Phase 2 Study of Ivonescimab in Patients With Cutaneous Squamous Cell Carcinoma

To learn if ivonescimab can help to control advanced cSCC. The safety and effects of ivonescimab will also be studied.

More details:

Primary Objective - To determine the ORR of ivonescimab in participants with cSCC Secondary Objectives * To evaluate other indicators of the antitumor efficacy of ivonescimab in participants with cSCC. * To evaluate the safety and tolerability of ivonescimab in participants with cSCC Exploratory Objective \- To evaluate potential predictors of response and resistance to ivonescimab in participants with cSCC.

Overview

Ivonescimab (AK112; SMT112) is a tetravalent bispecific antibody that targets PD‑1 and VEGF. It has completed multiple phase 3 studies in non–small cell lung cancer (NSCLC). In China, ivonescimab received marketing authorization in May 2024 for use with chemotherapy in EGFR‑mutated, nonsquamous NSCLC after EGFR‑TKI therapy, and in April 2025 as first‑line monotherapy for PD‑L1–positive NSCLC; it remains investigational in the United States and other Summit Therapeutics territories. (akesobio.com)

Mechanism of action

Ivonescimab binds PD‑1 and VEGF simultaneously and exhibits “cooperative binding,” increasing affinity to one target in the presence of the other, which enhances blockade of both PD‑1/PD‑L1 and VEGF/VEGFR signaling. The Fc region is engineered to reduce effector functions. These properties are proposed to increase activity in the tumor microenvironment while maintaining a favorable safety profile. (pmc.ncbi.nlm.nih.gov)

Efficacy

• First‑line PD‑L1–positive (TPS ≥1%) advanced NSCLC (HARMONi‑2, randomized, double‑blind, phase 3, China): Ivonescimab monotherapy significantly improved progression‑free survival (PFS) vs pembrolizumab at interim analysis (median PFS 11.1 vs 5.8 months; HR 0.51, 95% CI 0.38–0.69; P<0.0001). Results were consistent in PD‑L1 TPS 1–49% (HR 0.54) and TPS ≥50% (HR 0.48) subgroups. Objective response rate (ORR) was higher with ivonescimab (50.0% vs 38.5%) in the WCLC late‑breaking presentation. (thelancet.com)

• Post‑EGFR‑TKI, EGFR‑mutated nonsquamous NSCLC (HARMONi‑A, randomized, double‑blind, phase 3, China): Adding ivonescimab to carboplatin/pemetrexed significantly improved PFS vs chemotherapy alone (median 7.1 vs 4.8 months; HR 0.46, 95% CI 0.34–0.62). ORR was 50.6% vs 35.4%. Benefits were observed across key subgroups, including those previously treated with third‑generation EGFR‑TKIs and those with brain metastases. Primary HARMONi (global MRCT) subsequently confirmed a clinically meaningful PFS benefit (HR 0.52; median PFS 6.8 vs 4.4 months) with consistent effects across regions. (ascopubs.org)

• Phase 2 (first‑line advanced/metastatic NSCLC without EGFR/ALK alterations): Ivonescimab plus platinum doublet chemotherapy produced ORR 75% in squamous and 55% in nonsquamous cohorts, with durable responses in an open‑label multi‑center study. (ascopubs.org)

Safety

• In HARMONi‑2, grade ≥3 treatment‑related adverse events (TRAEs) occurred in 29% with ivonescimab vs 16% with pembrolizumab; the most common high‑grade TRAE with ivonescimab was hypertension (5%). Rates of grade ≥3 immune‑related AEs were similar (7% vs 8%). (ascopost.com)

• In HARMONi‑A, grade ≥3 treatment‑emergent AEs were 61.5% with ivonescimab plus chemotherapy vs 49.1% with chemotherapy (largely chemotherapy‑related). Grade ≥3 immune‑related AEs were 6.2% vs 2.5%; grade ≥3 VEGF‑related AEs were 3.1% vs 2.5%. (ascopubs.org)

Overall, the safety profile reflects expected immune‑checkpoint and anti‑VEGF class effects (e.g., immune‑related AEs, hypertension/proteinuria), with manageable toxicity in randomized studies. (ascopost.com)

Further reading

• Lancet: HARMONi‑2 randomized phase 3 (ivonescimab vs pembrolizumab) in PD‑L1–positive advanced NSCLC. (thelancet.com)
• JCO/ASCO 2024 abstract: HARMONi‑A randomized phase 3 (ivonescimab + chemo vs chemo) post‑EGFR‑TKI. (ascopubs.org)
• IASLC WCLC coverage: HARMONi‑2 late‑breaking results and summary. (iaslc.org)
• iScience 2025: Mechanistic study describing cooperative binding and Fc engineering. (sciencedirect.com)
• ASCO 2023 abstract: Phase 2 ivonescimab + chemotherapy in first‑line NSCLC. (ascopubs.org)

Notes on regulatory status: Ivonescimab is approved in China (EGFR‑mutant post‑TKI in May 2024; first‑line PD‑L1–positive in April 2025) and is investigational elsewhere. Ongoing global development includes additional registrational studies. (akesobio.com)

Last updated: Oct 2025

Inclusion Criteria:

* Ability to understand and willingness to sign informed consent form prior to initiation of the study and any study procedures.

* Age ≥18 years.

* Has advanced (unresectable and/or metastatic) cSCC.

* Refractory to anti-PD-1 therapy. There is no limit on the number of prior lines of therapy.

* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

* Measurable disease per the RECIST v1.1

* Life expectancy ≥3 months per treating physician's discretion.

* Adequate organ and marrow function as defined below within 28 days of study treatment initiation:

* Hemoglobin \>9.0 g/dL

* Absolute neutrophil count ≥1500/mL

* Platelets ≥100,000/mL

* Total bilirubin ≤1.5 institutional upper limit of normal (ULN). Documented Gilbert syndrome is allowed if total bilirubin is ≤3 × ULN.

* AST/alanine transaminase ≤2.5 × institutional ULN. Transaminases up to 3 × ULN in the presence of liver metastases.

* Serum creatinine ≤1.5 × ULN OR measured or calculated creatinine clearance (CrCl; glomerular filtration rate can also be used in place of creatinine or CrCl) ≥60 mL/min for participants with creatinine levels \>1.5 × institutional ULN (CrCl should be calculated per institutional standard).

* Urine protein \<2+ or 24-hour urine protein quantification \<1.0 g

* For participants not receiving therapeutic anticoagulation: international normalized ratio or activated partial thromboplastin time ≤1.5 × ULN. For patients receiving therapeutic anticoagulation: stable anticoagulant regimen.

* Albumin \>2.5 mg/dL.

* Participants must have adequate washout from prior therapy at the time of study treatment initiation: 4 weeks from major surgery; 4 weeks from antibody-based therapy; 2 weeks or 5 half-lives (whichever is shorter) from any targeted therapy or small molecule therapy; 3 weeks or 5 half-lives (whichever is shorter) from chemotherapy or 6 weeks in the case of certain therapies (e.g., extensive radiotherapy, mitomycin C, and nitrosoureas); 4 weeks from radiation therapy; and at least 2 weeks from palliative radiotherapy.

* Prior treatment with anti-VEGF therapy is allowed.

* Adequately controlled blood pressure with 0 or 1 antihypertensive medication (defined as blood pressure ≤150/100 mmHg at screening and no changes in antihypertensive medication within 7 days of Day 1 Cycle 1.

* Women of childbearing potential (WOCBP) should have a negative urine or serum pregnancy within 72 hours prior to study treatment initiation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

* WOCBP must agree to use adequate contraception during the study treatment period and for 120 days after completion of study treatment. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

* Male participants of childbearing potential must agree to use adequate contraception during the study treatment period and for 120 days after completion of study treatment.

Exclusion Criteria:

* Participants who have previously been treated with PD-1 inhibitors and required dose interruption, permanent discontinuation, or systemic immunosuppression due to irAEs.

* History of allergic reactions attributed to compounds of similar chemical or biologic composition to ivonescimab.

* Pregnant or breastfeeding.

* Participants with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.

* Known history of positive test for human immunodeficiency virus or known acquired immunodeficiency syndrome.

* Known history of acute or chronic hepatitis B virus or hepatitis C virus infection.

* Previous solid organ or allogeneic hematopoietic stem cell transplant.

* Active infection requiring IV antibiotics or other uncontrolled intercurrent illness requiring hospitalization.

* Unresolved toxicities from prior therapy (defined as having not resolved to NCI CTCAE v.5.0 Grade ≤1 or baseline) or any other toxicity that is deemed irreversible by the investigator. Exceptions include endocrinopathies from prior therapy or disease and successfully treated (such as hypothyroidism, diabetes mellitus), alopecia, vitiligo, and Grade ≤2 peripheral neuropathy.

* Major blood vessel invasion.

* Major surgical procedures or serious trauma within 4 weeks prior to study treatment initiation, or plans for major surgical procedures within 4 weeks after the first dose of study treatment (as determined by the investigator). Minor local procedures (excluding central venous catheterization and port implantation) within 3 days prior to study treatment initiation.

* Unstable angina, myocardial infarction, congestive heart failure (New York Heart Association \[NYHA\] classification Grade ≥2) or vascular disease (e.g., aortic aneurysm at risk of rupture) that required hospitalization within 12 months prior to study treatment initiation, or other cardiac impairment that may affect the safety evaluation of the study drug (e.g., poorly controlled arrhythmias, myocardial ischemia).

* History of esophageal gastric varices, severe ulcers, wounds that do not heal, abdominal fistula, intra-abdominal abscesses, or acute gastrointestinal bleeding within 6 months prior to study treatment initiation.

* History of arterial thromboembolic event, venous thromboembolic event of Grade ≥3 as specified in NCI CTCAE v5.0, transient ischemic attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy within 6 months prior to study treatment initiation.

* Acute exacerbation of chronic obstructive pulmonary disease within 4 weeks prior to study treatment initiation.

* History of perforation of the gastrointestinal tract and/or fistula, history of gastrointestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), extensive bowel resection (partial colectomy or extensive small bowel resection) within 6 months prior to study treatment initiation.

* Treatment with a live, attenuated vaccine within 4 weeks prior to study treatment initiation, or anticipation of need for such a vaccine during the course of the study.

* Has a known additional malignancy that is progressing or requires active treatment.

Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer.

* Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study.

* Inability to comply with the study and follow-up procedures.

* Participants who are receiving any other investigational agents.

* Participants with psychiatric illness/social situations that would limit compliance with study requirements.