Ivonescimab (development code AK112, brand name Yiruixi / 依沃西单抗 in China; partner code SMT112 from Summit Therapeutics outside Greater China) is a tetravalent bispecific antibody that simultaneously blocks PD-1 (an immune checkpoint on T cells) and VEGF (vascular endothelial growth factor, the angiogenesis signal that tumors use to grow blood vessels). Developed by Akeso Biopharma (China); Summit Therapeutics holds rights outside Greater China. China's NMPA has approved it for several non-small-cell lung cancer (NSCLC) indications since May 2024. The U.S. FDA has accepted Summit's BLA for ivonescimab + chemotherapy in EGFR-mutated NSCLC post-TKI; PDUFA goal action date November 14, 2026.

Ivonescimab (AK112) Clinical Trials (May 2026): 71 Recruiting Interventional Studies

Last updated: May 24, 2026

🗓️ Coming up at ASCO 2026: HARMONi-6 — Phase 3 ivonescimab + platinum chemotherapy versus tislelizumab + platinum chemotherapy in first-line squamous NSCLC — will be presented in the Plenary Session on Sunday, May 31, 2026 (LBA, 8am ET release). This is the highest-profile bispecific-antibody data drop of the meeting.

About Ivonescimab

Drug profile:

Ivonescimab (development code AK112; brand name Yiruixi / 依沃西单抗 in China; partner code SMT112 from Summit Therapeutics outside Greater China) is a tetravalent bispecific antibody developed by Akeso Biopharma. It simultaneously blocks PD-1 (an immune checkpoint on T cells) and VEGF (vascular endothelial growth factor, the angiogenesis signal that tumors use to grow blood vessels).

Mechanism of action:

Combining checkpoint blockade with anti-angiogenic therapy is established (e.g., atezolizumab + bevacizumab in HCC, pembrolizumab + bevacizumab in cervical cancer). Ivonescimab's distinction is doing both with a single molecule designed for cooperative binding: VEGF is abundant in the tumor microenvironment, and its presence enhances the avidity of the PD-1 binding arm at the same site — concentrating activity inside tumors versus systemic exposure. The clinical rationale is to combine the two mechanisms with potentially better tumor-selectivity than separate-molecule combinations.

Regulatory status:

Ivonescimab is the world's first approved bispecific PD-1/VEGF antibody. China's NMPA approval timeline:

May 2024: 1L EGFR-TKI-refractory EGFR-mutant NSCLC (HARMONi-A Phase 3)
September 2024: 1L PD-L1-positive NSCLC (HARMONi-2 Phase 3 — ivonescimab monotherapy superior to pembrolizumab monotherapy on PFS, the first single agent to beat pembrolizumab in 1L NSCLC)
2025: additional NSCLC indications and 1L hepatocellular carcinoma (+ lenvatinib)

U.S. FDA: Summit Therapeutics submitted a Biologics License Application for ivonescimab + chemotherapy in 2L+ EGFR-mutated non-squamous NSCLC after TKI progression. FDA has accepted the BLA for filing with a PDUFA goal action date of November 14, 2026. Submission based on the global Phase 3 HARMONi trial. Note on global Phase 3 HARMONi-3 (ivonescimab + chemo vs pembrolizumab + chemo in 1L NSCLC): in Q2 2026, the squamous cohort's planned interim PFS analysis did not meet the threshold for statistical significance; the independent data monitoring committee recommended the trial continue as planned and remain double-blinded. The overall study readout is still pending.

Active Research Directions in 2026

Lung cancer is the dominant focus — SCLC (15 recruiting trials, the largest single indication for ivonescimab) and NSCLC (11) together account for ~37% of the active pipeline. Multiple Phase 3 trials confirming HARMONi-A / HARMONi-2 readouts, plus new combinations and earlier-line maintenance settings.
HCC + lenvatinib + ivonescimab — building on the 2025 China approval for 1L HCC, multiple Phase 2/3 combination trials expand to TACE and earlier-line settings
Colorectal cancer — 7 trials including 1L Phase 3 chemo-IO combinations and the head-to-head Phase 3 against bevacizumab in metastatic CRC (NCT07228832)
Triple-negative breast cancer (TNBC) — Phase 3 1L ivonescimab + nab-paclitaxel (NCT06767527) and Phase 2 perioperative/adjuvant studies
Head & neck squamous cell carcinoma (HNSCC) — head-to-head Phase 3 against pembrolizumab (NCT06601335, with anti-CD47 AK117) and combinations with chemoradiation
Pancreatic cancer Phase 3 — ivonescimab + chemo ± AK117 (anti-CD47) in 1L mPDAC (NCT06953999)
Bispecific-on-bispecific combinations — ivonescimab + cadonilimab (the other Akeso bispecific, PD-1 × CTLA-4) in SCLC and HCC, exploring whether layering two bispecifics improves outcomes over either alone

Recruiting Trials by Indication

Small Cell Lung Cancer (SCLC) — 15 recruiting (largest indication cluster)

Ivonescimab has become a major investigational backbone in SCLC. The Phase 3 consolidation program is the most advanced:

NCT07010263 — Phase 3 ivonescimab as consolidation treatment for patients with ES-SCLC after 1L chemo-immunotherapy.
Multiple Phase 2 ivonescimab + cadonilimab combinations in 1L and recurrent SCLC (the Akeso bispecific-on-bispecific strategy).
Phase 2 combinations with chemotherapy, radiotherapy, and tarlatamab in extensive-stage and limited-stage SCLC.

Non-Small Cell Lung Cancer (NSCLC) — 11 recruiting

The approved indication in China and the focus of the global FDA-registration program:

NCT05899608 — Phase 3 ivonescimab for 1L NSCLC (China).
NCT06767514 — Phase 3 ivonescimab for 1L NSCLC (additional China trial).
NCT06928389 — Phase 3 ivonescimab + docetaxel in advanced NSCLC after platinum (2L+).
HARMONi-6 (China, 1L squamous NSCLC vs tislelizumab + chemo) — Plenary Session at ASCO 2026 on May 31; covered in the highlight box above.
Global Phase 3 HARMONi-3 (1L vs pembrolizumab + chemo, Summit-sponsored) remains blinded after the Q2 2026 squamous-cohort interim PFS analysis did not meet the early-significance threshold.

Hepatocellular Carcinoma (HCC) — 6 recruiting

Approved in China for 1L HCC (+ lenvatinib); active expansion into TACE combinations and earlier-line settings:

Phase 2/3 ivonescimab + lenvatinib in 1L advanced HCC (per 2025 NMPA approval).
Phase 2 ivonescimab + TACE + lenvatinib in intermediate-stage HCC.
Phase 2 ivonescimab + cadonilimab in advanced HCC (bispecific-on-bispecific).

Colorectal Cancer — 7 recruiting

Including a notable head-to-head Phase 3 against bevacizumab + chemo (the current 1L anti-angiogenic standard):

NCT07228832 — Phase 3 ivonescimab + chemo vs bevacizumab + chemo in metastatic CRC. If positive, ivonescimab could displace bevacizumab in 1L mCRC.
NCT06951503 — Phase 3 AK112 + chemotherapy as 1L treatment for metastatic colorectal adenocarcinoma.

Triple-Negative Breast Cancer (TNBC) — 7 recruiting

Phase 3 1L combination + perioperative/adjuvant settings:

NCT06767527 — Phase 3 AK112 or placebo + nab-paclitaxel as 1L treatment for metastatic TNBC.

Head & Neck Squamous Cell Carcinoma (HNSCC) — 6 recruiting

Including a head-to-head Phase 3 against pembrolizumab (the current 1L IO standard for HNSCC):

NCT06601335 — Phase 3 AK112 + AK117 (anti-CD47) vs pembrolizumab in HNSCC.
NCT07264075 — Phase 3 ivonescimab alone or in combination in squamous H&N cancer.

Pancreatic Cancer — 5 recruiting

NCT06953999 — Phase 3 ivonescimab + chemo with/without AK117 (anti-CD47) in 1L metastatic pancreatic cancer.

Other Indications

Cervical and gynecologic cancers: 4 trials — Phase 2 combinations with chemoradiation and bevacizumab in advanced cervical, ovarian, and endometrial.
Sarcoma: 4 trials — Phase 2 ivonescimab + anti-angiogenic TKI combinations.
Gastric/GEJ: 3 trials — Phase 2 combinations with chemotherapy in 1L and post-progression settings.
Mesothelioma: 2 trials — Phase 2 combinations with chemotherapy.
Renal cell carcinoma (RCC): 2 trials — Phase 2 combinations in 1L and post-IO settings.
Nasopharyngeal carcinoma: Phase 2 combinations with chemoradiation.
Bladder/urothelial: Phase 2 combinations.

Showing pivotal Phase 3 trials plus indication-cluster summaries. The full set of 71 recruiting interventional studies (plus 59 not-yet-recruiting in setup) includes additional investigator-initiated combinations not listed above. View the latest on ClinicalTrials.gov.

Patient Selection and Biomarkers

Ivonescimab trials use a mix of standard immunotherapy biomarkers and indication-specific enrichment:

PD-L1 expression (TPS or CPS) — key for 1L NSCLC trials (HARMONi-2 was PD-L1-positive specifically; other NSCLC studies test PD-L1-negative populations).
EGFR-mutation status — the China-approved indication is 1L EGFR-TKI-refractory EGFR-mutant NSCLC; the Summit FDA BLA is for 2L+ EGFR-mutant non-squamous NSCLC after TKI progression.
Histology (squamous vs non-squamous NSCLC) — squamous lung cancer trials monitor bleeding risk closely (a known anti-angiogenic concern); the HARMONi-3 squamous cohort interim PFS miss may reflect heterogeneity here.
MSI/MMR status in CRC — some colorectal trials are biomarker-stratified.
Indication-defining markers — HCC requires confirmed diagnosis (typically AFP + imaging); cervical/gynecologic trials may require HPV or specific histology subsets.

Side Effects and Practical Considerations

Combined immune + anti-angiogenic profile — the side-effect picture combines what you'd expect from PD-1 inhibitors (immune-related events) and VEGF inhibitors (vascular events).
Immune-related events — hypothyroidism, skin rash and pruritus, fatigue, immune-mediated colitis, hepatitis, and pneumonitis. Pre-existing autoimmune disease requires careful pre-treatment evaluation.
Anti-angiogenic events — hypertension (the most common Grade 3+ event reported in trials), proteinuria, bleeding (typically minor; serious hemorrhage and pulmonary embolism are rare but require monitoring). Squamous histologies have historically had higher bleeding risk with anti-angiogenics, and ivonescimab trials in squamous NSCLC monitor for this.
Delayed wound healing — standard with anti-angiogenic therapies. Plan for treatment interruptions around surgery.
Combination-specific toxicities — chemotherapy combinations add myelosuppression and neuropathy; lenvatinib combinations add hand-foot syndrome and hypertension on top of ivonescimab's baseline hypertension risk.
Geographic context — most clinical experience to date is from Chinese trials (which approved ivonescimab); the limited non-Chinese data from Summit's global trials has been broadly consistent.

Frequently Asked Questions

What is ivonescimab?

Ivonescimab (development code AK112, brand name Yiruixi / 依沃西单抗 in China; partner code SMT112 from Summit Therapeutics outside Greater China) is a tetravalent bispecific antibody that simultaneously blocks PD-1 (immune checkpoint) and VEGF (tumor angiogenesis). Developed by Akeso Biopharma; Summit Therapeutics holds rights outside Greater China. China's NMPA has approved it for several NSCLC indications since May 2024. The U.S. FDA has accepted Summit's BLA for ivonescimab + chemotherapy in EGFR-mutated NSCLC post-TKI; PDUFA goal action date November 14, 2026.

How is ivonescimab different from combining pembrolizumab and bevacizumab?

The therapeutic concept is similar — block PD-1 and VEGF together — but the design is different. Ivonescimab is a single tetravalent molecule with cooperative binding: VEGF abundance in the tumor microenvironment increases the avidity of PD-1 engagement at the same site, concentrating activity inside tumors. The HARMONi-2 Phase 3 trial in China showed ivonescimab monotherapy demonstrated superior progression-free survival compared with pembrolizumab monotherapy in 1L PD-L1-positive NSCLC — the first single agent to beat pembrolizumab in 1L NSCLC. Global head-to-head confirmation is in ongoing Phase 3 trials.

What ivonescimab trials are currently recruiting?

71 recruiting interventional ivonescimab trials as of May 2026 (plus 59 not-yet-recruiting in setup), including 10 Phase 3 pivotal studies. Indication leaders are SCLC (15 trials), NSCLC (11), colorectal (7), triple-negative breast (7), HCC (6), head and neck (6), pancreatic (5), cervical and gynecologic (4), sarcoma (4), gastric/GEJ (3), plus mesothelioma, RCC, nasopharyngeal, and bladder cancers. Most trials are sponsored or led from China; Summit is running additional global Phase 3 trials outside Greater China.

What are the main side effects of ivonescimab?

Side effects combine immune-related events (PD-1) and anti-angiogenic events (VEGF). Immune-related: hypothyroidism, skin rash, fatigue, immune-mediated colitis, hepatitis, pneumonitis. Anti-angiogenic: hypertension (most common Grade 3+), proteinuria, bleeding (typically minor; serious hemorrhage and pulmonary embolism are rare but require monitoring, especially in squamous histologies), delayed wound healing. Combined profile in published Phase 3 trials has been broadly manageable.

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