A Randomized Phase II Study of Sacituzumab Govitecan Alone, Ivonescimab Alone, or Sacituzumab Govitecan and Ivonescimab in Participants With Previously-Treated Actionable Genomic Alteration Positive Stage IV or Recurrent Non-Small Cell Lung Cancer (Lung-MAP Sub-Study)
Overview
- Phase
- Phase 2
- Status
- Not yet recruiting
- Sponsor
- SWOG Cancer Research Network
- Enrollment
- 117
- Primary Endpoint
- Progression-free survival (PFS) (Comparison between arms)
Overview
Brief Summary
This phase II Expanded Lung-MAP treatment trial compares how well sacituzumab govitecan alone, ivonescimab alone, or sacituzumab govitecan in combination with ivonescimab works in treating patients with non-small cell lung cancer (NSCLC) that has come back after a period of improvement (recurrent) or is stage IV and has a change in at least 1 of these genes: ALK, EGFR, HER2 (ERBB2), MET, NTRK, RET, and ROS1. This type of gene change is called an actionable genomic alteration (AGA), which means certain treatments can target the change to fight the cancer. Sacituzumab govitecan is a monoclonal antibody, called sacituzumab, linked to a toxic drug called SN-38. Sacituzumab govitecan is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of tumor cells, known as TROP2 receptors, and delivers SN-38 to kill them. Ivonescimab is a bispecific antibody that can bind to two different antigens at the same time. It binds to programmed cell death protein 1 (PD1), a protein found on the surface of T cells (a type of white blood cell) and vascular endothelial growth factor (VEGF), a protein found on the surface of tumor cells. Ivonescimab may strengthen the immune system and interfere with the ability of tumor cells to grow and spread. Giving a combination of sacituzumab govitecan and ivonescimab work better than either drug alone, and sacituzumab govitecan alone, ivonescimab alone, or sacituzumab govitecan and ivonescimab together may work better than standard treatments at shrinking NSCLC with an AGA.
Detailed Description
PRIMARY OBJECTIVES:
I. To compare progression-free survival (PFS) between participants randomized to the combination of sacituzumab govitecan plus ivonescimab (SG-I) and sacituzumab govitecan (SG) alone. (Comparison between arms) II. To compare progression-free survival (PFS) between participants randomized to SG-I and ivonescimab (I) alone. (Comparison between arms) III. To evaluate the response (confirmed and unconfirmed, complete and partial) rate of SG against historical response rates. (Single Arm evaluation) IV. To evaluate the response (confirmed and unconfirmed, complete and partial) rate of I against historical response rates. (Single Arm evaluation) V. To evaluate the response (confirmed and unconfirmed, complete and partial) rate of SG-I against historical response rates. (Single Arm evaluation)
SECONDARY OBJECTIVES:
I. To evaluate the rate of dose-limiting toxicities among participants treated with SG-I in the safety run-in analysis population.
II. To compare response rates between ivonescimab with or without sacituzumab govitecan.
III. To compare response rates of sacituzumab govitecan with or without ivonescimab.
IV. To compare overall survival between the SG-I and SG arms. V. To compare overall survival between the SG-I and I arms. VI. To summarize disease control rates within each treatment arm. VII. To summarize the duration of response (DoR) among responders within each treatment arm.
VIII. To evaluate the central nervous system (CNS) progression-free survival per local investigator assessment in participants with baseline CNS metastasis within each treatment arm.
VIII. To evaluate the frequency and severity of toxicities within each treatment arm.
IX. To evaluate if clinical outcomes (response, progression-free survival [PFS], overall survival [OS]) within each treatment arm differs between the subgroup of participants with EGFR mutations to those without EGFR mutations.
X. To evaluate if clinical outcomes (response, PFS, OS) within each treatment arm differs between the subgroup of participants by the presence or absence of PD-L1 expression (< 1% vs 1% or greater).
TRANSLATIONAL MEDICINE OBJECTIVES:
I. To perform comprehensive next-generation sequencing of circulating tumor deoxyribonucleic acid (DNA) (ctDNA) at baseline in all participants to assess its clinical utility in comparison to tumor tissue biomarker profiles.
II. To process and bank cell free DNA (cfDNA) at cycle 3 day 1 and progression for future development of a proposal to evaluate comprehensive next-generation sequencing of circulating tumor DNA (ctDNA).
III. To establish a tissue/blood repository to pursue future studies.
OUTLINE: Patients are randomized to 1 of 3 arms.
ARM 1: Patients receive ivonescimab intravenously (IV) over 1-2 hours on day 1 of each cycle and sacituzumab govitecan IV over 1-3 hours on day 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) and blood sample collection throughout the study.
ARM 2: Patients receive sacituzumab govitecan IV over 1-3 hours on day 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the study.
ARM 3: Patients receive ivonescimab IV over 1-2 hours on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the study.
After completion of study treatment, patients without disease progression are followed every 12 weeks or more often as clinically indicated until progression, then every 6 months for 2 years and then at end of 3 years from date of randomization. Patients with disease progression are followed every 6 months for 2 years and then at end of 3 years from date of randomization.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Participants must have been assigned to S1900N by the Southwest Oncology Group (SWOG) Statistics and Data Management Center (SDMC). Assignment to S1900N is determined by submission of documentation of NSCLC harboring an actionable genomic alteration (AGA) in the LUNGMAP protocol. AGA is defined in this protocol as an activating driver alteration with an approved targeted therapy for lung cancer in one of the following genes: ALK, EGFR, HER2 (ERBB2), MET, NTRK, RET, and ROS
- •Participants must have measurable disease documented by CT or MRI. The CT from a combined positron emission tomography (PET)/CT may be used to document only non-measurable disease unless it is of diagnostic quality. Measurable disease must be assessed within 28 days prior to randomization. Pleural effusions, ascites and laboratory parameters are not acceptable as the only evidence of disease. Non-measurable disease must be assessed within 42 days prior to randomization. All disease must be assessed and documented on the Baseline Tumor Assessment Form. Participants whose only measurable disease is within a previous radiation therapy port must demonstrate clearly progressive disease (in the opinion of the treating investigator) prior to randomization.
- •Participants must have a CT or MRI scan of the brain to evaluate for CNS disease within 42 days prior to randomization.
- •Participants with spinal cord compression or brain metastases must not have residual neurological dysfunction, unless no further recovery is expected, and the participant has been stable on weaning doses of corticosteroids (≤ 10 mg daily prednisone or equivalent) prior to randomization. Participants with spinal cord compression or brain metastases that require local treatment must have received local treatment to these metastases and remained clinically controlled and asymptomatic for at least 7 days following stereotactic radiation and/or 14 days following whole brain radiation, and prior to randomization.
- •Participants must not have leptomeningeal disease that requires CNS-specific treatment prior to randomization and must not be planning to receive the CNS-specific treatment while on study.
- •Participants must have progressed (in the opinion of the treating physician) during or following the most recent line of systemic therapy.
- •Participants must have previously received an appropriate targeted therapy for the lung cancer AGA (ALK, EGFR, HER2 (ERBB2), MET, NTRK, RET, and ROS1).
- •Participants must have previously received platinum-based chemotherapy for stage IV or recurrent disease.
- •Participants must have received no more than (\<=) 3 lines of prior cytotoxic therapy (including chemotherapy, antibody-drug conjugates) for NSCLC.
- •Participants must not have received prior TROP2-targeted antibody-drug conjugate or a systemic therapy containing sacituzumab govitecan/SN-
Exclusion Criteria
- Not provided
Arms & Interventions
Arm 1 (ivonescimab, sacituzumab govitecan)
Patients receive ivonescimab IV over 1-2 hours on day 1 of each cycle and sacituzumab govitecan IV over 1-3 hours on day 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the study.
Intervention: Biospecimen Collection (Procedure)
Arm 1 (ivonescimab, sacituzumab govitecan)
Patients receive ivonescimab IV over 1-2 hours on day 1 of each cycle and sacituzumab govitecan IV over 1-3 hours on day 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the study.
Intervention: Computed Tomography (Procedure)
Arm 1 (ivonescimab, sacituzumab govitecan)
Patients receive ivonescimab IV over 1-2 hours on day 1 of each cycle and sacituzumab govitecan IV over 1-3 hours on day 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the study.
Intervention: Ivonescimab (Biological)
Arm 1 (ivonescimab, sacituzumab govitecan)
Patients receive ivonescimab IV over 1-2 hours on day 1 of each cycle and sacituzumab govitecan IV over 1-3 hours on day 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the study.
Intervention: Magnetic Resonance Imaging (Procedure)
Arm 1 (ivonescimab, sacituzumab govitecan)
Patients receive ivonescimab IV over 1-2 hours on day 1 of each cycle and sacituzumab govitecan IV over 1-3 hours on day 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the study.
Intervention: Sacituzumab Govitecan (Biological)
Arm 2 (sacituzumab govitecan)
Patients receive sacituzumab govitecan IV over 1-3 hours on day 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the study.
Intervention: Biospecimen Collection (Procedure)
Arm 2 (sacituzumab govitecan)
Patients receive sacituzumab govitecan IV over 1-3 hours on day 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the study.
Intervention: Computed Tomography (Procedure)
Arm 2 (sacituzumab govitecan)
Patients receive sacituzumab govitecan IV over 1-3 hours on day 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the study.
Intervention: Magnetic Resonance Imaging (Procedure)
Arm 2 (sacituzumab govitecan)
Patients receive sacituzumab govitecan IV over 1-3 hours on day 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the study.
Intervention: Sacituzumab Govitecan (Biological)
Arm 3 (ivonescimab)
Patients receive ivonescimab IV over 1-2 hours on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the study.
Intervention: Biospecimen Collection (Procedure)
Arm 3 (ivonescimab)
Patients receive ivonescimab IV over 1-2 hours on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the study.
Intervention: Computed Tomography (Procedure)
Arm 3 (ivonescimab)
Patients receive ivonescimab IV over 1-2 hours on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the study.
Intervention: Ivonescimab (Biological)
Arm 3 (ivonescimab)
Patients receive ivonescimab IV over 1-2 hours on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the study.
Intervention: Magnetic Resonance Imaging (Procedure)
Outcomes
Primary Outcomes
Progression-free survival (PFS) (Comparison between arms)
Time Frame: From date of randomization to date of first documentation of progression, symptomatic deterioration, or death due to any cause, assessed up to 3 years
Will compare between participants randomized to the combination of sacituzumab govitecan plus ivonescimab (SG-I) and sacituzumab govitecan (SG) alone. The comparison of PFS will be done using a 1-sided 10% level log-rank test stratified by randomization stratification factors. Binary proportions along with 90% confidence intervals will be estimated for response to be consistent with 1-sided 5% level testing. With 35 participants per arm, binary proportions can be estimated to within 11% with 90% confidence. The distribution PFS will be estimated using the method of Kaplan-Meier. Comparisons of event time distributions between arms will be summarized by hazard ratios and 80% confidence intervals (consistent with 1-sided 10% level testing) from a Cox Proportional hazards model including the stratification factors.
PFS (Comparison between arms)
Time Frame: From date of randomization to date of first documentation of progression, symptomatic deterioration, or death due to any cause, assessed up to 3 years
Will between participants randomized to SG-I and ivonescimab (I) alone. The comparison of PFS will be done using a 1-sided 10% level log-rank test stratified by randomization stratification factors. Binary proportions along with 90% confidence intervals will be estimated for response to be consistent with 1-sided 5% level testing. With 35 participants per arm, binary proportions can be estimated to within 11% with 90% confidence. The distribution PFS will be estimated using the method of Kaplan-Meier. Comparisons of event time distributions between arms will be summarized by hazard ratios and 80% confidence intervals (consistent with 1-sided 10% level testing) from a Cox Proportional hazards model including the stratification factors.
Response rate of SG against historical response rates (Single arm evaluation)
Time Frame: Up to 3 years
Within each treatment arm, the objective is to evaluate if response rates show activity beyond standard of care, which generally would be single agent chemotherapy or docetaxel combined with ramucirumab. With 35 eligible and evaluable participants per arm, the evaluation has 90% exact power to rule out a 10% response rate using a 1-sided 5% level test (the exact level is 5.1% based on design assumptions), if the true response rate were at least 29%. The observation of at least 7 participants with a response (a 20% response rate) would be considered evidence to rule out a 10% response rate.
Response rate of I against historical response rates (Single arm evaluation)
Time Frame: Up to 3 years
Within each treatment arm, the objective is to evaluate if response rates show activity beyond standard of care, which generally would be single agent chemotherapy or docetaxel combined with ramucirumab. With 35 eligible and evaluable participants per arm, the evaluation has 90% exact power to rule out a 10% response rate using a 1-sided 5% level test (the exact level is 5.1% based on design assumptions), if the true response rate were at least 29%. The observation of at least 7 participants with a response (a 20% response rate) would be considered evidence to rule out a 10% response rate.
Response rate of SG-I against historical response rates (Single arm evaluation)
Time Frame: Up to 3 years
Within each treatment arm, the objective is to evaluate if response rates show activity beyond standard of care, which generally would be single agent chemotherapy or docetaxel combined with ramucirumab. With 35 eligible and evaluable participants per arm, the evaluation has 90% exact power to rule out a 10% response rate using a 1-sided 5% level test (the exact level is 5.1% based on design assumptions), if the true response rate were at least 29%. The observation of at least 7 participants with a response (a 20% response rate) would be considered evidence to rule out a 10% response rate.
Secondary Outcomes
- Rate of dose-limiting toxicities among participants treated with SG-I in the safety run-in analysis population(During the first cycle of treatment (21 days))
- Response rates(Up to 3 years)
- Overall survival (OS)(From date of randomization to date of death due to any cause, assessed up to 3 years)
- OS(From date of randomization to date of death due to any cause, assessed up to 3 years)
- Duration of response (DoR)(From date of first documentation of response to date of first documentation of progression, symptomatic deterioration, or death due to any cause among participants who achieve a response, assessed up to 3 years)
- Central nervous system (CNS) PFS(From date of randomization to date of first documentation of progression, symptomatic deterioration, or death due to any cause, assessed up to 3 years)
- Frequency and severity of toxicities(During the first cycle of treatment (21 days))
- Clinical outcomes by EGFR subgroups(Up to 3 years)
- Clinical outcomes by PD-L1 expression subgroups(Up to 3 years)