PD-1 × VEGF-A Target Pair Landscape — What's Happening and Why It Matters

1. Executive Snapshot

PD-1 × VEGF-A is the most commercially charged checkpoint × angiogenesis pair in bispecific development — and the most contested. One asset, [ivonescimab (AK112/SMT112; Akeso → Summit)](https://www.akesobio.com/en/rd-and-science/products-center/ivonescimab/), a first-in-class tetravalent, Fc-silent bispecific ([JITC](https://jitc.bmj.com/content/11/Suppl_1/A1316)), dominates: three NMPA approvals in China, a US BLA accepted (PDUFA 2026-11-14), and a head-to-head PFS win over pembrolizumab (49% risk reduction, HARMONi-2). Deal gravity is high — up to $5B Summit–Akeso (2022), ~$11B BMS–BioNTech on adjacent pumitamig (2025). The negatives are equally real: HARMONi-2 OS (22.3% risk reduction) fell far short of PFS, HARMONi-3's interim OS missed, and Western-patient benefit looks thinner. Direct competition is sparse (four named assets) with one company owning nearly all clinical depth — a hot pair with fragile proof.

2. Asset Landscape

Preclinical

• CTX-10726 (Compass, NASDAQ: CMPX): "differentiated" PD-1×VEGF-A bispecific; SITC 2025 data claim improved PD-1 blockade ([Compass PR](https://www.nasdaq.com/press-release/compass-therapeutics-presents-preclinical-data-ctx-10726-differentiated-pd-1-x-vegf)).

Clinical

• CR-001 (Crescent, NASDAQ: CBIO): PD-1×VEGF-A bispecific in global Phase 1/2 ASCEND; first patient dosed; ASCO 2026 TiP ([marketscreener](https://in.marketscreener.com/news/crescent-biopharma-announces-trial-in-progress-presentation-for-ascend-study-of-cr-001-a-pd-1-x-veg-ce7f5adfd98cf62c)).
• SIM0689 (Simcere): NMPA trial approval 2026-06-12; not yet in clinic ([Simcere announcement](https://www.cnfin.com/announ/detail/index.html?id=834631705597&code=02096&dannoun=hkdetail&announ=hk)).

Approved

• Ivonescimab (依达方®, AK112/SMT112) — NMPA approvals: 2L EGFRm NSCLC + chemo (2024-05, HARMONi-A) ([Summit PR](https://smmttx.com/news/press-releases/news-details/2024/Ivonescimab-in-Combination-with-Chemotherapy-Approved-in-China-by-NMPA-for-2L-EGFRm-NSCLC-based-on-HARMONi-A-Clinical-Trial-Positive-Trend-Observed-in-Overall-Survival-towards-Ivonescimab-Plus-Chemotherapy-05-31-2024-12-00-AM/)); 1L PD-L1+ NSCLC (2025-04-28, HARMONi-2) ([OncLive](https://www.onclive.com/view/ivonescimab-wins-nmpa-approval-in-china-for-first-line-pd-l1-advanced-nsclc)); 1L squamous NSCLC + chemo (2026-08-12, HARMONi-6) ([Morningstar/PR](https://www.morningstar.com/news/business-wire/20260812443578/ivonescimab-in-combination-with-chemotherapy-approved-in-china-by-nmpa-for-first-line-treatment-of-patients-with-squamous-non-small-cell-lung-cancer)). US BLA accepted 2026-01-29 (EGFRm later-line), PDUFA 2026-11-14 ([Summit PR](https://content-archive.fast-edgar.com/20260129/AKZZC22CZ22SU2Z2222S22ZZHN3TZZGS7582/a2026_prx0129xfdablaacce.htm)).

Discontinued

• No named direct PD-1×VEGF-A termination found — likely a data gap. Adjacent warnings: bintrafusp alfa (PD-L1×TGF-β) failed phase III in lung cancer ([pharmaphorum](https://pharmaphorum.com/news/gsk-merck-cos-hopeful-bintrafusp-alfa-fails-in-key-lung-cancer-trial)); ImmuneOnco regained IMM2510 (PD-L1×VEGF) rights in 2026-01 after Axion Bio termination (deal >$2B) ([ImmuneOnco PR](https://cn.immuneonco.com/news/gsdynamics/594.html)).

3. Companies

• Originator: Akeso (HKEX: 09926) — ivonescimab originator, China rights.
• Licensee: Summit (NASDAQ: SMMT) — US/Canada/Europe/Japan rights via the 2022-12 license worth up to $5B ([Akeso PR](https://akesobio.com/en/media/akeso-news/20221206/)); essentially a one-asset company.
• Followers: Compass (CTX-10726), Crescent (CR-001), Simcere (SIM0689).
• Adjacent PD-L1×VEGF: Biotheus → BioNTech ($800M-upfront acquisition, 2024-11) → BMS global co-development of pumitamig (2025-06, ~€10B/~$11B) ([Nasdaq](https://www.nasdaq.com/articles/biontech-acquire-biotheus-upfront-consideration-800m), [European Biotechnology](https://european-biotechnology.com/latest-news/super-deal-for-biontech-bms-licenses-potential-blockbuster-for-e10bn/)).
• Big pharma stance: BMS in via pumitamig; ~$15B AstraZeneca interest in Summit/ivonescimab (June 2026) is an unverified rumor, not fact ([pharmaphorum](https://pharmaphorum.com/news/summit-climbs-rumour-15bn-astrazeneca-interest)); Merck is publicly skeptical that bispecifics beat the PD-1 mAb + anti-VEGF mAb combination ([biopharmadive](https://www.biopharmadive.com/news/pharma-merck-summit-vegf-pd1-drug-research-cancer/822035/)).

4. Clinical & Deal Timeline

5. Risks & Failures

• OS/PFS disconnect: HARMONi-2 OS (22.3% risk reduction, HR≈0.777) fell far short of the 49% PFS signal; Summit's stock crashed on the AACR 2025 readout ([FiercePharma](https://www.fiercepharma.com/pharma/summit-stock-crashes-akeso-shares-bispecifics-first-overall-survival-data-keytruda-head-head)).
• HARMONi-3 interim OS miss (2025-10): the global phase III failed its interim OS bar; Summit amended to histology-stratified analysis and cancelled a $500M share offering ([Biospace](https://www.biospace.com/drug-development/summits-bispecific-misses-survival-endpoint-in-global-phase-iii-trial-but-analysts-remain-optimistic)).
• Western-patient signal weaker: Summit's 10-Q disclosed that longer-follow-up PFS including all Western patients showed reduced benefit — the core "China vs West" registration risk ([Summit 10-Q](https://www.publicnow.com/view/14DA238BDACD2F37EB4EE19A2AD34E31281D1135)).
• HARMONi-6 narrowing (Grade C): at approval #3, trade media reported survival benefit degrades with longer follow-up — reported, not independently confirmed ([thebiointel](https://www.thebiointel.com/article/summit-and-akeso-win-third-china-approval-for-ivonescimab-as-harmoni-6-survival-signal-weakens)).
• FDA exposure: review rests on single-country data in an EGFRm later-line population ([intelligencia](https://www.intelligencia.ai/pd1-vegf-bispecifics-fda-risk-analysis/)).
• Thesis question: does one-molecule co-engagement beat PD-1 mAb + anti-VEGF mAb co-administration? ([biopharmadive](https://www.biopharmadive.com/news/pharma-merck-summit-vegf-pd1-drug-research-cancer/822035/)).
• Class-effect safety (Grade C): anti-VEGF toxicities (bleeding, hypertension, proteinuria) stacked on PD-1 irAEs; detailed tables not public.
• Concentration risk: one asset carries the entire direct-pair thesis; the three followers are preclinical/early.

6. Discovery Questions

• Co-engagement vs combination: does single-molecule dual binding with TME enrichment beat PD-1 mAb + anti-VEGF mAb co-administration — and what evidence (enrichment imaging, paired-receptor binding) proves it?
• Format/design space: is the tetravalent, Fc-silent architecture necessary, or do bivalent / effector-competent designs shift the efficacy-toxicity window?
• Epitope & isoform coverage: how much PD-L1 vs PD-L2 blockade per PD-1 arm; which VEGF-A isoforms (165/121) and VEGFR1/R2 selectivity — do these tune efficacy vs bleeding risk?
• OS vs PFS mismatch: why strong PFS but weak/delayed OS across trials — crossover, follow-up time, or biology (angiogenesis inhibition limited in late disease)?
• China vs West: what drives the response gap (genetics, HBV/HCC background, TME, SOC differences) — the key global-registration uncertainty?
• Biomarkers: does PD-L1 TPS (HARMONi-7 targets TPS≥50%), an angiogenic signature, or ctDNA dynamics predict benefit?
• Resistance & sequencing: VEGF-independent angiogenesis, alternative checkpoints (LAG-3/TIGIT), EGFR-TKI sequencing — how do next combinations build on this?
• Follower differentiation: how do CTX-10726 and CR-001 out-position a dominant incumbent — epitope, effector function, tissue specificity, or indication?

7. Why This Matters Now

What changed (last 12 months): the pair moved from promising China data to a global pivotal stakes game — a third NMPA approval (2026-08-12), an FDA BLA with a November 2026 PDUFA, a statistically significant HARMONi-6 OS win in The Lancet, and ~$11B of adjacent-class validation (BMS–BioNTech). Meanwhile, HARMONi-3's interim OS miss, the HARMONi-2 OS disappointment, weaker Western-patient PFS, and Grade C reports of HARMONi-6 benefit narrowing show the pair's central vulnerability: PFS wins, but OS proof stays inconsistent.

Why it matters: this pair is the live experiment testing whether the bispecific checkpoint × angiogenesis thesis — one molecule, two mechanisms, TME synergy — holds at registration level. The November 2026 PDUFA is binary for the field: approval validates co-engagement economics and pulls capital to followers (CTX-10726, CR-001, SIM0689); a miss or narrow label reinforces the "just combine two mAbs" argument and deflates adjacent PD-L1×VEGF valuations. Sparse direct competition means the next 12–24 months decide whether ivonescimab stays a one-company franchise or becomes a contested category.

8. Sources

• [JITC: ivonescimab MOA abstract](https://jitc.bmj.com/content/11/Suppl_1/A1316)
• [Akeso PR: Summit–Akeso license (2022-12)](https://akesobio.com/en/media/akeso-news/20221206/)
• [Summit PR: NMPA approval #1 / HARMONi-A (2024-05)](https://smmttx.com/news/press-releases/news-details/2024/Ivonescimab-in-Combination-with-Chemotherapy-Approved-in-China-by-NMPA-for-2L-EGFRm-NSCLC-based-on-HARMONi-A-Clinical-Trial-Positive-Trend-Observed-in-Overall-Survival-towards-Ivonescimab-Plus-Chemotherapy-05-31-2024-12-00-AM/)
• [JAMA: HARMONi-A publication (2024-06)](https://pubmed.ncbi.nlm.nih.gov/38820549/)
• [Nasdaq PR: HARMONi-2 PFS (2024-09)](https://www.nasdaq.com/press-release/ivonescimab-monotherapy-reduced-risk-disease-progression-or-death-49-compared)
• [FiercePharma: HARMONi-2 OS / stock crash (2025-04)](https://www.fiercepharma.com/pharma/summit-stock-crashes-akeso-shares-bispecifics-first-overall-survival-data-keytruda-head-head)
• [OncLive: NMPA approval #2 (2025-04-28)](https://www.onclive.com/view/ivonescimab-wins-nmpa-approval-in-china-for-first-line-pd-l1-advanced-nsclc)
• [Biospace: HARMONi-3 interim OS miss (2025-10)](https://www.biospace.com/drug-development/summits-bispecific-misses-survival-endpoint-in-global-phase-iii-trial-but-analysts-remain-optimistic)
• [Summit 10-Q: Western-patient PFS analysis](https://www.publicnow.com/view/14DA238BDACD2F37EB4EE19A2AD34E31281D1135)
• [Summit PR: FDA BLA acceptance (2026-01-29)](https://content-archive.fast-edgar.com/20260129/AKZZC22CZ22SU2Z2222S22ZZHN3TZZGS7582/a2026_prx0129xfdablaacce.htm)
• [Summit release / ASCO 2026: HARMONi-6 OS](https://www.tradeshownews.com/news/home/20260531161413/en/Ivonescimab-with-Chemotherapy-Demonstrated-a-Statistically-Significant-Overall-Survival-Benefit-Compared-to-Tislelizumab-Plus-Chemotherapy-in-1L-Treatment-of-Patients-with-Squamous-NSCLC-in-the-HARMONi-6-Study-Conducted-by-Akeso-in-China)
• [The Lancet: HARMONi-6](https://www.sciencedirect.com/science/article/abs/pii/S0140673626009669)
• [Morningstar/PR: NMPA approval #3 (2026-08-12)](https://www.morningstar.com/news/business-wire/20260812443578/ivonescimab-in-combination-with-chemotherapy-approved-in-china-by-nmpa-for-first-line-treatment-of-patients-with-squamous-non-small-cell-lung-cancer)
• [thebiointel: HARMONi-6 survival signal weakens (Grade C)](https://www.thebiointel.com/article/summit-and-akeso-win-third-china-approval-for-ivonescimab-as-harmoni-6-survival-signal-weakens)
• [Nasdaq: BioNTech–Biotheus acquisition (2024-11)](https://www.nasdaq.com/articles/biontech-acquire-biotheus-upfront-consideration-800m)
• [European Biotechnology: BMS–BioNTech pumitamig deal (2025-06)](https://european-biotechnology.com/latest-news/super-deal-for-biontech-bms-licenses-potential-blockbuster-for-e10bn/)
• [ImmuneOnco PR: IMM2510 rights returned (2026-01)](https://cn.immuneonco.com/news/gsdynamics/594.html)
• [pharmaphorum: bintrafusp alfa phase III failure](https://pharmaphorum.com/news/gsk-merck-cos-hopeful-bintrafusp-alfa-fails-in-key-lung-cancer-trial)
• [biopharmadive: are pharmas chasing the wrong target?](https://www.biopharmadive.com/news/pharma-merck-summit-vegf-pd1-drug-research-cancer/822035/)
• [intelligencia: FDA risk analysis](https://www.intelligencia.ai/pd1-vegf-bispecifics-fda-risk-analysis/)
• [Compass PR: CTX-10726 preclinical data](https://www.nasdaq.com/press-release/compass-therapeutics-presents-preclinical-data-ctx-10726-differentiated-pd-1-x-vegf)
• [marketscreener: Crescent CR-001 ASCEND TiP](https://in.marketscreener.com/news/crescent-biopharma-announces-trial-in-progress-presentation-for-ascend-study-of-cr-001-a-pd-1-x-veg-ce7f5adfd98cf62c)
• [Simcere announcement: SIM0689 IND (2026-06-12)](https://www.cnfin.com/announ/detail/index.html?id=834631705597&code=02096&dannoun=hkdetail&announ=hk)
• [pharmaphorum: AZ interest rumor — unverified (Grade D)](https://pharmaphorum.com/news/summit-climbs-rumour-15bn-astrazeneca-interest)

Research tools this landscape implies: a human/cyno/mouse panel of PD-1 ECD (His/Fc/Avi-biotin) and VEGF-A165/121 proteins; pathway controls (PD-L1 ECD, PD-L2, VEGFR1-Fc/VEGFR2-Fc); sequential dual-binding BLI/SPR reagents to prove single-molecule co-engagement; competition and epitope-binning kits vs pembrolizumab/nivolumab/bevacizumab and an ivonescimab-class BsAb positive control; functional panels (PD-1/PD-L1 reporter, T-cell reactivation, HUVEC proliferation/tubule formation, dual-target co-culture) — the exact kit a BsAb discovery team needs to enter or benchmark this pair.