Overcoming Resistance to Immunotherapy Combining Gemcitabine With Ivonescimab in Advanced NSCLC

NCT07158489 | Not Yet Recruiting Phase 2

• 1 other identifier: SAKK 18/25
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 7

Brief Summary

This Phase II clinical trial (investigates the efficacy of combining gemcitabine, a chemotherapy agent, with ivonescimab, a bispecific PD-1/VEGF antibody, in patients with advanced non-small cell lung cancer (NSCLC) who have experienced disease progression following chemoimmunotherapy (CIT). Lung cancer remains the leading cause of cancer-related death globally, and treatment options after CIT failure are limited. Gemcitabine has demonstrated immunostimulatory properties, including enhanced T-cell infiltration and reduced immunosuppressive cell populations, which may synergize with immune checkpoint inhibitors. Ivonescimab targets both PD-1 and VEGF pathways, potentially enhancing antitumor immune responses and inhibiting tumor angiogenesis. The trial aims to evaluate the objective response rate (ORR) according to RECIST v1.1 criteria. The combination therapy is expected to offer a novel and effective treatment strategy for patients with relapsed NSCLC, addressing a significant unmet medical need.

Conditions

NSCLC; NSCLC (Advanced Non-small Cell Lung Cancer)

Keywords

advanced NSCLC; immune checkpoint inhibitors; Resistance to immunotherapy; Gemcitabine and Ivonescimab; Gemcitabine; Ivonescimab

Outcome Measures

Primary Outcomes (1)

• Objective response rate (ORR) according to RECIST v1.1

  ORR according to RECIST v1.1 is defined as the proportion of patients, whose best overall response is either complete response (CR) or partial response (PR) achieved before disease progression according to RECIST v1.1 or start of a subsequent anti-cancer treatment whichever occurs first. Patients with CR or PR as best observed response will be considered as success; otherwise as failures for this endpoint. Patients without any tumor assessment or with non-evaluable response (NE) during trial treatment will be considered as failures for this endpoint. The primary analysis will be based on the results from the Independent Response Review.

  At the end of trial treatment, up to 2 years from registration.

Secondary Outcomes (2)

• Duration of response (DoR) according to RECIST v1.1

  From first response up to 2 years from treatment start.

• Progression-free Survival (PFS) according to RECIST v1.1

  From first dose of ivonescimab/gemcitabine, up to 2 years from treatment start.

Study Arms (1)

Gemcitabine + Ivonescimab in Advanced NSCLC Resistant to Immunotherapy

EXPERIMENTAL

Drug: Gemcitabine + Ivonescimab

Interventions

Gemcitabine + Ivonescimab DRUG

The trial combines two Investigational Medicinal Products (IMPs): * Gemcitabine, either alone or in combination regimens, is the standard of care (SoC) for several solid tumors, such as advanced or metastatic non-small cell lung cancer (mNSCLC). * Ivonescimab is developed for cancer immunotherapy. Ivonescimab binds to human vascular endothelial growth factor (VEGF) which is involved in tumor angiogenesis, and to human programmed cell death 1 (PD-1) that is a cell surface receptor expressed primarily on activated T cells and acts to inhibit their activation.

Gemcitabine + Ivonescimab in Advanced NSCLC Resistant to Immunotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent according to Swiss law and ICH GCP E6 regulations before registration and prior to any trial specific procedures including patient screening.
• Confirmed squamous or non-squamous mNSCLC stage IIIB-IV (based on 9th edition Tumor-Node-Metastasis (TNM) classification of lung cancers with disease recurrence or progression during or after one or more prior immunotherapy or CIT regimens for metastatic disease.
• Patients with treated and stable central nervous system (CNS) metastases are eligible, if:
• Previous CNS-directed therapy has been completed at least 4 weeks prior to treatment start.
• No evidence of progression after completion of CNS-directed therapy as ascertained by clinical examination and brain imaging with Magnetic Resonance Imaging (MRI) or CT.25
• Patients with known HIV-infection are eligible, if:
• CD4+ T-cell counts are ≥ 350 cells/µl
• No history of AIDS-defining opportunistic infection within past 12 months
• Patient agrees to concomitant antiretroviral therapy (ART) if not currently on ART, or is on ART for ˃ 4 weeks and has a HIV viral load ˂ 400 copies/ml.26
• Patients with a previously treated malignancy are eligible if this is clinically stable and does not require concurrent tumor-directed treatment.
• Exception: patients suffering from prostate cancer under hormonal ablation therapy (hormone sensitive disease).
• Patients with measurable disease according to RECIST v1.1.
• Availability of newly collected or archival (maximum 3 months) samples for TR prior to treatment initiation.
• Age ≥ 18 years
• ECOG performance status 0-2.

You may not qualify if:

• Symptomatic brain metastases.
• Prior treatment with gemcitabine in combination with immunotherapies.
• Tumor progression within the first 8 weeks from start of first-line treatment.
• Activating EGFR or ALK mutations.
• Concomitant use of other anti-cancer drugs or radiotherapy.
• Major surgery within 1 month prior to treatment start.
• Known history of any uncontrolled active systemic infection requiring intravenous antimicrobial treatment.
• Known history of tuberculosis, primary immunodeficiency, allogeneic tissue/solid organ transplant, or receipt of live attenuated vaccine.
• History of interstitial lung disease or severe pneumonitis.
• Concomitant use of corticosteroids as premedication for gemcitabine therapy.
• Concomitant or prior use of immunosuppressive medication such as interferon or methotrexate within 28 days prior to trial treatment start, with the exceptions of local (i.e., intranasal, inhaled and topical) corticosteroids.
• Major blood vessel tumor invasion.
• 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 (NYHA classification Grade ≥2;27) 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.

Sponsors & Collaborators

• Swiss Cancer Institute: lead

Study Sites (7)

Kantonsspital Baden

Baden, 5404, Switzerland

Location

Universitätsspital Basel

Basel, 4031, Switzerland

Location

IOSI Ospedale Regionale di Bellinzona e Valli

Bellinzona, 6500, Switzerland

Location

Kantonsspital Graubuenden

Chur, CH-7000, Switzerland

Location

Hôpital Fribourgeois - Hôpital Cantonal

Fribourg, Switzerland

Location

Hôpitaux Universitaires de Genève

Geneva, 1211, Switzerland

Location

Kantonsspital Winterthur

Winterthur, 8401, Switzerland

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Gemcitabine

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Study Officials

• Alessandra Curioni-Fontecedro, Prof

  Cantonal Hospital Fribourg / University of Fribourg

  STUDY CHAIR

Central Study Contacts

Jana Musilova, PhD

CONTACT

031 389 91 91; trials@swisscancerinstitute.ch

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 28, 2025
• First Posted: September 5, 2025
• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): July 31, 2029
• Last Updated: April 21, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

CH (7)