A Study of Atezolizumab in Combination With Bevacizumab in Patients With EGFR Mutation Positive Stage IIIB-IV Non-Squamous Non-Small Cell Lung Cancer

Carcinoma, Non-Small-Cell Lung Clinical Trial

Official title:

A Single Arm, Phase II Study of Atezolizumab (MPDL3280A, Anti-PD-L1 Antibody) in Combination With Bevacizumab in Patients With EGFR Mutation Positive Stage IIIB-IV Non-Squamous Non-Small Cell Lung Cancer Pretreated With Epidermal Growth Factor Receptor Tyrosine-Kinase Inhibitors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04426825
• Other study ID #: ML41256
• Status: Completed
• Phase: Phase 2
• Start date: September 9, 2020
• Est. completion date: February 10, 2023

Study information

• Verified date: May 2024
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is an open-label, single-arm, phase II, multicenter study designed to evaluated the efficacy and safety of atezolizumab in combination with bevacizumab in PD-L1-selected patients with Stage IIIB-IV Non-Squamous NSCLC harbored EGFR mutation after EGFR TKI therapy.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 23
• Est. completion date: February 10, 2023
• Est. primary completion date: January 19, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Life expectancy = 10 months

• Histologically or cytologically confirmed stage IIIB, IIIC, or IV non-squamous NSCLC. Patients with tumors of mixed histology are eligible if the major histological component appears to be non-squamous.

• No prior treatment for Stage IIIB, IIIC, or IV non-squamous NSCLC, with the following exceptions:

Patients with a sensitizing mutation in the EGFR gene must have experienced disease progression or were intolerant to treatment with one or more EGFR TKIs. Patients who have progressed on or were intolerant to first-line osimertinib or other thirdgeneration EGFR TKIs are eligible.

Patients who have progressed on or were intolerant to first- or second-generation EGFR TKIs, and who have no evidence of the EGFR T790M mutation after TKI therapy are eligible.

Patients who have progressed on or were intolerant to first- or second-generation EGFR TKIs and who have evidence of the T790M mutation must have also progressed on or were intolerant to osimertinib to be eligible.

• TKIs approved for treatment of NSCLC discontinued >7 days prior to enrollment.

• Measurable disease per RECIST v1.1. PD-L1 expression of =1% as documented through central testing of a representative tumor tissue specimen either from previously obtained archival tumor tissue or tissue obtained from a biopsy at screening

• ECOG Performance Status of 0-1

• Adequate hematologic and end-organ function

• Negative HIV test at screening

• Negative hepatitis B surface antigen (HBsAg) test at screening

• Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening. The HBV DNA test will be performed only for patients who have a positive total HBcAb test.

• Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening. The HCV RNA test will be performed only for patients who have a positive HCV antibody test.

• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating eggs.

• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm.

Exclusion Criteria:

• Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases as determined by CT or MRI evaluation during screening and prior radiographic assessments

• History of leptomeningeal disease

• Prior chemotherapy or other systemic therapy for stage IIIB, IIIC, or IV disease

• Active or history of autoimmune disease or immune deficiency

• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan

• Active tuberculosis

• Significant cardiovascular disease within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina

• History of malignancy other than NSCLC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death

• Prior allogeneic stem cell or solid organ transplantation

• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab

• Current treatment with anti-viral therapy for HBV

• Treatment with investigational therapy within 28 days prior to initiation of study treatment

• Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies

• Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment

• Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment

• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins

• Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab or bevacizumab formulations

• Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months after the final dose of atezolizumab, 6 months after the final dose of bevacizumab

• Prior history of hypertensive crisis or hypertensive encephalopathy

• Significant vascular disease within 6 months prior to initiation of study treatment

• History of Grade = 2 hemoptysis within 1 month prior to enrollment

• Evidence of bleeding diathesis or coagulopathy. Current or recent use of aspirin, clopidogrel or treatment with dipyramidole, ticlopidine, or cilostazol

• Current use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes that has not been stable for > 2 weeks prior to enrollment

• History of stroke or transient ischemic attack within 6 months prior to enrollment

• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to the first dose of bevacizumab

• History of abdominal or tracheosphageal fistula or gastrointestinal perforation within 6 months prior to enrollment

• History of intra-abdominal inflammatory process within 6 months prior to initiation of study treatment, including but not limited to active peptic ulcer disease, diverticulitis,or colitis

• Clinical signs of gastrointestinal obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding

• Evidence of abdominal free air not explained by paracentesis or recent surgical procedure

• Proteinuria

• Clear tumor infiltration into the thoracic great vessels is seen on imaging

• Clear cavitation of pulmonary lesions is seen on imaging

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung

Intervention

Drug:
• Atezolizumab
Atezolizumab will be administered at a dose of 1200 mg intravenously on Day 1 of each 21-day cycle.
• Bevacizumab
Bevacizumab will be administered by IV infusion at a dose of 15 mg/kg on Day 1 of each 21-day cycle.

Locations

Country	Name	City	State
China	Beijing Cancer Hospital	Beijing
China	Beijing Chest Hospital; Oncology Department	Beijing
China	Beijing Hospital; Internal Medicine-Oncology	Beijing
China	West China Hospital, Sichuan University	Chengdu
China	Sun Yet-sen University Cancer Center	Guangzhou City
China	Zhejiang Cancer Hospital; Zhejiang Cancer Hospital cancer department	Hangzhou City
China	Harbin Medical University Cancer Hospital	Harbin
China	Shandong Cancer Hospital	Jinan
China	Guangxi Cancer Hospital of Guangxi Medical University	Nanning City
China	The Affiliated Hospital of Medical College Qingdao University	Qingdao

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective Response Rate (ORR)	Objective response rate (ORR) was defined as the percentage of participants with a complete response (CR) or partial response (PR) on two consecutive occasions >=4 weeks apart, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1).	Baseline up to approximately 10 months
Secondary	Duration of Objective Response (DOR)	Duration of objective response (DOR) was defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause whichever occurs first, as determined by the investigator according to RECIST v1.1.	Baseline up to approximately 2.5 years
Secondary	Time to Response (TTR)	Time to response (TTR) was defined as the time from the start of the treatment to the first objective tumor response observed for participants who achieved CR or PR, as determined by the investigator according to RECIST v1.1.	Baseline up to approximately 2.5 years
Secondary	Disease Control Rate (DCR)	Disease control rate (DCR) was defined as the proportion of participants who have a best overall response of CR or PR or stable disease (SD), as determined by the investigator according to RECIST v1.1.	Baseline up to approximately 2.5 years
Secondary	Overall Survival (OS)	OS after enrollment was defined as the time from enrollment to death from any cause.	Baseline until death due to any cause (up to approximately 2.5 years)
Secondary	Progression-Free Survival (PFS)	Progression-free survival (PFS) was defined as the time from enrollment to the first occurrence of disease progression or death from any cause, whichever occurs first, as determined by the investigator according to RECIST v1.1.	Baseline up to approximately 2.5 years
Secondary	PFS Rate at 6 and 12 Months	PFS rate at 6 and 12 months is defined as the percentage of participants who have not experienced disease progression or death from any cause at 6 and 12 months, as determined by the investigator according to RECIST v1.1.	Baseline to 6 months and 12 months
Secondary	OS Rate at 1 and 2 Years	OS rate at 1 and 2 years was defined as the percentage of participants who have not experienced death from any cause at 1 and 2 years.	Baseline to 1 and 2 Years
Secondary	Percentage of Participants With Adverse Events	Percentage of participants with adverse events.	Baseline up to approximately 2.5 years
Secondary	Percentage of Participants With Serious and Non-Serious Immune-Mediated Adverse Events (irAEs)	Percentage of serious and non-serious immune-mediated adverse events related to atezolizumab treatment. The AESIs were graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria. The grading is as follows: Grade 1=Mild AE, Grade 2=Moderate AE, Grade 3=Severe AE, Grade 4=Life-threatening or disabling AE, Grade 5=Death related to AE.	Baseline up to approximately 2.5 years
Secondary	Objective Response Rate (ORR) According to iRECIST	Objective response rate (ORR) is defined as the proportion of participants with a complete response (CR) or partial response (PR) on two consecutive occasions =4 weeks apart, as determined by the investigator according to Modified RECIST v1.1 (iRECIST).	Baseline up to approximately 2.5 years
Secondary	Disease Control Rate (DCR) According to iRECIST	Disease control rate (DCR) is defined as the proportion of participants who have a best overall response of CR or PR or stable disease (SD), as determined by the investigator according to modified RECIST v1.1 (iRECIST).	Baseline up to 2 years and approximately 5 months
Secondary	Duration of Objective Response (DOR) According to iRECIST	Duration of objective response (DOR) is defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause whichever occurs first, as determined by the investigator according to modified RECIST v1.1 (iRECIST).	Baseline up to approximately 2.5 years
Secondary	Progression-Free Survival (PFS) According to iRECIST	Progression-free survival (PFS) is defined as the time from enrollment to the first occurrence of disease progression or death from any cause, whichever occurs first, as determined by the investigator according to modified RECIST v1.1 (iRECIST).	Baseline up to approximately 2.5 years
Secondary	Progression-Free Survival (PFS) Rate at 12 Months According to iRECIST	Progression-free survival (PFS) rate is defined as the time from enrollment to the first occurrence of disease progression or death from any cause, whichever occurs first at 12 months, as determined by the investigator according to modified RECIST v1.1 (iRECIST).	Baseline up to approximately 12 months
Secondary	Time to Deterioation (TTD) Using EORTC	Time to deterioration (TTD) using European Organization for Research and treatment of Cancer (EORTC) Quality-of-life Questionnaire Core 30 (QLQ C30) and its Lung Cancer Module (QLQ LC13) is defined as the time from baseline to the first time the patient's score shows a >=10 points increase above baseline in any of the following EORTC-transformed symptom subscale scores (whichever occurs first): cough, dyspnoea (single item), dyspnoea (multi-item subscale), chest pain, or arm/shoulder pain, whichever occurred first. Scores ranged from 0-10. A higher score represented more severe symptoms.	Baselsine up to approximately 1 year
Secondary	Change From Baseline in Health-Related Quality of Life (HRQoL) and Health Status	The 30-item EORTC QLQ-C30 version 3 is composed by five multi-item function scales (physical, role, cognitive, emotional, and social), three multi-item symptom scales (fatigue, nausea and vomiting, and pain), six single-item symptom scales (dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and financial difficulties), and a two-item global quality of life scale. All EORTC scales and single-item measures are linearly transformed so that each score has a range of 0-100. A high score for the functional and general health areas represent better functional status and quality of life. Higher scores for the symptom scales represent more symptoms or problems (poor quality of life). A participant was classified as improved if a decrement of 10 points or worse was observed in the change from baseline scores. A participant was classified as worsened if a 10-point or greater increase was observed in the change from baseline scores.	Baseline up to approximately 1 year
Secondary	Change From Baseline in Lung Cancer Related Symptoms	The EORTC QLQ-LC13 is a specific module for lung cancer. It consists of 13 items covering lung cancer symptoms (dyspnoea, coughing, hemoptysis, pain in chest, pain in arm or shoulder and pain in other parts) and the side effects of chemo- and radiotherapy (alopecia, peripheral neuropathy, sore mouth, and dysphagia), which are divided into 10 fields, all are symptom types. All EORTC symptom scores are linearly transformed so that each score has a range of 0-100. A participant was classified as improved if a decrement of 10 points or worse was observed in the change from baseline scores. A participant was classified as worsened if a 10-point or greater increase was observed in the change from baseline scores.	Baseline up to approximately 1 year