Overview

The study is a prospective multi-cohort clinical study. Cohort A is evaluating the efficacy and safety of IBI318 in combined with lenvatinib in advanced NSCLC patients who had failed first-line PD-1/PD-L1 inhibitor therapy. Cohort B is the efficacy and safety of advanced NSCLC with EGFR-sensitive mutation /ALK fusion after EGFR-TKI /ALK-TKI treatment resistance. Cohort C is the efficacy and safety of first-line treatment of advanced NSCLC with negative PD-L1 expression and EGFR, ALK, and ROS1 wild-type. After being screened to meet the inclusion criteria, they will receive IBI318 combined with lenvatinib until the disease progresses, death, toxicity is intolerable, informed consent is withdrawn, new anti-tumor therapy is started, or the treatment is terminated for other reasons specified in the plan.

Eligibility

Inclusion Criteria:

• Eligible subjects selected for this study must meet all of the following criteria:
  1. Sign written informed consent before implementing any trial-related procedures;
  2. Age ≥18 years old and ≤75 years old;
  3. No limit on the gender;
  4. Cohort A: histological or cytological confirmed locally advanced (IIIB-IIIC) or metastatic (stage IV) NSCLC (International Association for the Study of Lung Cancer and Joint Committee on the American Classification of Cancer, TNM Lung cancer stage 8) without EGFR gene sensitive mutations, ALK gene fusion or ROS1 gene fusion confirmed by histological specimens, Relapse after failure of first-line anti-PD-1 /PD-L1 antibody therapy, as follows:
  5. Only one anti-PD-1/PD-L1 antibody monotherapy or combination therapy is accepted in the advanced stage of the disease, and other immunotherapy is not allowed;
  6. Previous anti-PD-1/L1 antibody monotherapy or combination therapy has the best curative effect (according to RECIST 1.1 criteria) as partial remission, complete remission, or stable disease for ≥6 months (defined as within 6 months from the first medication) No disease progression has occurred);
  7. Disease progression confirmed by imaging studies occurred during or after the most recent treatment.

        Cohort B: histological or cytological confirmed locally advanced (IIIB-IIIC) or metastatic
        (stage IV) NSCLC (International Association for the Study of Lung Cancer and Joint
        Committee on the American Classification of Cancer, TNM Lung cancer stage 8) with
        histologically confirmed EGFR-sensitive mutations or ALK fusion, Relapse after failure of
        anti-EGFR-TKI or ALK-TKI therapy, as follows:
        In patients with EGFR-tKI sensitive mutations, the specific history of previous EGFR-TKI
        treatment can be one of the following:
          1. There is no T790M mutation in 20 exon after the failure of previous one or two
             generations of EGFR-TKI (including gefitinib, erlotinib, icotinib and afatinib);
          2. The 20 exon T790M mutation occurred after the treatment failure of the first or second
             generation EGFR-TKI monotherapy (including gefitinib, erlotinib, icotinib, and
             afatinib, etc.), and disease progression recurred after treatment with osimertinib or
             other third generation EGFR-TKI;
          3. Failure of prior osimertinib or other third-generation EGFR-TKI therapy as first-line
             therapy (regardless of EGFR T790M mutation status);
          4. Those who are allowed to receive neoadjuvant/adjuvant targeted therapy in the early
             stage and develop drug resistance after subsequent adjuvant targeted therapy, and
             their drug resistance status meets one of the three requirements of appeal.
             For patients with ALK fusion NSCLC, disease progression should occur after adequate
             ALK-TKI treatment, and there is no opportunity for subsequent targeted therapy.
             Cohort C: Locally advanced NSCLC that is not suitable for radical surgery or
             radiotherapy, or that has relapsed without systematic treatment, or that has
             metastasized without systematic treatment and is negative for PD-L1 expression.
             Patients who have previously received neoadjuvant or adjuvant therapy can also receive
             neoadjuvant or adjuvant therapy (but neoadjuvant or adjuvant therapy is
             chemotherapy/radiotherapy, not immunotherapy), and the end of neoadjuvant/adjuvant
             therapy should be ≥6 months after tumor progression; If the pathological type is
             adenocarcinoma, the absence of EGFR-sensitive mutations or ALK fusion or ROS1 fusion
             should be confirmed. Negative expression of PD-L1 was defined as TPS <1% using 22C3
             test.
        5. According to the evaluation criteria for the efficacy of solid tumors (RECIST v1.1
        version), there is at least one imaging measurable lesion. The lesions located in the
        radiation field of the previous radiotherapy can be regarded as measurable lesions if the
        progress is confirmed; 6. Subjects with brain metastases asymptomatic or with stable
        symptoms after local treatment are allowed to be included in the group, as long as the
        subjects meet the following conditions:
          1. There are measurable lesions outside the central nervous system;
          2. no symptoms of the central nervous system or no worsening of symptoms within at least
             2 weeks;
          3. No need for glucocorticoid therapy, or stop glucocorticoid therapy within 7 days
             before the first administration, or the dosage of glucocorticoid is stable and reduced
             to less than 10mg/day prednisone (or equivalent dose) within 7 days before the first
             administration ; 7. Subjects are allowed to receive palliative radiotherapy (including
             craniocerebral radiotherapy for symptomatic brain metastases), but the radiotherapy
             must be completed at least 1 week before enrollment, and the radiotherapy-related
             toxicity should be restored to less than or equal to 1 degree (CTCAE 5.0, except for
             hair loss).
        8. ECOG score 0-1 points; 9. Expected survival time> 3 months; 10. Sufficient organ
        function, subjects need to meet the following laboratory indicators:
          1. The absolute value of neutrophils (ANC) ≥1.5x109/L when no granulocyte
             colony-stimulating factor is used in the past 14 days;
          2. In the case of no blood transfusion in the past 14 days, platelets ≥100×109/L;
          3. In the past 14 days without blood transfusion or erythropoietin, hemoglobin>9g/dL;
          4. Total bilirubin≤1.5×upper limit of normal (ULN);
          5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) within ≤2.5×ULN
             (subjects with liver metastases are allowed to have ALT or AST ≤5×ULN);
          6. Serum creatinine ≤1.5×ULN and creatinine clearance rate (calculated by Cockcroft-Gault
             formula) ≥50ml/min;
          7. Good coagulation function, defined as International Normalized Ratio (INR) or
             Prothrombin Time (PT) ≤ 1.5 times ULN;
          8. Normal thyroid function is defined as thyroid-stimulating hormone (TSH) within the
             normal range. If the baseline TSH is out of the normal range, subjects whose total T3
             (or FT3) and FT4 are within the normal range can also be included in the group;
          9. Myocardial enzyme spectrum is within the normal range (for example, simple laboratory
             abnormalities that are judged by the investigator to be of no clinical significance
             are also allowed to be included in the group); 11. For female subjects of childbearing
             age, a urine or serum pregnancy test and the result should be negative within 3 days
             before receiving the first study drug administration (day 1 of cycle 1). If the urine
             pregnancy test result cannot be confirmed as negative, a blood pregnancy test is
             required. Women of non-bearing age are defined as at least 1 year after menopause, or
             have undergone surgical sterilization or hysterectomy; 12. If there is a risk of
             conception, all subjects (whether male or female) need to adopt a low annual failure
             rate during the entire treatment period until 120 days after the last study drug
             administration (or 180 days after the last study drug administration) Less than 1% of
             contraceptive measures; 13. Blood pressure can be adequately controlled with or
             without anti hypertensive medication, defined as blood pressure≤150/ 90 mm Hg, and
             blood pressure was under stable control within 1 week before randomization.
        14. Patients must have recovered from toxicity or complications if they have previously
        received surgery or radiation > 30Gy.
        Exclusion Criteria:
          -  Subjects who meet the following criteria cannot be selected for this study:
               1. The pathology is small cell lung cancer (SCLC), including lung cancer mixed with
                  SCLC and NSCLC;
               2. There is imaging evidence of tumor voids, tumor inclusion or invasion of large
                  vessels. In addition, the proximity of the tumor to the large blood duct should
                  be considered and the risk of severe bleeding associated with tumor
                  shrinkage/necrosis after lenvatinib treatment should be excluded. (The large
                  vessels in the chest include the main pulmonary artery, left pulmonary artery,
                  right pulmonary artery, 4 pulmonary veins, superior vena cava, inferior vena cava
                  and aorta);
               3. To cohort A: subjects who have previously used anti-PD-1, PD-L1 or other
                  immunotherapy and meet the following conditions:
               1. The toxicity that caused permanent discontinuation occurred before the
                  termination of immunotherapy;
               2. Prior to the administration of the study drug, the toxicity of the previous
                  immunotherapy has not recovered or has not recovered to level 0-1. Asymptomatic
                  and stable control of endocrine toxicity level 2 with appropriate replacement
                  therapy is allowed to enter the group;
               3. Adverse events that require additional immunosuppressive agents in addition to
                  corticosteroids, or adverse events that still recur in the use of corticosteroids
                  during previous immunotherapy.
        To cohort B and C: Prior treatment: anti-PD-1, anti-PD-L1, or anti-PD-L2 drugs or drugs
        that target another stimulating or co-inhibiting T-cell receptor (including but not limited
        to CTLA-4, OX-40, CD137, etc.); Anti-pd-1, anti-PD-L1, or anti-PD-L2 drugs or drugs that
        target another stimulating or co-inhibiting T cell receptor (including but not limited to
        CTLA-4, OX-40, CD137, etc.); 4. Have received the following treatments:
          1. Received systemic anti-tumor therapy within 2 weeks before treatment, such as
             chemotherapy, targeted therapy, immunotherapy (including Chinese herbal medicine with
             anti-tumor indications), etc.;
          2. Previously received lenvatinib, bevacizumab, anlotinib monotherapy, or in combination
             with anti-PD-1 / PD-L1 drugs
          3. Have received any investigational drug treatment within 4 weeks before treatment;
          4. Received large doses of immunosuppressive drugs within 4 weeks before treatment
             (systemic glucocorticoid exceeding 10mg/day prednisone or its equivalent dose);
          5. Received live attenuated vaccine within 4 weeks before treatment (or plan to receive
             live attenuated vaccine during the study period);
          6. Have received major surgery (such as open cavity, thoracotomy, or Kaifu surgery), or
             unhealed surgical wounds, ulcers or fractures within 4 weeks before treatment.
        5. Clinically significant cardiovascular damage occurred within 12 months of the first dose
        of study treatment.
        6. Gastrointestinal diseases that may affect oral absorption of study drugs. 7. Prior
        gastrointestinal or grade ≥3 non-gastrointestinal fistula. 8. A history of other
        malignancies is known, and unless the participant has undergone potentially curative
        treatment, there is no evidence of disease recurrence in the 3 years since the start of
        that treatment.
        9. Severe allergy to IBI318 and lenvatinib. 10. There is clinically uncontrollable pleural
        effusion/abdominal effusion (subjects who do not need to drain the effusion or stop
        drainage for 3 days without a significant increase in effusion can be included in the
        group); 11. Subjects who have received thoracic radiotherapy of greater than 30 Gy within 6
        months before treatment or palliative radiotherapy of 30 Gy or less within 7 days before
        treatment (allowing palliative treatment of bone lesions or intracranial lesions) Radiation
        Therapy); 12. An active autoimmune disease that requires systemic treatment (such as the
        use of disease-relieving drugs, glucocorticoids, or immunosuppressive agents) occurred
        within 2 years before the first administration. Alternative therapies (such as thyroxine,
        insulin, or physiological glucocorticoids for adrenal or pituitary insufficiency, etc.) are
        not considered systemic treatments; 13. Known allogeneic organ transplantation (except
        corneal transplantation) or allogeneic hematopoietic stem cell transplantation; 14. Before
        starting treatment, have not fully recovered from toxicity and/or complications caused by
        any intervention (ie, ≤ Grade 1 or reached baseline, excluding fatigue or hair loss); 15.
        Known history of human immunodeficiency virus (HIV) infection (ie HIV 1/2 antibody
        positive); 16. Untreated active hepatitis B (defined as HBsAg positive and the number of
        HBV-DNA copies detected at the same time is greater than the upper limit of the normal
        value of the laboratory department of the research center);
        Note: Hepatitis B subjects who meet the following criteria can also be included in the
        group:
          1. Before the first administration, the HBV viral load is less than 1000 copies/ml (200
             IU/ml), and the subject should receive anti-HBV treatment during the entire study
             chemotherapy drug treatment to avoid viral reactivation
          2. For subjects with anti-HBc (+), HBsAg (-), anti-HBs (-) and HBV viral load (-), there
             is no need to receive preventive anti-HBV treatment, but close monitoring of virus
             reactivation is required 17. Active HCV infected subjects (HCV antibody-positive and
             HCV-RNA level is higher than the lower limit of detection); 18. Live vaccines have
             been vaccinated within 30 days before the first administration (cycle 1, day 1); Note:
             It is allowed to receive inactivated virus vaccine for seasonal influenza injection
             within 30 days before the first administration; however, it is not allowed to receive
             live attenuated influenza vaccine for intranasal administration.
        19. Pregnant or lactating women; 20. There are any serious or uncontrollable systemic
        diseases, such as:
          1. The resting electrocardiogram has major abnormalities in rhythm, conduction or
             morphology that are severe and difficult to control, such as complete left bundle
             branch block, heart block above degree II, ventricular arrhythmia or atrial
             fibrillation;
          2. Left ventricular ejection fraction (LVEF) was lower than normal; 3）QTc interval is
             extended to more than 480 ms；
        4) Unstable angina pectoris, congestive heart failure, chronic heart failure of New York
        Heart Association (NYHA) grade ≥ 2; 5) Myocardial infarction occurred within 6 months
        before enrollment; 6) A history of non-infectious pneumonia requiring glucocorticoid
        treatment within 1 year before the first administration, or current clinically active
        interstitial lung disease; 7) Active tuberculosis; 8) There is an active or uncontrolled
        infection that requires systemic treatment; 9) There is clinically active diverticulitis,
        abdominal abscess, gastrointestinal obstruction; 10) Liver diseases such as liver
        cirrhosis, decompensated liver disease, acute or chronic active hepatitis; 11) Poor control
        of diabetes (fasting blood glucose (FBG)> 10mmol/L); 12) Urine routines suggest that urine
        protein is ≥++, and the 24-hour urine protein quantification is confirmed to be greater
        than 1.0 g; 13) Subjects who have mental disorders and cannot cooperate with treatment; 21.
        The medical history or disease evidence, abnormal treatment or laboratory test values that
        may interfere with the test results, prevent the subject from participating in the study,
        or the investigator believes that it is not suitable for inclusion this research.