Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
The study will evaluate the clinical activity of nivolumab in combination with 3 separate investigational agents, glesatinib, sitravatinib, or mocetinostat.
Detailed description
Glesatinib is an orally administered multi-targeted tyrosine kinase inhibitor (TKI) that primarily targets the Axl and Mesenchymal-Epithelial Transition (MET) receptors. Sitravatinib is an orally-available, potent small molecule inhibitor of a closely related spectrum of receptor tyrosine kinases (RTKs) including MET, Axl, MERTK, VEGFR family, PDGFR family, KIT, FLT3, Trk family, RET, DDR2 and selected Eph family members. Mocetinostat is an orally administered histone deacetylase (HDAC) inhibitor. Nivolumab is a human IgG monoclonal antibody that binds to the programmed cell death-1(PD-1) receptor and blocks its interaction with programmed cell death ligand-1 (PD-L1) and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response including anti-tumor immune response. Combining an immunotherapeutic PD-L1 checkpoint inhibitor with an agent that has both immune modulatory and antitumor properties could enhance the antitumor efficacy observed with either agent alone. The study will begin with a lead-in dose escalation evaluation of two dose levels of each investigational agent in combination with nivolumab. Following completion of the lead-in dose escalation, enrollment into the Phase 2 study will proceed.
Interventions
DRUGGlesatinib
Glesatinib is a small molecule multi-targeted receptor tyrosine kinase inhibitor
DRUGSitravatinib
Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases.
DRUGMocetinostat
Mocetinostat is an HDAC inhibitor.
DRUGNivolumab
nivolumab is a programmed death receptor-1 (PD-1) blocking antibody
Sponsors
Mirati Therapeutics Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of non-small cell lung cancer. * Prior treatment with a checkpoint inhibitor (as appropriate per cohort) * Adequate bone marrow and organ function
Exclusion criteria
* Uncontrolled tumor in the brain * Unacceptable toxicity with prior checkpoint inhibitor * Impaired heart function
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) as Defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. | Up to 40.6 months | ORR is defined as the percentage of participants that were documented to have a confirmed complete response (CR) or partial response (PR) as defined by RECIST v1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Day 1 up to 28 days after the last dose (median time on treatment was: CIT experienced 3.7 months; CIT naïve 4.8 months) | TEAEs were defined as any event that first occur or increase in severity on or after the first dose of study treatment and not more than 28 days after the last dose of study treatment and prior to the initiation of subsequent systemic anti- cancer therapy. Any clinically significant changes in laboratory tests were recorded as TEAEs. |
| Duration of Response (DOR) | Up to 38.8 months | DOR was defined as the time in months from date of the first documentation of objective response (CR or PR) to the first documentation of objective progressive disease (PD) or to death due to any cause in the absence of documented PD. (Be aware, the population analyzed here is the Clinical Activity Evaluable Population and not the Full Analysis Set as used in outcome measure 1). |
| Progression Free Survival (PFS) | Up to 40.6 months | PFS was defined as the time from the first dose of study drug to the date of PD or death due to any cause in the absence of documented PD, whichever occurs first. |
| Overall Survival (OS) | Up to 43.8 months | OS was defined as the time from first dose of study drug to the date of death due to any cause. |
| Blood Plasma Concentrations | Cycle 1 Day 1 through Cycle 5 Day 1 | Predose (trough) concentrations for sitravatinib |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled across 25 sites in the United States from November 2016 to November 2021.
Pre-assignment details
Participants enrolled: 161, 156 included for sitravatinib + nivolumab and 5 for glesatinib + nivolumab. Main study groups: CIT Experienced and CIT Naive. Enrollment into glesatinib cohorts was discontinued November 2017. Enrollment into mocetinostat cohorts was never initiated. These decisions were not based on participant safety in Study MRTX-500.
Participants by arm
| Arm | Count |
|---|---|
| CIT Experienced: Sitravatinib and Nivolumab Participants who had previously received checkpoint inhibitor therapy (CIT) received sitravatinib 120 mg oral capsules once daily (QD) in combination with nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks intravenously. | 124 |
| CIT Naïve: Sitravatinib and Nivolumab Participants who had not previously received CIT received sitravatinib 120 mg oral capsules QD in combination with nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks intravenously. | 32 |
| Glesatinib and Nivolumab Participants received glesatinib 500 mg oral tablets twice daily in combination with nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks intravenously. | 5 |
| Total | 161 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 92 | 11 | 2 |
| Overall Study | Lost to Follow-up | 3 | 2 | 0 |
| Overall Study | Miscellaneous | 2 | 1 | 1 |
| Overall Study | Study Terminated by Sponsor | 18 | 10 | 1 |
| Overall Study | Withdrawal by Subject | 9 | 8 | 1 |
Baseline characteristics
| Characteristic | CIT Experienced: Sitravatinib and Nivolumab | CIT Naïve: Sitravatinib and Nivolumab | Glesatinib and Nivolumab | Total |
|---|---|---|---|---|
| Age, Customized 30 to 89 years | 124 Participants | 32 Participants | 5 Participants | 161 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 3 Participants | 0 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 118 Participants | 29 Participants | 5 Participants | 152 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized [Not specified] American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized [Not specified] Asian | 3 Participants | 1 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized [Not specified] Black or African American | 8 Participants | 3 Participants | 2 Participants | 13 Participants |
| Race/Ethnicity, Customized [Not specified] Native Hawaiin or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized [Not specified] Other | 5 Participants | 1 Participants | 0 Participants | 6 Participants |
| Race/Ethnicity, Customized [Not specified] White | 107 Participants | 26 Participants | 3 Participants | 136 Participants |
| Sex: Female, Male Female | 66 Participants | 20 Participants | 2 Participants | 88 Participants |
| Sex: Female, Male Male | 58 Participants | 12 Participants | 3 Participants | 73 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 92 / 124 | 11 / 32 | 2 / 5 |
| other Total, other adverse events | 122 / 124 | 31 / 32 | 5 / 5 |
| serious Total, serious adverse events | 62 / 124 | 17 / 32 | 1 / 5 |
Outcome results
Primary
Objective Response Rate (ORR) as Defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
ORR is defined as the percentage of participants that were documented to have a confirmed complete response (CR) or partial response (PR) as defined by RECIST v1.1.
Time frame: Up to 40.6 months
Population: The Full Analysis Set (FAS) was defined as all participants who received at least 1 dose of both study treatments (sitravatinib or glesatinib) and nivolumab. Data was only planned to be reported for participants in the Phase 2 study, so no data is present for the 5 participants who received glesatinib in the lead- in phase only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CIT Experienced: Sitravatinib and Nivolumab | Objective Response Rate (ORR) as Defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. | 15.3 percentage of participants |
| CIT Naïve: Sitravatinib and Nivolumab | Objective Response Rate (ORR) as Defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. | 25 percentage of participants |
Secondary
Blood Plasma Concentrations
Predose (trough) concentrations for sitravatinib
Time frame: Cycle 1 Day 1 through Cycle 5 Day 1
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CIT Experienced: Sitravatinib and Nivolumab | Blood Plasma Concentrations | 76.57 ng/ml | Standard Deviation 51.041 |
| CIT Naïve: Sitravatinib and Nivolumab | Blood Plasma Concentrations | 59.25 ng/ml | Standard Deviation 36.759 |
| Cycle 2 Day 15 | Blood Plasma Concentrations | 52.87 ng/ml | Standard Deviation 26.265 |
| Cycle 3 Day 1 | Blood Plasma Concentrations | 46.41 ng/ml | Standard Deviation 26.183 |
| Cycle 5 Day 1 | Blood Plasma Concentrations | 30.04 ng/ml | Standard Deviation 12.239 |
Secondary
Duration of Response (DOR)
DOR was defined as the time in months from date of the first documentation of objective response (CR or PR) to the first documentation of objective progressive disease (PD) or to death due to any cause in the absence of documented PD. (Be aware, the population analyzed here is the Clinical Activity Evaluable Population and not the Full Analysis Set as used in outcome measure 1).
Time frame: Up to 38.8 months
Population: Clinical Activity Evaluable Population was defined as all participants who received at least 1 dose of both study treatments (sitravatinib or glesatinib) and nivolumab, had an evaluable baseline tumor assessment, and ≥ 1 postbaseline tumor assessment. DOR was only calculated for the participants that achieved a confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CIT Experienced: Sitravatinib and Nivolumab | Duration of Response (DOR) | 11.0 months |
| CIT Naïve: Sitravatinib and Nivolumab | Duration of Response (DOR) | 11.1 months |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
TEAEs were defined as any event that first occur or increase in severity on or after the first dose of study treatment and not more than 28 days after the last dose of study treatment and prior to the initiation of subsequent systemic anti- cancer therapy. Any clinically significant changes in laboratory tests were recorded as TEAEs.
Time frame: Day 1 up to 28 days after the last dose (median time on treatment was: CIT experienced 3.7 months; CIT naïve 4.8 months)
Population: The Safety Population was defined as all participants who received at least 1 dose of any study treatment (sitravatinib, glesatinib, or nivolumab). Per statistical analysis plan, only AEs for sitravatinib + nivolumab will be summarized. TEAE tables for glesatinib + nivolumab were not produced and therefore will not be reported here.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CIT Experienced: Sitravatinib and Nivolumab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 123 Participants |
| CIT Naïve: Sitravatinib and Nivolumab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 32 Participants |
Secondary
Overall Survival (OS)
OS was defined as the time from first dose of study drug to the date of death due to any cause.
Time frame: Up to 43.8 months
Population: FAS was defined as all participants who received at least 1 dose of both study treatments (sitravatinib or glesatinib) and nivolumab. Data was only planned to be collected for participants in the Phase 2 study, so no data is present for the 5 participants who received glesatinib in the lead-in phase only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CIT Experienced: Sitravatinib and Nivolumab | Overall Survival (OS) | 11.5 months |
| CIT Naïve: Sitravatinib and Nivolumab | Overall Survival (OS) | NA months |
Secondary
Progression Free Survival (PFS)
PFS was defined as the time from the first dose of study drug to the date of PD or death due to any cause in the absence of documented PD, whichever occurs first.
Time frame: Up to 40.6 months
Population: The FAS was defined as all participants who received at least 1 dose of both study treatment (sitravatinib or glesatinib) and nivolumab. Data was only planned to be collected for participants in the Phase 2 study, so no data is present for the 5 participants who received glesatinib in the lead-in phase only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CIT Experienced: Sitravatinib and Nivolumab | Progression Free Survival (PFS) | 5.4 months |
| CIT Naïve: Sitravatinib and Nivolumab | Progression Free Survival (PFS) | 7.1 months |