Phase II Open‑Label Study of Cemiplimab Plus Platinum‑Gemcitabine in Treatment‑Naïve Advanced Squamous NSCLC Selected by Low Cytidine Deaminase Activity

Trial ID: 2024-517799-40-00
Protocol: GOIRC-04-2024
Sponsor: G.O.I.R.C. Gruppo Oncologico Italiano Di Ricerca Clinica

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Diseases & Conditions

Squamous cell carcinoma of lung

Objectives

The primary objective is to explore the efficacy of a platinum‑gemcitabine backbone combined with cemiplimab in treatment‑naïve patients with advanced squamous non‑small cell lung cancer and low baseline cytidine deaminase activity, thereby assessing the therapeutic benefit of this biomarker‑selected regimen.

Secondary objectives include:

Evaluation of the activity of platinum‑gemcitabine plus cemiplimab as first‑line therapy in patients with low baseline CDA activity.
Evaluation of the activity of carboplatin‑paclitaxel plus cemiplimab as first‑line therapy in patients with high baseline CDA activity.
Assessment of the safety and tolerability profile of platinum‑gemcitabine plus cemiplimab in the low‑CDA cohort.
Assessment of the safety and tolerability profile of carboplatin‑paclitaxel plus cemiplimab in the high‑CDA cohort.

Participants

The trial enrolled adult patients (≥18 years) of both sexes with confirmed Advanced squamous non‑small cell lung cancer that was stage IV or recurrent, treatment‑naïve for metastatic disease, and exhibited measurable disease per RECIST v1.1. Participants were required to have an ECOG performance status of 0‑1, a life expectancy of at least 12 weeks, and adequate hematologic, hepatic, and renal function. Selection required histologic or cytologic confirmation, known PD‑L1 tumor status, and absence of prior systemic chemotherapy or anti‑PD‑(L)1 therapy for metastatic disease (prior curative‑intent therapy was permitted after a ≥6‑month washout). Both male and female subjects were included; females of child‑bearing potential and sexually active males had to adhere to defined contraceptive measures throughout treatment and for a specified period after the last dose. Additional exclusion considerations included the need for concurrent chest irradiation and insufficient organ function. The sponsor did not provide the total number of participants enrolled.

Plans and Procedures

The CECYDE trial is a multicenter open‑label phase II study evaluating the combination of intravenous cemiplimab 350 mg with platinum‑gemcitabine chemotherapy in treatment‑naïve patients with advanced squamous non‑small cell lung cancer selected for low baseline cytidine deaminase activity. Eligible participants undergo a screening visit to confirm inclusion criteria, followed by a baseline visit on day 1 of cycle 1 where the first infusion of cemiplimab and chemotherapy is administered. Subsequent treatment cycles are given every three weeks, with clinical and laboratory assessments performed at each infusion visit; imaging for tumor response is scheduled every eight weeks. Follow‑up visits continue after the last scheduled dose to monitor survival and safety until the end‑of‑study visit, which occurs at 12 months after registration or at the time of study discontinuation. Participant involvement therefore extends from screening through the final follow‑up, typically spanning 12 months or longer if survival permits. Early termination may occur due to disease progression, unacceptable toxicity, withdrawal of consent, or loss to follow‑up. The overall trial recruitment period is planned from May 2026 to December 2031.

Treatment

The investigational product is Cemiplimab, administered as an intravenous infusion at a dose of 350 mg per administration. The infusion is delivered through a peripheral or central venous line according to the study‑specified schedule, and the pharmaceutical form is a sterile solution prepared for infusion.

All participants receive standard‑of‑care chemotherapy consisting of a platinum compound in combination with gemcitabine. Both agents are given intravenously in accordance with institutional protocols for advanced squamous non‑small cell lung cancer, and are administered on the same treatment cycles as the investigational antibody.

Dosing cycles are defined by the protocol and repeat at regular intervals throughout the treatment period. Compliance with the infusion schedule is monitored by documenting infusion start and end times, verifying dose calculations, and recording any deviations in the case report form. Adherence to the chemotherapy regimen is similarly tracked, with dose modifications and delays recorded per protocol‑defined criteria.

Efficacy

The efficacy evaluation incorporates a primary endpoint of Overall Survival, defined as the interval from the date of registration to death from any cause and analyzed as the 1‑year survival rate within the low cytidine deaminase activity cohort. Secondary efficacy parameters include median Overall Survival, survival rates at 3 years and 5 years, Progression Free Survival (time from registration to disease progression per investigator assessment or death, reported as median, 6‑month, and 12‑month rates), Objective Response Rate (sum of complete and partial responses per RECIST 1.1), median Duration of Response (from first documented response to first progression), time to tumor response, and Disease control rate (complete response + partial response + stable disease). Efficacy outcomes will also be stratified by PD‑L1 expression levels (<1 %, 1‑49 %, ≥50 %).

Assessment methods employ investigator‑determined tumor measurements according to the standardized RECIST 1.1 criteria for response and progression, with adverse event severity graded using the CTCAE version 5.0. Survival endpoints are calculated from the registration date, and radiographic evaluations are performed at protocol‑specified intervals to capture response dynamics. Data analysis will compute median values, survival rates at predefined time points, and categorical response rates, with subgroup analyses based on PD‑L1 status.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
Known PD-L1 tumor status as determined by an IHC assay performed by local laboratory on previously obtained archival tumor tissue or tissue obtained from a biopsy at screening
No need for concomitant chest irradiation
ECOG performance status 0-1
Life expectancy ≥ 12 weeks
At least one lesion measurable according to RECIST v 1.1 outside of the CNS, not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements.
Adequate hematologic function as evidenced by absolute neutrophil count (ANC) ≥ 1,500/μL, hemoglobin ≥ 9.0 g/dL (5.58 mmol/L), and platelet count ≥ 100,000/μl.
Adequate hepatic and renal function: • Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) • ALT (SGPT), AST (SGOT) ≤ 2.5 x institutional upper limit of normal (≤ 5 x ULN if the liver has tumor involvement) • Serum creatinine ≤ 1.5 times the ULN or creatinine clearance ≥ 60 mL/min, calculated according to the standard Cockcroft and Gault formula.
The patient has adequate coagulation function as defined by International Normalized Ratio (INR) ≤ 1.5 and a partial thromboplastin time (PTT) (PTT/aPTT) < 1.5 x ULN. Patients on full-dose anticoagulation must be on a stable dose (minimum duration 14 days) of oral anticoagulant or low molecular weight heparin (LMWH). If receiving warfarin, the patient must have an INR ≤ 3.0.
Female patients must have a negative pregnancy test and not be breast-feeding prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: • Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments. • Women under 50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range for the institution. • Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation • For female patients of childbearing potential, agreement (by patient and/or partner) to use a highly effective form of contraception that results in a low failure rate (< 1% per year) when used consistently and correctly, and to continue its use for 6 months after the last dose of chemotherapy or at least 4 months after the last dose of cemiplimab, whichever occurs last. Such methods include: combined (estrogen and progestogen containing) hormonal contraception, progestogen-only hormonal contraception associated with inhibition of ovulation together with another additional barrier method always containing a spermicide, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, and vasectomized partner (on the understanding that this is the only one partner during the whole study duration). Female patients of childbearing potential should agree not to donate eggs (ova/oocytes) to others or to freeze or store eggs for reproductive purposes from the start of dosing until 6 months after discontinuation of the study treatment.
Male patients who are sexually active must be willing to use barrier contraceptives (i.e.; by use of condoms) during sex with all partners during treatment with chemotherapy and for at least 6 months after the last dose of chemotherapy or at least 4 months after the last dose of cemiplimab, whichever occurs last. Men must refrain from donating sperm from the start of dosing until 6 months after discontinuing study treatment.
Written informed consent and any locally required authorization obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations
Ability to comply with the study protocol, in the investigator's judgment
Age ≥ 18 years at the time of study entry.
Histologically or cytologically (cell blocks only; smears are not acceptable) documented pulmonary squamous carcinoma
Stage IV or recurrent disease according to the AJCC 8th edition Cancer Staging Manual
No prior chemotherapy or treatment with another systemic anti-cancer agent. for the metastatic disease
Patients who have received prior neo-adjuvant, adjuvant chemotherapy or chemoradiotherapy with curative intent for non-metastatic disease must have experienced a treatment-free interval of at least 6 months from enrolment since the last chemotherapy or completion of chemoradiotherapy
Patients who received prior anti-PD-(L)1 as adjuvant or neoadjuvant therapy at stage 3B /3C disease will be allowed if have experienced a treatment-free interval of at least 6 months from enrolment since the last immunotherapy dose

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Exclusion Criteria

Patients with a sensitizing mutation in the epidermal growth factor receptor (EGFR) gene, or with anaplastic lymphoma kinase (EML4-ALK) translocations or with ROS1 proto-oncogene receptor tyrosine kinase (ROS1) translocations. EGFR mutations, ALK and ROS1 translocations will be assessed in never- smoker patients
Participants with HBsAg positive who have controlled infection (serum HBV DNA PCR that is below the limit of detection and receiving anti-viral therapy for hepatitis B) are eligible. Participants with controlled infections must undergo periodic monitoring of HBV DNA. Participants must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study medication
Participants with HBsAg negative but total HBcAb positive are permitted with the following requirements: If serum HBV DNA PCR is above the limit of detection at CECYDE trial - GOIRC-04-2024 v. 1.0 of 25 August 2025 Page 28 of 91 screening, initiate HBV antiviral therapy before study entry.
Participants who are HCV Ab+ who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are eligible
Known positive serology for HIV. Participants with known controlled HIV infection (undetectable viral load on HIV RNA PCR) and CD4 count above 350 either spontaneously or on a stable antiviral regimen are eligible. For these participants monitoring will be performed per local standards.
Any infection requiring hospitalization or treatment with IV anti-infectives within 2 weeks of first dose of study medication
Significant traumatic injury or radiotherapy involving an extensive field within the last 4 weeks prior to first dose of study treatment or anticipation of the need for major surgery during study treatment. Palliative radiotherapy to a limited field is allowed if concluded at least 2 weeks prior enrolment.
Other malignancies (previous or current), except for adequately treated in situ carcinoma of the uterine cervix, basal or squamous cell carcinoma of the skin, localized prostate cancer surgically treated with curative intent or ductal carcinoma in situ treated surgically treated with curative intent or if previous malignancy was more than 5 years prior and there are no signs or symptoms of recurrence.
Major surgery (including open biopsy) within 28 days prior to first dose of protocol therapy
Prior allogeneic stem cell or solid organ transplantation
Patients with any underlying medical condition that might be aggravated by treatment or which cannot be controlled i.e. patients with active serious infection, uncontrolled diabetes mellitus, pericardial effusion
Symptomatic brain metastases or spinal cord compression (CT or MRI of the head is required within 4 weeks prior to registration) requiring immediate radiotherapy for palliation
Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment other than those in the present study. Concurrent use of hormonal therapy for non-cancer- related conditions (e.g., hormone replacement therapy) is acceptable.
Treatment with any other investigational agent within 30 days prior to starting study treatment, or concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contra- indicates the use of an investigational drug or puts the patient at high risk for treatment- related complications.
Active or prior documented autoimmune or inflammatory disorders
History or active autoimmune neurologic paraneoplastic syndrome (e.g. non-infectious encephalitis, Lambert-Eaton syndrome etc.) or any other immune-mediated paraneoplastic syndrome. Patients with SIADH or ectopic ATCH production are allowed on the study.
Patient has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP. Receipt of COVID-19 vaccination within 1 week of planned start of study medication or for which the planned COVID-19 vaccinations would not be completed 1 week prior to start of study medication.
History of idiopathic pulmonary fibrosis, including pneumonitis, drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
Prior therapy for metastatic disease with any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent and anti-CTL-A4 agent.
Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 drug elimination half-lives (whichever is longer) prior to initiation of study treatment
Any condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of randomization
History of leptomeningeal disease
History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
History of allergies or hypersensitivity to any study drugs or study drug components or excipients.
Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria: a) Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. b) Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with carboplatin, paclitaxel, gemcitabine or cemiplimab may be included only after consultation with the Study Physician.
Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results
Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 6 months after last chemotherapy dose at least 4 months after the last dose of cemiplimab, whichever occurs last.
Patients should not donate blood whilst on this study.
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures.Patients with indwelling catheters (e.g., Pleura-Cath) are allowed.
Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected calcium > ULN).
History of cardiac disease: congestive heart failure >NYHA class 2; active CAD (MI or acute coronary syndrome more than 12 months prior to study entry is allowed); cardiac arrythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted) or uncontrolled hypertension.
Transient ischemic attack or stroke within 1 year
Active SARS- COV-2 infection.
Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C