A Study of Ivonescimab in Combination With Dato-DXd or Osimertinib in People With Non-Small Cell Lung Cancer

Recruiting now · Phase 1/Phase 2

Conditions studied: Non-Small Cell Lung Cancer

In brief

The researchers are doing this study to find out whether ivonescimab in combination with datopotamab deruxtecan- (Dato-DXd) or osimertinib are safe and effective treatments in people with non-small cell lung cancer (NSCLC) that has an EGFR mutation. The researchers will test different doses of the Dato-DXd or osimertinib with an unchanging (fixed) dose of ivonescimab to find the best dose that causes few or mild side effects in participants. Once the dose is found the researchers will test ivonescimab with Dato-DXd or osimertinib in a new group of participants to see if it is effective in treating their NSCLC with an EGFR mutation.

Key facts

Study ID: NCT07535437
Run by: Memorial Sloan Kettering Cancer Center
People needed: 66
Starts: 2026-04-09
Expected to finish: 2028-04-01
Last updated by the study team: 2026-07-13

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

Written informed consent by participant
Biopsy-proven metastatic non-small cell lung cancer
Somatic activating mutation in EGFR in pre-treatment tumor biopsy or cfDNA (including all mutations with sensitivity to osimertinib) by any CLIA certified assay.
Prior treatment with 3rd-generation EGFR TKI therapy and platinum-based chemotherapy (or ineligible for platinum-based chemotherapy)
At least one measurable (RECIST 1.1) indicator lesion not previously irradiated
ECOG PS 0-1
Age ≥18 years old
Ability to swallow oral medications (Study Cohort B only)
Adequate organ function
AST, ALT ≤ 2.5 x ULN; For patients with liver metastases, AST and ALT ≤ 5 × ULN
Total bilirubin ≤ 1.5x ULN; For patients with liver metastases or confirmed/suspected Gilbert syndrome, TBIL ≤3 × ULN Creatinine clearance (CrCl) ≥ 50 mL/min using the Cockcroft-Gault formula or estimated glomerular filtration rate (eGFR) value ≥50 mL/min using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
Urine protein < 2+ or 24 hour urine protein quantification < 1.0 g
Absolute neutrophil count (ANC) ≥ 1500 cells/mm\^3
Hemoglobin ≥ 9.0 g/dL (red blood cell/plasma transfusion is not allowed within 2 weeks prior to screening assessment)
Platelets ≥100,000/mm3 (platelet transfusion is not allowed within 10 days prior to screening assessment)
Coagulation: prothrombin time (PT) or international normalized ratio (INR) ≤ 1.5 × ULN, and partial prothrombin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN (unless abnormalities are unrelated to coagulopathy). This applies only to patients who are not on therapeutic anti-coagulation. Patients receiving therapeutic anti-coagulation should be on a stable dose.
Female patients of childbearing age must have negative serum pregnancy test and a negative urine pregnancy test on the day of first dose prior to dosing.
Female patient of childbearing potential having sex with an unsterilized male partner must agree to use a highly effective method of contraception from the beginning of screening until 90 days after the last dose of the ivonescimab and/or 3 months after last dose of Dato-DXd or 6 weeks after last dose of osimertinib
Unsterilized male patients having sex with a female partner of childbearing potential, or a pregnant or breastfeeding partner must agree to use barrier contraception (male condom plus spermicide) for the duration of the treatment period until 90 days after the last dose of ivonescimab and/or 6 months after the last dose of Dato-DXd or 6 weeks after last dose osimertinib. Male patients with female partners of childbearing potential must have the female partner agree to use at least 1 form of highly effective contraception for the duration of the treatment period until 90 days after the last dose of ivonescimab and/or 3 months after the last dose of Dato-DXd or 6 weeks after last does of osimertinib.

You may not qualify if…

EGFR exon 20 insertion positive lung cancer with expected lack of sensitivity to osimertinib (Study Cohort B only).
Pregnant or lactating women
Participation in another clinical study and receiving treatment with an investigation product during the last 4 weeks before enrollment
Prior exposure to anti-PD-1 inhibitor therapy
Prior exposure to antibody drug conjugate (ADC) containing chemotherapeutic agent targeting topoisomerase I, TROP2 antibody (Study Cohort A only).
History of clinically significant corneal disease (Study Cohort A only)
Poorly controlled hypertension with repeated systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg after oral antihypertensive therapy
Major surgical procedures or serious trauma within 4 weeks of study enrollment, or plans for major surgical procedures within 4 weeks after the first dose (as determined by the investigator). Minor local procedures (excluding central venous catheterization and port implantation) within 3 days prior study enrollment.
History of bleeding tendencies or coagulopathy and/or clinically significant bleeding symptoms or risk within 4 weeks of study enrollment, including but not limited to:
Hemoptysis (defined as coughing up ≥ 0.5 teaspoon of fresh blood or small blood clots). Note: transient hemoptysis associated with diagnostic bronchoscopy is allowed.
Significant nasal bleeding /epistaxis (bloody nasal discharge is allowed)
Current use of prophylactic or full-dose anticoagulants or anti-platelet agents for therapeutic purposes that is not stable prior to first study drug treatment is not allowed. The use of full-dose anticoagulants is permitted as long as the international normalized ratio (INR) or activated partial thromboplastin time (aPTT) is within therapeutic limits according to the medical standard of the enrolling institution.
Active (eg, with disease modifying drugs, prednisone >10 mg daily or equivalent, immunosuppressant therapy) or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
Short course of steroids if given for infection
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is permitted.
Intermittent use of bronchodilators, inhaled corticosteroids, or local corticosteroid injections is permitted
Patients with vitiligo or alopecia
Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
Any chronic skin condition that does not require systemic therapy
Patients without active disease in the last 5 years may be included but only after consultation with the study physician
Patients with celiac disease controlled by diet alone
History of major diseases before first study drug treatment, specifically:
Unstable angina, myocardial infarction, congestive heart failure (New York Heart Association [NYHA] classification ≥ grade 2) or unstable vascular disease (eg, aortic aneurysm at risk of rupture, Moyamoya disease) that required hospitalization within 12 months prior to first study drug treatment, or other cardiac impairment that may affect the safety evaluation of the study drug (eg, 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 of study enrollment
History of any grade arterial thromboembolic event as specified in National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 5.0, transient ischemic attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy within 12 months before first ivonescimab infusion

Where it is running

Memorial Sloan Kettering Basking Ridge (All Protocol Activities) — Basking Ridge, New Jersey, United States (enrolling)
Memorial Sloan Kettering Monmouth (All Protocol Activities) — Middletown, New Jersey, United States (enrolling)
Memorial Sloan Kettering Bergen (All Protocol Activities) — Montvale, New Jersey, United States (enrolling)
Memorial Sloan Kettering Suffolk - Commack (All Protocol Activities) — Commack, New York, United States (enrolling)
Memorial Sloan Kettering Westchester (All Protocol Activities) — Harrison, New York, United States (enrolling)
Memorial Sloan Kettering Cancer Center (All Protocol Activities) — New York, New York, United States (enrolling)
Memorial Sloan Kettering Nassau (All Protocol Activities) — Uniondale, New York, United States (enrolling)

Full record on ClinicalTrials.gov

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