Non-Small Cell Lung Cancer
Conditions
Keywords
females, chemoimmunotherapy, Non-Small Cell Lung Cancer, Programmed Death-Ligand 1 (PD-L1) ≥ 50 %
Brief summary
While documented gender differences exist in drug efficacy and safety, men and women are often treated equally due to the absence of gender-specific clinical trials and approvals. Immune checkpoint blockade is used to enhance the immune system's ability to combat cancer cells and is approved for stage IV non-small cell lung cancer (NSCLC) patients with over 50% PD-L1 expression on tumor surfaces. However, uncertainty remains regarding whether immunotherapy alone or in combination with chemotherapy yields better results. Although both treatment strategies are approved, head-to-head evidence comparing these approaches is lacking. Large trials indicate that women derive less benefit from immunotherapy alone compared to men, while benefiting more from a combination therapy. However, women are often still treated with immunotherapy alone due to a lack of prospective clinical trial evidence supporting combined treatment's superiority. This world's first gender-specific trial aims to determine whether combined treatment is better than immunotherapy alone for female patients. All patients will be randomly assigned to one of the two treatment strategies, with the primary endpoint being the time until disease progression. Additional analyses will evaluate survival and quality of life differences. This investigator-initiated trial, has the potential to reshape clinical practice and improve outcomes for women with lung cancer worldwide.
Interventions
DRUGPembrolizumab
Pembrolizumab (200 mg intravenously, d1, q3W)
Carboplatin (AUC 5), i.v., d1, q3W, for four cycles
DRUGCisplatin (75 mg/m²)
Cisplatin (75 mg/m²) , i.v., d1, q3W, four cycles
DRUGPemetrexed (500 mg/m²)
Pemetrexed (500 mg/m²), i.v., d1, q3W, for four cycles as combination chemoimmunotherapy, after as maintanance therapy with pembrolizumab
DRUGnab-Paclitaxel (100 mg/m² )
nab-Paclitaxel (100 mg/m² ), i.v. on days 1, 8, and 15 (q3W), four cycles
Sponsors
German Cancer Research Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Ability to understand the nature, significance, and individual consequences of the clinical trial. 2. Written informed consent obtained prior to any trial-related procedures. 3. Female participant aged ≥18 years at the time of signing the informed consent form. 4. Histologically or cytologically confirmed stage IV NSCLC (squamous cell carcinoma or adenocarcinoma). 5. Negative molecular testing for EGFR, ALK, and ROS1 alterations (tested locally). 6. PD-L1 tumor proportion score (TPS) ≥50%, tested locally by QUiP®-certified immunohistochemistry. 7. ECOG performance status ≤2. 8. At least one measurable lesion according to RECIST v1.1. 9. Adequate hepatic, renal, and bone marrow function, confirmed within 14 days prior to randomization: Hematology (Hemoglobin ≥ 8.0 g/dL, Absolute neutrophil count (ANC) ≥ 2.0 × 10⁹/L, Total leukocyte count \> 4.0 × 10⁹/L, Platelet count ≥ 100 × 10⁹/L, Serum albumin ≥ 3.0 g/dL) Renal function (Calculated creatinine clearance ≥ 60 mL/min (CKD-EPI equation, Serum creatinine ≤ 1.5 × ULN, Blood urea nitrogen (BUN) ≤ ULN) Hepatic function (Total bilirubin ≤ 1.5 × ULN (≤ 3 × ULN for participants with Gilbert's syndrome, AST and ALT ≤ 2.5 × ULN (≤ 5 × ULN if liver metastases present, Alkaline phosphatase ≤ 2.5 × ULN (≤ 5 × ULN if bone or liver metastases present Coagulation (INR and aPTT ≤ 1.5 × ULN unless on anticoagulant therapy (values within therapeutic range allowed) 10. Female participants of childbearing potential (WOCBP) must use a highly effective contraceptive method (failure rate \<1% per year) during treatment and for 6 months after the last dose. Participants who are postmenopausal or surgically sterile do not require contraception.
Exclusion criteria
* 1\. Mixed histology including any small-cell component. Participants with mixed non-small cell histology (e.g., squamous and non-squamous) may be eligible only if the predominant component (≥50%) is squamous cell carcinoma or adenocarcinoma. 2\. Concurrent participation in another interventional clinical trial involving administration of an investigational medicinal product. Participation in non-interventional studies or registries is allowed. 3\. Prior systemic treatment for metastatic or locally advanced disease or prior PD-1/PD-L1 immunotherapies (including CD137 agonists or immune checkpoint inhibitors such as anti-CTLA-4, anti-TIGIT, anti-PD-1, or anti-PD-L1 antibodies). 4\. Concurrent radiotherapy for cancer treatment, except limited palliative radiotherapy for non-target lesions. 5\. Candidate for complete surgical removal of oligometastatic disease; participants refusing surgery/ablations may be included. 6\. Symptomatic or neurologically unstable CNS metastases or requiring increasing doses of steroids to manage CNS symptoms within 2 weeks prior to study entry (maximum acceptable dose: ≤10 mg prednisolone). 7\. Leptomeningeal disease. 8. History of interstitial lung disease. 9. Active infection requiring intravenous systemic therapy within 2 weeks prior to first study treatment. Participants with infections of CTCAE grade 1-2 that have been treated and clinically stabilized (e.g., uncomplicated urinary tract infection treated with oral antibiotics) may be included. 10\. Known additional malignancy other than NSCLC, either untreated or requiring active treatment within the past 3 years. 11\. Significant cardiovascular disease, including NYHA class ≥III congestive heart failure, clinically significant arrhythmias, or recent myocardial infarction (within 6 months). Left ventricular ejection fraction (LVEF) must be ≥50% (or ≥ institutional lower limit of normal) as assessed by echocardiogram or MUGA scan. 12\. Active autoimmune disease or history of autoimmune or chronic inflammatory disorders requiring systemic treatment (e.g., corticosteroids, immunosuppressants) within the past 2 years, including but not limited to celiac disease, systemic lupus erythematosus, sarcoidosis, Wegener's granulomatosis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis. Note: Diverticulitis is considered under this criterion only if recurrent or chronic; uncomplicated diverticulosis is allowed. Exceptions: 1. Vitiligo or alopecia 2. Hypothyroidism stable on hormone replacement 3. Controlled Type I diabetes mellitus on insulin 4. Chronic skin conditions not requiring systemic therapy 5. No active disease in the last 5 years (requires PI approval) 13. Current or prior use of immunosuppressive medication within 14 days before first pembrolizumab dose. Exceptions: 1. Intranasal, inhaled, topical steroids, or local injections 2. Systemic corticosteroids at doses ≤10 mg/day prednisone equivalent 3. Steroids as premedication for hypersensitivity reactions 14. Treatment with systemic immunostimulatory agents (e.g., interferon, IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to study treatment. 15\. Live vaccine within 30 days prior to first dose of study treatment. 16. Known allergy or hypersensitivity to any component of the chemotherapy regimen or pembrolizumab. 17\. Any co-existing medical condition that, in the investigator's judgment, substantially increases risk associated with participation. 18\. Pregnant or breastfeeding women. 19. Participant incarcerated or involuntarily institutionalized by court order or authorities.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS) | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months after the last patient is included in the study. (estimated 90 months from FPI) | Progression-free survival (PFS) according to RECIST v1.1, defined as the time from randomization until documented disease progression per RECIST v1.1 or death from any cause, whichever occurs first (composite variable strategy) assessed up to 24 months after LPI. Measurement will be based on imaging assessments at predefined intervals. |
Outcome results
None listed