Prospective registration

A Study of?JS207?(PD-1/?VEGF Bispecific Antibody) in Combination With Chemotherapy in Advanced Non-small Cell Lung Cancer

A Study of?JS207?(PD-1/?VEGF Bispecific Antibody) in Combination With Chemotherapy in Advanced Non-small Cell Lung Cancer

Zhang Ying 

Zhou Qing 

16F, Building 7, No. 6, Lane 100, Pingjiaqiao Road, Pudong New Area, Shanghai

No.106 Zhongshan Er Road, Guangzhou, China

Shanghai Junshi Biosciences Co., Ltd.

Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sciences)

Yes

Ethics Review Committee of Guangdong Provincial People's Hospital

Bai Sheng

No.106 Zhongshan Er Road, Guangzhou, China

Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sciences)

No.106 Zhongshan Er Road, Guangzhou, China

Shanghai Junshi Biosciences Co., Ltd.

Advanced non-squamous non-small cell lung cancer positive for driver gene and treatment failure with TKI therapy

Interventional study

2

Single arm 

The clinical best response recorded between the start of the study treatment and the date of the end of treatment or subsequent anti-Neoplasm therapy, whichever occurs first, is the proportion of subjects with partial response (PR) or complete response (CR).

1. Age 18 to 75 years (inclusive) at the time of signing informed consent, both male and female; 2. Histologically or cytologically confirmed local late (stage IIIB/IIIC) or metastatic or recurrent non-squamous NSCLC that is not eligible for radical surgery or radical radiotherapy; 3. Driver gene positive and NMPA-approved first-line targeted therapy, including but not limited to one of the following: EGFR-sensitive mutations (exon 18 G719X mutation, exon 19 deletion mutation, exon 20 S768I or T790M mutation, exon 21 L858R or L861Q mutation), ALK fusion, ROS1 fusion, BRAFV600E mutation, NTRK fusion, MET14 exon skipping mutation, RET fusion; 4. Failure of prior TKI therapy and no current standard TKI therapy. For patients with different mutations, the specific requirements are as follows: For patients with EGFR-sensitive mutations, one of the following conditions must be met: 1) No T790M mutation after failure of previous first- or second-generation EGFR-TKI monotherapy; 2) subjects who have failed three prior generations of EGFR-TKI monotherapy (regardless of their EGFR T790M mutation status); 3) For subjects with recurrent non-squamous NSCLC who have received prior neoadjuvant/consolidation/adjuvant therapy (chemotherapy, radiotherapy, or other treatments): a) Subjects who have progressed on the last treatment (surgery, chemotherapy and adjuvant EGFR-TKI therapy, whichever is later) to the time interval of recurrence of more than 6 months before receiving the third generation of EGFR-TKI monotherapy (direct therapy or follow-up therapy with T790M mutation positivity after failure of the first and second generation EGFR-TKI) can be enrolled; b) Subjects who have progressed on adjuvant first-generation EGFR-TKI postoperatively, and who have progressed on adjuvant therapy or within 6 months after discontinuation of the established length of treatment with positive T790M mutation, and who have progressed on monotherapy with a third-generation EGFR-TKI may be enrolled (if adjuvant chemotherapy has been received postoperatively, the time interval between the last adjuvant chemotherapy and the time interval of recurrence after adjuvant EGFR-TKI therapy should also be more than 6 months); c) Subjects who have progressed during single-agent adjuvant/consolidation therapy with a third-generation EGFR-TKI or within 28 days after discontinuation of the established length of treatment may be enrolled (if adjuvant chemotherapy is received postoperatively, the interval between the last adjuvant and relapse should also be more than 6 months); For ALK fusion-positive patients, one of the following criteria is required: 1) Failure to receive a third-generation ALK-TKI after treatment failure with a previous first- or second-generation ALK-TKI; 2) failure of previous three generations of ALK-TKI therapy; 3) For subjects with recurrent non-squamous NSCLC who have received neoadjuvant/consolidation/adjuvant therapy (chemotherapy, radiotherapy or other treatments) in the past, subjects who have progressed during the treatment of the third generation of ALK-TKI monotherapy adjuvant therapy or within 28 days after the completion of the established length of treatment and the interval between the last treatment and recurrence of other systemic antitumor therapies is more than 6 months can be enrolled; For patients with other mutations, failure of prior TKI therapy is required; Note: The above TKIs only include products that have been approved for marketing by the NMPA. For example, the first- or second-generation EGFR-TKI includes gefitinib, erlotinib, icotinib and afatinib, and the third-generation EGFR-TKI includes osimertinib, ametinib, furmetinib, befatinib, rizitinib, reitinib, etc.; First-generation ALK-TKIs include crizotinib, second-generation ALK-TKIs include alectinib, ceritinib, ensartinib, brigatinib, iruac, etc., and third-generation ALK-TKIs include lorlatinib; 5. PD-L1 positivity (TPS≥1%) confirmed by central laboratory testing. Tissue samples must be provided for PD-L1 testing, preferably newly obtained tissues, and archival samples can be provided for patients who cannot provide newly obtained tissues, and the sample requirements are about 5 unstained serial sections of formalin-fixed, paraffin-embedded tissues (minimum requirement is 3), and the thickness is 3-5 μm; 6. Provide a positive test report of the driver gene that meets the requirements, or agree to provide a sample that meets the requirements for driver gene testing; Note: Positive mutations in driver genes can be tested on tissue or blood specimens; The T790M mutation test should be a specimen collected after EGFR-TKI treatment failure, and T790M negative status will only accept tissue test results with acceptable tumor content 7. Subject has at least 1 measurable lesion according to RECIST v1.1 criteria; 8. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1 (Appendix 2); 9. Expected survival>=12 weeks; 10. The function of vital organs meets the following requirements (Note: no blood components and hematopoietic growth factors are allowed to be used within 14 days before screening); a. Absolute neutrophil count (ANC) >=1.5×10^9/L; b. Platelet >=100×10^9/L; c. Hemoglobin >=9 g/dL; d. Total bilirubin < = 1.5 × upper limit of normal (ULN); e. Alanine aminotransferase (ALT) < = 2.5 × ULN, aspartate aminotransferase (AST) < = 2.5 × ULN; For subjects with concomitant liver metastases, ALT and AST <=5×ULN; creatinine clearance rate (CrCL) > = 60 mL/min (cisplatin) or CrCL >= 50 mL/min (carboplatin) (Cockcroft-Gault formula, Appendix 3); g. Qualitative urine protein<=1; If the qualitative urine protein is >=2, a 24-hour urine protein quantitative test is required, and the 24-hour urine protein quantitative < 1 g is required. h. Activated partial thromboplastin time (aPTT)/partial thromboplastin time (PTT) <=1.5 × ULN, international normalized ratio (INR) <=1.5 (stable doses of anticoagulant therapy such as low molecular weight heparin or warfarin are acceptable, and the INR is within the expected therapeutic range of the anticoagulant); 11. Female subjects of childbearing potential, as well as male subjects whose partner is a female of childbearing potential, are required to use a highly effective contraceptive method for the duration of study treatment, and for at least 6 months after the last dose, Female patients of childbearing potential must have a negative blood HCG within 7 days prior to study enrollment and must be non-lactating; 12. Voluntarily join this study, sign the informed consent form, have good compliance, and cooperate with follow-up.

1. Concomitant study disease states of: a. Histological or cytological pathology of the tumor confirmed with neuroendocrine tumor (including small cell lung cancer, large cell neuroendocrine carcinoma, etc.), or more than 10% of squamous cell carcinoma components; b. Patients with known meningeal metastases; c. Patients with symptomatic brain metastases; For asymptomatic patients with brain metastases, those who are assessed as stable by the investigator can be enrolled, including: 1) those who have received radiation therapy for brain metastases and remain stable, the criteria for stability need to meet all of the following conditions: symptomatic treatment such as corticosteroids and mannitol needs to be discontinued at least 7 days before study drug administration, and no disease progression is found after the end of treatment for brain metastases and before the first use of study drug imaging compared with pre-treatment imaging (at least 4 weeks apart); 2) Patients with asymptomatic brain metastases who have not received local treatment need to meet all the following conditions: no use of corticosteroids and mannitol to control symptoms related to brain metastases, no long-diameter >=1cm of any brain metastases, no metastases of the midbrain, pons, bulbar or spinal cord, and no history of intracranial hemorrhage in the past; d. The tumor surrounds important blood vessels or has obvious necrosis or cavitation, and in the opinion of the investigator, it may cause a risk of bleeding; Clinically significant hemoptysis (>=2.5 ml) or tumor hemorrhage of any cause within one month prior to the first dose of study drug; f. Pleural effusion, pericardial effusion, or ascites that are uncontrollable or require repeated drainage (once a month or more); Subjects whose symptoms are stable for at least 1 week after drainage may be enrolled; g. Spinal cord compression without surgery and/or radiotherapy, or previously diagnosed spinal cord compression with no clinical evidence of stable disease prior to enrollment >=4 weeks; 2. Have received any of the following treatments: a. Immune-mediated therapy, including but not limited to anti-PD-1, anti-PD-L1 therapy; b. platinum-doublet chemotherapy; Only patients who received adjuvant or neoadjuvant platinum-doublet chemotherapy with a time interval of >6 months from the last chemotherapy to relapse may be enrolled; c. Anti-VEGF pathway target agents; d. Receipt of any investigational drug within 4 weeks or 5 half-lives prior to the first dose of study drug, whichever is shorter; e. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study, or the subject is in the follow-up period of the interventional clinical study; f. Requires systemic therapy with corticosteroids (> 10 mg prednisone equivalent dose per day) or other immunosuppressants within 2 weeks prior to the first dose of study drug. Inhaled or topical corticosteroids are permitted. Receipt of short-term corticosteroids (as before intravenous contrast) within 2 weeks prior to the first dose is permitted; g. Receipt of proprietary Chinese medicine with anti-tumor indication within 1 week prior to the first dose; h. Subjects who have received immunomodulatory drugs (thymopeptide, interferon, interleukin, etc.) within 2 weeks or 5 half-lives prior to the first dose, or subjects who need to continue treatment with these drugs during the study, whichever is shorter; i. Those who have received anti-tumor vaccines or have received live vaccines within 4 weeks prior to the first dose of study drug; j. Major surgery or significant traumatic injury within 4 weeks prior to the first use of study drug; Rough needle aspiration biopsy or other minor surgery within 7 days prior to the first use of study drug, excluding placement of vascular infusion devices; k. Use of antiplatelet therapy or anticoagulant therapy for therapeutic intent within 10 days prior to the first use of study drug; 3. Presence of significant bleeding tendency or history of severe coagulopathy, or Grade 3 and above bleeding events within 6 months prior to the first dose, or current presence of Grade ≥2 bleeding or factors judged by the investigator to have a high risk of bleeding (such as active peptic ulcer or esophageal varices); 4. Gastrointestinal perforation, intra-abdominal fistula, or intra-abdominal abscess within 6 months prior to the first dose, or currently judged by the investigator to have high-risk factors for hollow visceral perforation/fistula formation, such as tumor infiltration into the outer layer of the hollow visceral wall, or active inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis, or appendicitis; 5. Presence of severe, non-healing or dehiscence wounds, active ulcers, or untreated fractures; 6. Presence of poorly controlled hypertension, or a history of hypertensive crisis or hypertensive encephalopathy; 7. Expected toxicity from prior anti-tumor therapy that has not recovered to <=CTCAE Grade 1 (except for toxicities that are judged by the investigator to be long-existing, cannot be recovered, and do not increase safety risk<=Grade 2); 8. Known allergy to study drugs or excipients, pemetrexed, platinum-based drugs (carboplatin/cisplatin), or known previous allergy to antibody-based drugs >=grade 3; 9. Active autoimmune disease, history of autoimmune disease (such as interstitial pneumonia, colitis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism, including but not limited to these diseases or syndromes); Patients who do not need any intervention after adulthood, patients who are treated with stable doses of thyroid replacement hormone therapy, and patients with type I diabetes mellitus treated with stable doses of insulin, except for vitiligo or recovered childhood asthma/allergies, patients who do not need any intervention after adulthood, patients treated with stable doses of thyroid replacement hormone, and patients treated with type I diabetes mellitus with stable doses of insulin, etc.; 10. Have a history of immunodeficiency, including a positive HIV test, or have other acquired, congenital immunodeficiency diseases, or have a history of organ transplantation and allogeneic bone marrow transplantation, or autologous hematopoietic stem cell transplantation; 11. Severe infection (CTCAE> grade 2) within 4 weeks prior to the first use of the study drug, such as severe pneumonia requiring hospitalization, infection comorbidities, etc.; Presence of active lung inflammation on baseline chest imaging, presence of symptoms and signs of infection within 2 weeks prior to the first dose of study drug, requiring oral or intravenous antibiotic therapy (except in the case of prophylactic antibiotic use); 12. Confirmed or suspected history of interstitial lung disease or idiopathic pulmonary fibrosis, drug-induced pneumonitis, idiopathic pneumonitis, or other moderate-to-severe pulmonary disease that seriously affects lung function (except <=grade 1 radiation pneumonitis); 13. Patients with active tuberculosis infection found by medical history or CT examination, or with a history of active tuberculosis infection within 1 year prior to enrollment, or patients with a history of active tuberculosis infection more than 1 year ago without formal treatment; 14. Presence of active tuberculosis, hepatitis B (HBsAg positive with HBV DNA >=500 IU/mL), hepatitis C (HCV Ab positive and HCV RNA above the lower limit of detection of the analytical method); 15. Diagnosis of any other malignancy within 5 years prior to the first dose of study drug, with the exception of malignancies with low risk of metastasis (5-year survival rate >90%), such as adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix or breast, or adequately treated localized prostate cancer; 16. Uncontrolled intercurrent illness including, but not limited to: symptomatic congestive heart failure, left ventricular ejection fraction (LVEF) <50%, unstable angina, uncontrolled cardiac arrhythmias, aortic aneurysm requiring surgical repair, any arterial thrombic/embolic event, grade 3 and above (CTCAE 5.0) venous thrombosis/embolic event, transient ischemic attack, cerebrovascular accident, tracheo-esophageal fistula, gastrointestinal perforation, intra-abdominal abscess, gastrointestinal obstruction, or psychiatric illness/social situation that may affect study compliance, result in a significant increase in the risk of adverse events, or affect the patient's ability to provide written informed consent; 17. Other severe, acute or chronic medical illness or psychiatric illness or laboratory abnormality, as judged by the investigator, that may increase the risk associated with participation in the study, or that may interfere with the interpretation of the study results.

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EDC system is used for data acquisition and management