Sintilimab ± IBI305 Plus Chemotherapy (Pemetrexed + Cisplatin) for EGFRm + Locally Advanced or Metastasis Non-Squamous NSCLC Patients After EGFR-TKI Treatment Failure

Study Overview
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Brief Summary
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The anti-tumor activity of anti-PD-1 therapy and VEGF inhibitor in TKI-resistant EGFR-mutated non-squamous NSCLC Chinese patients will be investigated in this clinical trial.

Official Title
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A Randomized, Double-blind, Multi-center, Phase III Clinical Study Assessing the Efficacy and Safety of Sintilimab ± IBI305 Combined With Pemetrexed and Cisplatin in Patients With EGFR-mutant Locally Advanced or Metastatic Non-squamous Non-small Cell Lung Cancer Who Have Failed Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) Treatment (ORIENT-31)

Conditions
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Non-Squamous Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Sintilimab
* Drug: IBI305
* Drug: Pemetrexed
* Drug: Cisplatin
* Drug: Placebo1
* Drug: Placebo2


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Signed written informed consent before any trial-related processes; Age ≥ 18 years and <75 years male or females; Has a histologically or cytologically confirmed stage IIIB/IIIC (American Joint Committee on Cancer [AJCC] 8th edition) NSCLC that is unresectable and not fit for radical concurrent chemoradiotherapy, or metastatic / recurrent non-squamous NSCLC; Patients with EGFR mutation confirmed by tumor histology or cytology or hematology prior to EGFR-TKI treatment EGFR-TKI resistance, confirmed by RECIST 1.1 The investigator confirms at least one measurable lesion according to RECIST 1.1. A measurable lesion located in the field of previous radiation therapy or after local treatment may be selected as a target lesion if progression is confirmed; The Eastern Cancer Cooperative Group (ECOG) performance score of 0 or 1; Exclusion criteria: Squamous cell > 10%. If small cell types are present, the subject is not eligible for inclusion.; Has previously received systemic anti-tumor treatment other than EGFR-TKI for or advanced non-squamous NSCLC (including cytotoxic chemotherapy for radiotherapy, do not include other systemic treatment for other cured tumors); Has previously received the following therapies: anti-PD-1, anti-PD-L1 or anti-PD-L2 drugs or any other stimulatory or inhibitory agents of T cell receptors (eg CTLA-4, OX-40, CD137); Has received EGFR-TKI treatment within 2 weeks; Diagnosed of immunodeficiency or has received systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drugs. History of pneumonitis requiring steroid therapy or the presence of interstitial lung disease within 1 year prior to the first dose of study drugs; Symptomatic central nervous system metastases (CNS) metastasis and/or cancerous meningitis. Hemoptysis within 3 months, Full-dose oral or parenteral anticoagulant or thrombolytic agent for 10 consecutive days within 2 weeks. prophylactic use of anticoagulants is allowed;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sintilimab +IBI305+Pemetrexed+Cisplatin<br>Drug: Sintilimab 200mg IV Q3W Other Name: IBI308 Drug: IBI305 15mg/kg IV Q3W Drug: Pemetrexed 500mg/m2 IV Q3W Drug: Cisplatin 75mg/m2 IV Q3W | Drug: Sintilimab<br>* 200mg IV Q3W<br>* Other names: IBI308;Drug: IBI305<br>* 15mg/kg IV Q3W<br>Drug: Pemetrexed<br>* 500mg/m2 IV Q3W<br>Drug: Cisplatin<br>* 75mg/m2 IV Q3W<br>|
| Experimental: Sintilimab +Placebo2+Pemetrexed+Cisplatin<br>Drug: Sintilimab 200mg IV Q3W Other Name: IBI308 Drug: Pemetrexed 500mg/m2 IV Q3W Drug: Cisplatin 75mg/m2 IV Q3W Drug: Placebo2 Placebo2 IV Q3W | Drug: Sintilimab<br>* 200mg IV Q3W<br>* Other names: IBI308;Drug: Pemetrexed<br>* 500mg/m2 IV Q3W<br>Drug: Cisplatin<br>* 75mg/m2 IV Q3W<br>Drug: Placebo2<br>* Placebo2 IV Q3W<br>|
| Active Comparator: Placebo1+Placebo2+Pemetrexed+Cisplatin<br>Drug: Pemetrexed 500mg/m2 IV Q3W Drug: Cisplatin 75mg/m2 IV Q3W Drug: Placebo1 Placebo1 IV Q3W Drug: Placebo2 Placebo2 IV Q3W | Drug: Pemetrexed<br>* 500mg/m2 IV Q3W<br>Drug: Cisplatin<br>* 75mg/m2 IV Q3W<br>Drug: Placebo1<br>* Placebo1 IV Q3W<br>Drug: Placebo2<br>* Placebo2 IV Q3W<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS (Progression Free Survival) |  | Time from randomization to first documented disease progression (radiographic) assessed by Independent Imaging Assessment Committee (IRRC) or death due to any cause. up to 24month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OS (Overall Survival) |  | Time from randomization to the death of the subject due to any cause assessed up to 36 months. | 
| ORR (overall response rate) |  | The proportion of subjects who have a complete response (CR) or a partial response (PR) assessed up to 24 months. | 
| PFS (Progression Free Survival) |  | Time from randomization to first documented disease progression (radiographic) assessed by investigator or death due to any cause up to 24 month. | 
| DCR(Disease control rate ) |  | The proportion of subjects in the analysis population who had a complete response (CR) or partial response (PR) or stable disease (SD) up to 24 month. | 
| TTR（Time to objective response ) |  | For subjects with CR or PR, defined as the time from randomization to the first documented CR or PR up to 24 month. | 
| DOR(Duration of response) |  | For subjects with CR or PR, defined as the time from the first documented CR or PR to disease progression or death up to 24 month. |