and medical affairs teams is not whether these agents are biologically active—they demonstrably are—but whether they have generated the depth and breadth of comparative evidence needed to displace well-established anti-PD-1/PD-L1 standards.
Landscape of Major PD-1 Bispecific Programs (2025–2026)
The PD-1 bispecific field encompasses several distinct mechanistic clusters, spanning early discovery through regulatory approval 12. The programs most relevant to standard-of-care replacement are summarized in Table 1.
Table 1. Representative Late-Stage or Approved PD-1–Directed Bispecific Programs (2025–2026)
| Agent | Target Class | Sponsor(s) | Highest Stage/Status | Representative Indications | Positioning vs. Standard of Care |
|---|---|---|---|---|---|
| Ivonescimab (AK112/SMT112) | PD-1/VEGF | Akeso; Summit Therapeutics | NMPA approved (Apr 2025, 1L PD-L1+ NSCLC); FDA BLA accepted (Jan 2026, EGFR-mut post-TKI NSCLC) | Advanced NSCLC (multiple settings), EGFR-mut NSCLC post-TKI | Upgrade/replacement in selected NSCLC niches; awaiting FDA and EMA decisions |
| Cadonilimab (AK104/Kaitanni) | PD-1/CTLA-4 | Akeso; Shanghai Pharmaceuticals | NMPA approved (gastric, cervical) | 1L gastric, 1L cervical, HCC | Replacement of PD-1 monotherapy in PD-L1–low gastric; complement in cervical |
| Volrustomig (MEDI-5752) | PD-1/CTLA-4 | AstraZeneca | Phase III | NSCLC (PD-L1 <50%), mesothelioma, HNSCC, cervical | Targeting PD-L1–low NSCLC; data pending |
| Rilvegostomig (AZD-2936) | PD-1/TIGIT | AstraZeneca | Phase III | NSCLC stage IV, HER2+ gastric/GEJ, gastric | Novel TIGIT target; Phase III ARTEMIDE-Gastric01 enrolling |
| Erfonrilimab (KN046) | PD-L1/CTLA-4 | Suzhou Alphamab; HEC Pharm | Phase III (ENREACH-L-01 met primary PFS endpoint) | 1L squamous NSCLC, hepatic, ESCC | Positive interim Phase III PFS signal; OS pending |
| BNT327 (PM8002) | PD-L1/VEGF-A | BioNTech; Biotheus | Phase 2/3 (ROSETTA Lung-01/02; ES-SCLC vs. atezolizumab, NSCLC vs. pembrolizumab) | ES-SCLC, NSCLC, TNBC, mesothelioma | Registrational trials vs. established standards; efficacy data pending |
| IBI-318 | PD-1/PD-L1 | Innovent; Eli Lilly | Phase III | SCLC, hematologic neoplasms | Distinct mechanism; limited data in retrieved materials |
| ZG005 | PD-1/TIGIT | Suzhou Zelgen | Phase 1/2 | Cervical cancer, HCC | Early-phase; promising ORR in cervical cohorts |
Abbreviations: NSCLC, non–small cell lung cancer; EGFR-mut, EGFR-mutated; 1L, first-line; HCC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; ESCC, esophageal squamous cell carcinoma; ES-SCLC, extensive-stage small cell lung cancer; TNBC, triple-negative breast cancer; GEJ, gastroesophageal junction; ORR, objective response rate; PFS, progression-free survival; OS, overall survival.
Clinical Evidence by Tumor Type
Non–Small Cell Lung Cancer (NSCLC)
NSCLC is the tumor type with the most mature, source-resolved Phase III evidence for PD-1 bispecific antibodies in 2025–2026 27.
Ivonescimab vs. pembrolizumab (first-line PD-L1–positive advanced NSCLC; HARMONi-2, NCT05499390): In a double-blind, randomized Phase III trial of 398 Chinese patients with PD-L1 tumor proportion score (TPS) ≥1% and no actionable driver mutations, ivonescimab (20 mg/kg every 3 weeks) achieved a median PFS (mPFS) of 11.14 months versus 5.82 months for pembrolizumab (hazard ratio [HR] 0.51; p<0.0001), with ORR 50.0% versus 38.5%. The benefit was consistent across PD-L1 TPS ≥50% (HR 0.46), TPS 1–49% (HR 0.54), squamous (HR 0.48), and non-squamous histologies (HR 0.54). However, grade ≥3 treatment-related adverse events (TRAEs) were 29% versus 16%, grade ≥3 VEGF-related adverse events were 10.2% versus 1.0%, and the OS data were not yet reported from this record 27. Notably, the China NMPA approved ivonescimab for this population in April 2025, and the 2026 CSCO NSCLC guideline issued a Class I recommendation for ivonescimab monotherapy in PD-L1–positive, driver gene–negative NSCLC 2329.
Ivonescimab plus chemotherapy in EGFR-mutated NSCLC post-TKI failure (HARMONi-A): In 322 patients globally (38% Western countries), ivonescimab plus pemetrexed/carboplatin versus placebo plus chemotherapy demonstrated mPFS of 7.06 versus 4.80 months (HR 0.46; p<0.0001) and final OS of 16.8 versus 14.1 months (HR 0.74; p=0.02). Subgroup benefits included brain metastases (HR 0.40) and T790M-positive disease (HR 0.22). The FDA accepted the BLA for this indication in January 2026, with a PDUFA target action date of November 14, 2026 13171828.
Ivonescimab plus chemotherapy vs. tislelizumab plus chemotherapy in first-line squamous NSCLC (HARMONi-6): In 532 Chinese patients, ivonescimab demonstrated superior PFS (median 11.14 vs. 6.90 months; HR 0.60; p<0.0001), with benefit across all PD-L1 subgroups, including TPS <1% (HR 0.55). At 21.36 months' follow-up, median OS was 27.89 versus 23.69 months (HR 0.66; p=0.0017). Grade ≥3 TRAEs were 69.2% (ivonescimab) versus 58.9% (tislelizumab). These results were presented as a plenary session at ESMO 2025, and the NMPA accepted a supplemental NDA for this indication in September 2025; a Class II CSCO recommendation was issued 314192324.
Erfonrilimab (KN046, PD-L1/CTLA-4) plus chemotherapy in squamous NSCLC (ENREACH-L-01, Phase III): This trial in 482 Chinese patients met its co-primary PFS endpoint against chemotherapy alone, with no new safety signals; OS data are not yet available 27.
Hepatocellular Carcinoma (HCC)
The most credible comparative dataset outside NSCLC in the retrieved materials is the Phase II/III QL1706 study in first-line advanced HCC (n=120; four arms including QL1706 + bevacizumab + XELOX vs. sintilimab + bevacizumab as control). At a median follow-up of 6.7 months, the 6-month PFS rate was 78.5% in the selected triplet arm versus 50.3% in the control arm; however, OS was immature, ORR was not reported despite being a co-primary endpoint, and grade ≥3 TRAEs were 46.7% versus 37.9% 2.
Cadonilimab plus lenvatinib (Phase Ib/II, 1L advanced HCC): ORR was 35.5–35.7% across dose cohorts, mPFS 8.61–9.82 months, median duration of response (DoR) approximately 13.6–13.7 months, and median OS 27.1 months or not reached at 27.4 months' follow-up—clinically meaningful signals, but grade ≥3 TRAEs reached 66.1% and the study lacked a randomized comparator 2.
Gastric/Gastroesophageal Junction Cancer
Cadonilimab plus chemotherapy was approved by the NMPA in May 2024 for first-line advanced gastric cancer, with final Phase III COMPASSION-15 results presented at ESMO 2025 showing OS HR 0.49 (p=0.025) versus PD-1 inhibitor-based regimens in the PD-L1 CPS <5 subgroup—addressing a genuine unmet need in this biomarker-defined population. The NMPA additionally approved cadonilimab for first-line gastric cancer with NRDL inclusion effective 2026. An international Phase III registration study (COMPASSION-37) comparing cadonilimab plus chemotherapy versus nivolumab plus chemotherapy has been authorized for FDA-regulated initiation as of late 2025 151621.
Other Solid Tumors
ZG005 (PD-1/TIGIT) in advanced cervical cancer (Phase 1/2, n=41): ORR was 69.2% at 10 mg/kg and 80.0% at 20 mg/kg in first-line patients receiving concurrent chemotherapy ± bevacizumab; grade ≥3 TRAEs were 29.3%, with no discontinuations or TRAE-related deaths. These are encouraging early-phase signals, but the study is small and non-comparative 5.
BNT327 (PD-L1/VEGF-A) in ES-SCLC and NSCLC: Phase 2 China data presented at ELCC 2025 showed anti-tumor activity and acceptable safety in ES-SCLC and second-line SCLC. Global Phase III ROSETTA Lung-01 (vs. atezolizumab) and ROSETTA Lung-02 (vs. pembrolizumab) are enrolling approximately 982 patients for first-line NSCLC; no efficacy data are yet available from these trials 3031.
Rilvegostomig (PD-1/TIGIT) in HER2+ gastric/GEJ cancer: Phase III ARTEMIDE-Gastric01, enrolling approximately 840 patients across ~25 countries, evaluates rilvegostomig with trastuzumab deruxtecan (T-DXd) and chemotherapy; no efficacy readout is yet available 26.
Safety and Tolerability
A consistent theme across all retrieved datasets is that efficacy gains are often accompanied by higher rates of grade ≥3 adverse events compared with control arms or conventional PD-1 monotherapy (Table 2) 2327.
Table 2. Safety Comparison: Key PD-1 Bispecific Programs Versus Control Arms
| Program/Trial | Grade ≥3 TRAEs (Bispecific) | Grade ≥3 TRAEs (Control) | Notable Toxicity Signal |
|---|---|---|---|
| Ivonescimab vs. pembrolizumab (HARMONi-2) | 29% | 16% | VEGF-related: proteinuria, hypertension (10.2% vs. 1.0%) |
| Ivonescimab + chemo vs. placebo + chemo (HARMONi-A) | 67.1% | 54.7% | Grade ≥3 irAE 6.2% vs. 2.5% |
| Ivonescimab + chemo vs. tislelizumab + chemo (HARMONi-6) | 69.2% | 58.9% | Hemorrhage 1.9% vs. 0.8% (predominantly grades 1–2) |
| QL1706 triplet vs. sintilimab + bev (1L HCC) | 46.7% | 37.9% | Higher immune-related and GI toxicity |
| Cadonilimab + lenvatinib (1L HCC, Phase Ib/II) | 66.1% | N/A (no comparator) | High toxicity burden in triple combination |
| ZG005 + chemo (cervical, Phase 1/2) | 29.3% | N/A | No treatment-related deaths or discontinuations |
Despite these higher overall TRAE rates, the critical observation from HARMONi-6 is that VEGF-related grade ≥3 hemorrhage was only 1.9% in squamous NSCLC patients—contradicting historical concerns about anti-VEGF agents in this histology and reflecting ivonescimab's engineered, tumor microenvironment-selective binding architecture 3.
Regulatory, Guideline, and Implementation Outlook
As of July 2026, regulatory adoption of PD-1 bispecific antibodies remains geographically concentrated in China, with global adoption pending 131415162332:
- NMPA (China): Ivonescimab approved for 1L PD-L1+ advanced NSCLC (April 2025) and sNDA accepted for 1L squamous NSCLC (September 2025); cadonilimab approved for gastric cancer (2024), cervical cancer (June 2025), and included in the NRDL effective 2026.
- FDA (United States): BLA accepted for ivonescimab in EGFR-mutated NSCLC post-TKI (PDUFA date November 14, 2026); cadonilimab remains investigational with COMPASSION-37 initiating late 2025.
- EMA (European Union): No PD-1 bispecific antibody has received EMA approval as of July 2026.
- CSCO Guidelines (China, 2026): Ivonescimab received Class I recommendations for 1L PD-L1+ driver gene–negative NSCLC and post-TKI EGFR-mutated NSCLC, and a Class II recommendation for 1L squamous NSCLC; cadonilimab received the only Category I Level IA Evidence recommendation for 1L advanced gastric cancer 232425.
- NCCN and ESMO Guidelines: As of July 2026, neither NCCN nor ESMO guidelines have incorporated PD-1 bispecific antibodies as preferred first-line agents, with guideline updates anticipated following FDA and EMA decisions 3233.
Conclusion: Complement or Replacement?
Based on the totality of evidence retrieved through July 2026, PD-1 bispecific antibodies have not yet achieved sufficient clinical evidence, geographic regulatory coverage, or guideline integration to broadly replace current standard-of-care immunotherapy regimens across oncology. However, the picture is nuanced and rapidly evolving:
In specific niches, replacement or meaningful upgrade is supported by current evidence:
- EGFR-mutated NSCLC post-TKI progression (China and pending FDA): Ivonescimab plus chemotherapy replaces chemotherapy alone with a 2.7-month OS improvement.
- First-line squamous NSCLC (China): Ivonescimab plus chemotherapy demonstrates statistically significant PFS and OS superiority over a conventional PD-1 inhibitor plus chemotherapy, with CSCO Class I/II endorsement.
- PD-L1–low (CPS <5) gastric cancer (China): Cadonilimab addresses an unmet need where single-agent PD-1 inhibitors show limited benefit.
In contrast, broad global displacement of conventional anti-PD-1/PD-L1 monotherapy, PD-1 plus chemotherapy, or CTLA-4 combinations is constrained by five factors: (1) geographic concentration of approvals in China; (2) pending FDA and EMA regulatory decisions; (3) lack of head-to-head data versus pembrolizumab-based regimens in most Western trial populations; (4) incomplete long-term OS and safety data for most programs; and (5) absence of NCCN and ESMO guideline integration 121232.
For oncologists in 2025–2026, the actionable guidance is clear: continue established standards (anti-PD-1/PD-L1 monotherapy, PD-1 plus chemotherapy, ipilimumab plus nivolumab where appropriate) as first-line approaches for most patients, while recognizing that ivonescimab and cadonilimab represent genuine advances in biomarker-defined populations already approved in China. Monitoring of Phase III readouts from volrustomig, BNT327 ROSETTA trials, rilvegostomig ARTEMIDE-Gastric01, and the HARMONi-3 global pembrolizumab comparator trial will be critical to determining the ultimate scope of replacement versus complementary positioning for this promising drug class 2021223031.