Fulzerasib Sequential Sintilimab Plus Platinum-Doublet Neoadjuvant Therapy for Resectable KRAS G12C-Mutant NSCLC

Evaluation of Efficacy and Safety of Fulzerasib Sequentially Combined With Sintilimab Plus Platinum-Doublet Chemotherapy as Neoadjuvant Therapy in Patients With Resectable Non-Small Cell Lung Cancer With KRAS G12 Mutation: a Single-Arm, Phase II Clinical Trial

This is an exploratory study evaluating the efficacy and safety of neoadjuvant therapy with fulzerasib sequentially combined with sintilimab plus platinum-doublet chemotherapy in patients with resectable non-small cell lung cancer (NSCLC) harboring KRAS G12C mutation.

Approximately 30 treatment-naïve patients with stage IB-IIIA (AJCC 8th edition) NSCLC and confirmed KRAS G12C mutation will be enrolled.

Eligible subjects will receive 6 weeks of fulzerasib followed by a 2-week washout period, then 3 cycles (q3w) of sintilimab plus investigator's choice of platinum-doublet chemotherapy.

An end-of-treatment visit will be performed within 7 days after the last dose of neoadjuvant therapy.

Following neoadjuvant therapy, subjects without disease progression (per RECIST 1.1) and meeting criteria for radical resection will undergo curative surgery within 7-28 days after the last dose of neoadjuvant therapy. Subjects with disease progression (per RECIST 1.1) or who do not meet criteria for radical resection will discontinue study treatment. Subjects assessed with disease progression during neoadjuvant therapy will also discontinue study treatment, with subsequent therapy at the investigator's discretion; subjects without disease progression will continue to complete remaining neoadjuvant therapy. Adjuvant and other postoperative therapy will be determined by the investigator.

Pathologic complete response (pCR) and major pathologic response (MPR) rates will be evaluated by the investigator in resected pathological specimens according to the International Expert Consensus on Neoadjuvant Immunotherapy for NSCLC.

Clinical tumor imaging assessments will be performed by the investigator per RECIST 1.1. Preoperative imaging will include at least neck, chest, abdomen, and pelvis (after 6 weeks of neoadjuvant targeted therapy and before sequential chemo-immunotherapy, and 7-28 days after the last neoadjuvant treatment and prior to surgery). Tumor assessment will be performed 14-28 days after surgery as the postoperative baseline, to be completed before the first adjuvant therapy. Imaging assessments will then be conducted every 12 weeks (±7 days) post-baseline for up to 2 years, or until disease progression, withdrawal, loss to follow-up, death, or other protocol-specified criteria, whichever occurs first.

Inclusion Criteria:

1. Sign the Informed Consent Form (ICF) and be able to comply with the visit and related procedures as stipulated in the protocol.
2. Be male or female, aged ≥18 years old.
3. Histologically or cytologically confirmed primary non-small cell lung cancer (NSCLC).
4. Clinical stage IB to IIIA disease, according to the 8th edition of the TNM classification for lung cancer as defined by the International Association for the Study of Lung Cancer (IASLC) and the American Joint Committee on Cancer (AJCC).
5. All subjects must have a written test report before enrollment to prove the presence of KRAS G12C mutation; and must have no sensitive mutations of Epidermal Growth Factor Receptor (EGFR), Anaplastic Lymphoma Kinase (ALK).
6. The patient is deemed by a thoracic surgeon to be a candidate for curative resection (R0 resection) and has adequate pulmonary function to undergo the planned pulmonary resection.
7. Have at least one measurable lesion according to RECIST 1.1 criteria.
8. Have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1.
9. Have not received any systemic anti-tumor treatment for locally advanced or metastatic NSCLC before.
10. Have adequate organ and bone marrow function (subjects who have received any cell or growth factor therapy within 2 weeks before the first administration of the study drug should be excluded), defined as follows:

1) Blood routine: Absolute neutrophil count (ANC) ≥1.5×109/L or within the normal range; platelet (PLT) count ≥100×109/L; hemoglobin (HGB) content ≥9.0 g/dL.

2) Liver function: Serum total bilirubin (TBIL) ≤1.5×Upper Limit of Normal Value (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN.

3) Renal function: Serum creatinine (Cr) ≤1.5×ULN or clearance of creatinine (CCr) ≥50 mL/min, calculated by the Cockcroft-Gault formula (using actual body weight); urine routine test shows urine protein <2+; for subjects with urine protein ≥2+ at baseline as detected by urine test strips, a 24-hour urine collection should be performed and the protein content in 24-hour urine should be <1 g (if both methods are used, the value obtained from 24-hour urine collection will be used to determine eligibility).

4) Coagulation function: Activated Partial Thromboplastin Time (APTT) ≤ 1.5×ULN and International Normalized Ratio (INR) ≤ 1.5; 11. Female subjects of childbearing age or male subjects whose partners are of childbearing age must take effective contraceptive measures throughout the treatment period and for 180 days after the treatment.

12.Female subjects have evidence of postmenopausal status, or the urine or serum pregnancy test results of premenopausal female subjects are negative.

Exclusion Criteria:

1. Histological or cytological pathology confirms the presence of small cell carcinoma, neuroendocrine carcinoma, sarcoma, lymphoepithelioma-like carcinoma, salivary gland tumors, or mesenchymal tumor components.
2. Tumor invasion of the diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina.
3. Superior sulcus (Pancoast) tumor.
4. Presence of tumor nodules in the contralateral lung lobe. Biopsy is required to confirm if contralateral lung nodules are clinically suspected.
5. Documented brain metastasis. Patients with suspected brain metastasis must undergo brain imaging for further confirmation.
6. Have significant cardiovascular or cerebrovascular diseases, such as:

1)Experienced definite cardiovascular abnormal events within 6 months, such as myocardial infarction, angina pectoris, heart failure, severe arrhythmia, or undergone angioplasty, vascular stent implantation, coronary artery bypass surgery, etc.

2)Have clinically significant QT/QTcF interval prolongation (QTcF > 470ms for females or > 450ms for males).

7.Significant or active gastrointestinal disease characterized by diarrhea as the major symptom.

8.Receipt of strong inhibitors or strong inducers of CYP3A4 or P-gp within 14 days prior to the first dose of study treatment, or within 5 half-lives of such agents (whichever is longer), or use of traditional Chinese medicine within 7 days prior to the first dose of study treatment.

9.Participants who have received known CYP2D6, CYP3A4, P-gp, and BCRP sensitive substrates within 14 days or 5 half-lives (whichever is longer) before the first dose of this study, and the therapeutic window of the substrate is narrow, unless agreed by the investigator and the sponsor to be enrolled.

10.Receipt of proton pump inhibitors (PPIs) or H2 receptor antagonists within 7 days prior to the first dose of study treatment.

11.Systemic therapy with Chinese herbal medicines with anti-tumor indications or immunomodulatory agents (including thymopeptides, interferons, interleukins) within 2 weeks prior to the first dose of study treatment.

12.Participants who are simultaneously involved in another interventional clinical study, except for observational (non-interventional) clinical studies or those in the follow-up stage after the end of an interventional study.

13.Participants who have received live attenuated vaccines within 4 weeks before the first dose of study treatment or plan to receive them during the study period.

Note: Inactivated virus vaccines for seasonal influenza by injection are allowed within 4 weeks before the first dose of study treatment; however, live attenuated influenza vaccines are not allowed.

14.Patients requiring long-term systemic corticosteroid use. Any other form of immunosuppressive therapy within 7 days prior to randomization.

Note: Topical glucocorticoids (nasal, inhaled, or other routes), physiological doses of systemic glucocorticoids (≤10 mg/day prednisone or equivalent), or use for pre-medication (e.g., prevention of contrast agent allergy) are permitted.

15.Major surgical procedure (craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to the first dose of study treatment, or presence of non-healing wounds, ulcers, or fractures.

16.History of radiation pneumonitis, idiopathic pneumonitis, active pneumonitis, pulmonary fibrosis, diffuse interstitial lung disease, or organizing pneumonia (e.g., bronchiolitis obliterans).

17.Participants with known allergies to study treatment or any of its components.

18.Known primary immunodeficiency. 19.Active autoimmune or inflammatory disease (including inflammatory bowel disease [e.g., colitis, Crohn's disease], diverticulitis [excluding diverticulosis], celiac disease, systemic lupus erythematosus, sarcoidosis, granulomatosis with polyangiitis (Wegener's syndrome), Graves' disease, hypophysitis, uveitis, etc.), or history of such disease within the previous 2 years.

Patients with vitiligo, psoriasis, alopecia that do not require systemic therapy within the past 2 years, hypothyroidism requiring only thyroid hormone replacement, and type 1 diabetes mellitus requiring only insulin replacement are eligible.

20.Have major acute or chronic infections, including:

1. Active infections requiring systemic treatment;
2. Positive human immunodeficiency virus antibody (HIV-Ab) at baseline;
3. Active hepatitis B virus (HBV) infection (positive HBsAg and positive HBV-DNA). For patients with negative HBsAg and positive HBcAb, HBV-DNA testing is required; patients with positive HBV-DNA are excluded;
4. Active hepatitis C virus (HCV) infection (positive HCV-Ab and positive HCV-RNA);
5. Active pulmonary tuberculosis,, receiving anti-tuberculosis therapy, or having received anti-tuberculosis therapy within 1 year prior to the first dose of study treatment
6. Active syphilis. 21.History of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.

22.Diagnosis of another malignancy within 5 years prior to the first dose,except for radically treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin,radically resected carcinoma in situ, radically treated localized prostate cancer, papillary thyroid carcinoma, and similar diseases.

23.Uncontrolled concurrent disease, including:

1)Serious infection occurring within 4 weeks prior to initiation of study treatment, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia; or therapeutic oral or intravenous antibiotics administered within 2 weeks prior to initiation of study treatment; 2)Symptomatic congestive heart failure (New York Heart Association Class III-IV), left ventricular ejection fraction (LVEF) < 50% by echocardiography, or uncontrolled cardiac arrhythmia; 3)Uncontrolled hypertension despite standard therapy (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg); 4)Uncontrolled or symptomatic hypercalcemia (>1.5 mmol/L ionized calcium, or serum calcium >12 mg/dL, or corrected serum calcium > ULN); 5)Esophageal or gastric varices requiring immediate intervention (e.g., banding or sclerotherapy), or subjects with evidence of portal hypertension (including splenomegaly on imaging) or a history of variceal bleeding considered to be at high risk of bleeding by the investigator or in consultation with a gastroenterologist or hepatologist; endoscopic evaluation must be performed within 3 months prior to enrollment; 6)History of deep vein thrombosis or any other severe thromboembolism within 3 months prior to enrollment (implanted venous access port or catheter-related thrombosis, or superficial venous thrombosis is not considered severe); 7）Any life-threatening hemorrhagic event within 3 months prior to enrollment; 8)Uncontrolled metabolic disorders or other acute or chronic non-malignant organ or systemic diseases, or paraneoplastic syndromes that may confer high medical risk and/or uncertainty in survival assessment; 9)History of gastrointestinal perforation and/or fistula within 6 months prior to enrollment; 10)Subjects at risk of intestinal obstruction or perforation (including but not limited to acute diverticulitis, intra-abdominal abscess, history of intra-abdominal cancer), or history of extensive bowel resection (partial colectomy or extensive small bowel resection with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea; 11)Significant malnutrition requiring intravenous nutritional supplementation, unless malnutrition had been corrected for more than 4 weeks prior to the first dose of study treatment; 12)Post-placement of intraluminal esophageal or tracheal stents; 13)Other acute or chronic medical conditions that may increase risk related to study participation or study drug administration, interfere with the interpretation of study results, or are deemed by the investigator to render the subject ineligible for the study; 14)Neurological, psychiatric, or social conditions that would impair compliance with study requirements, significantly increase the risk of adverse events, or affect the subject's ability to provide written informed consent (e.g., schizophrenia, history of drug abuse, etc.).

24.Pregnant or lactating women