Study of Efficacy and Safety of JDQ443 Single-agent as First-line Treatment for Patients With Locally Advanced or Metastatic KRAS G12C- Mutated Non-small Cell Lung Cancer With a PD-L1 Expression < 1% or a PD-L1 Expression ≥ 1% and an STK11 Co-mutation.

Study Overview
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Brief Summary
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This study aims to assess the antitumor activity and safety of JDQ443 single-agent as first-line treatment for participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors harbor a KRAS G12C mutation and a PD-L1 expression < 1% regardless of STK11 mutation status (cohort A), or a PD-L1 expression ≥ 1% and an STK11 co-mutation (cohort B).

Detailed Description
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This is a non-randomized, open-label, single arm, multicenter, phase II study evaluating the antitumor activity and safety of JDQ443 single agent as first-line treatment for participants with locally advanced or metastatic KRAS G12C-mutated NSCLC. The study will have 2 non-comparative cohorts (Cohort A and B) that will recruit participants in parallel. The study treatment begins on Cycle 1 Day 1 (C1D1) with the first administration of JDQ443. Each cycle is 21 days. Study completion is defined as the earliest occurrence of one of the following: The last participant completes last study visit (and the assessments associated with this visit have been documented and followed-up appropriately by the Investigator), dies, withdraws consent or is lost to follow-up, whichever comes first. In the event of an early study termination decision, the date of that decision. Another clinical study becomes available that can continue to provide JDQ443 to study participants and all participants with ongoing treatment are transferred to that clinical study.

Official Title
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KontRASt-06: An Open-label Phase II Trial Evaluating the Activity and Safety of JDQ443 Single-agent as First-line Treatment for Patients With Locally Advanced or Metastatic KRAS G12C-mutated Non-small Cell Lung Cancer With a PD-L1 Expression < 1% or a PD-L1 Expression ≥ 1% and an STK11 Co-mutation.

Conditions
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Locally Advanced or Metastatic KRAS G12C-mutated NSCLC With a PD-L1 Expression <1% or a PD-L1 Expression ≥ 1% and an STK11 Co-mutation

Intervention / Treatment
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* Drug: JDQ443


Participation Criteria
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Eligibility Criteria
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Key Inclusion criteria Histologically confirmed locally advanced (stage IIIb/IIIc not eligible for definitive chemoradiation or surgical resection with curative intent) or metastatic (stage IV) NSCLC without previous systemic treatment for metastatic disease. Prior (neo)adjuvant treatment with chemotherapy and/or immunotherapy, or prior radiotherapy administered sequentially or concomitantly with chemotherapy and/or immunotherapy for localized or locally advanced disease are accepted if the time between therapy completion and enrollment is > 12 months. Presence of a KRAS G12C mutation (all participants) and: Cohort A: PD-L1 expression < 1%, regardless of STK11 mutation status Cohort B: PD-L1 expression ≥ 1% and an STK11 co-mutation At least one measurable lesion per RECIST 1.1. ECOG performance status ≤ 1. Participants capable of swallowing study medication. Key Exclusion criteria Participants whose tumors harbor an EGFR-sensitizing mutation and/or ALK rearrangement by local laboratory testing. Participants with other known druggable alterations will be excluded, if required by local guidelines Previous use of a KRAS G12C inhibitor or previous systemic treatment for metastatic NSCLC. A medical condition that results in increased photosensitivity (i.e. solar urticaria, lupus erythematosus, etc). Know active (unstable/symptomatic) central nervous system (CNS) metastases and/or carcinomatous meningitis Participants who are taking a prohibited medication (strong CYP3A inducers) that cannot be discontinued at least seven days prior to the first dose of study treatment and for the duration of the study Other inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A- PD-L1<1%<br>Participants whose tumors harbor a KRAS G12C mutation and a PD-L1 expression <1%, regardless of STK11 mutation status. | Drug: JDQ443<br>* JDQ443 orally administered<br>|
| Experimental: Cohort B- PD-L1≥ 1% and STK11 mutation<br>Participants whose tumors harbor a KRAS G12C mutation, a PD-L1 expression ≥ 1% and an STK11 co-mutation. | Drug: JDQ443<br>* JDQ443 orally administered<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) by blinded independent review committee (BIRC) in cohort A | ORR is defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) as best overall response (BOR) per response evaluation criteria in solid tumors (RECIST) version 1.1 by BIRC in cohort A | Up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR by BIRC in cohort B | ORR is defined as the percentage of participants with a CR or PR as BOR per RECIST 1.1 by BIRC in cohort B | Up to approximately 24 months | 
| Duration of response (DOR) by BIRC in both cohorts | DOR is defined as the time from the first occurrence of a PR or a CR per RECIST 1.1 by BIRC to the occurrence of disease progression or death due to any cause. DOR will be calculated separately for each of the two cohorts. | From first documented response to disease progression or death, up to approximately 24 months | 
| Progression Free Survival (PFS) by BIRC in both cohorts | PFS is defined as the time from the date of first dose of study treatment to the date of the first documented disease progression per RECIST 1.1 by BIRC or date of death due to any cause. PFS will be calculated separately for each of the two cohorts. | From first study treatment to first documented progression or death, up to approximately 24 months | 
| Overall survival (OS) in both cohorts | OS is defined as the time from the date of enrollment to the date of death due to any cause. OS will be calculated separately for each of the two cohorts. | From enrollment to death, up to approximately 36 months | 
| Disease control rate (DCR) by BIRC in both cohorts | DCR is defined as the percentage of participants with a BOR of confirmed CR, PR and stable disease (SD) per RECIST 1.1 by BIRC. DCR will be calculated separately for each of the two cohorts. | Up to approximately 24 months | 
| Time to response (TTR) by BIRC in both cohorts | TTR is defined as the time from the date of enrollment to the date of first documented response of either CR or PR per RECIST 1.1 by BIRC. TTR will be calculated separately for each of the two cohorts. | From enrollment to first documented response, up to approximately 24 months | 
| ORR by local radiology assessment in both cohorts | ORR is defined as the percentage of participants with a CR or PR as BOR per RECIST 1.1 by local review assessment. ORR will be calculated separately for each of the two cohorts. | Up to approximately 24 months | 
| DOR by local review assessment in both cohorts | DOR is defined as the time from the first occurrence of a PR or a CR per RECIST 1.1 by local review assessment to the occurrence of disease progression or death due to any cause. DOR will be calculated separately for each of the two cohorts. | From first documented response to disease progression or death, up to approximately 24 months | 
| DCR by local review assessment in both cohorts | DCR is defined as the percentage of participants with a BOR of confirmed CR, PR and SD per RECIST 1.1 by local review assessment. DCR will be calculated separately for each of the two cohorts. | Up to approximately 24 months | 
| TTR by local review assessment in both cohorts | TTR is defined as the time from the date of enrollment to the date of first documented response of either CR or PR per RECIST 1.1 by local review assessment. TTR will be calculated separately for each of the two cohorts. | From enrollment to first documented response, up to approximately 24 months | 
| PFS by local review assessment in both cohorts | PFS is defined as the time from the date of first dose of study treatment to the date of the first documented disease progression per RECIST 1.1 by local review assessment or date of death due to any cause. PFS will be calculated separately for each of the two cohorts. | From first study treatment to first documented progression or death, up to approximately 24 months | 
| ORR by BIRC and local radiology assessment for participants whose tumors harbor an STK11 mutation regardless of PD-L1 expression status (pooled from both cohorts) | ORR is defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) as best overall response (BOR) per RECIST 1.1 by local review assessment and by BIRC. ORR will be calculated for all participants whose tumors harbor an STK11 mutation by pooling participants from both cohorts | Up to approximately 24 months | 
| DOR by BIRC and local radiology assessment for participants whose tumors harbor an STK11 mutation regardless of PD-L1 expression status (pooled from both cohorts) | DOR is defined as the time from the first occurrence of a PR or a CR per RECIST 1.1 by local review assessment and by BIRC to the occurrence of disease progression or death due to any cause. DOR will be calculated for all participants whose tumors harbor an STK11 mutation by pooling participants from both cohorts. | From first documented response to disease progression or death, up to approximately 24 months | 
| DCR by BIRC and local radiology assessment for participants whose tumors harbor an STK11 mutation regardless of PD-L1 expression status (pooled from both cohorts) | DCR is defined as the percentage of participants with a BOR of confirmed CR, PR and stable disease (SD) per RECIST 1.1 by local review assessment and by BIRC. DCR will be calculated for all participants whose tumors harbor an STK11 mutation by pooling participants from both cohorts | Up to approximately 24 months | 
| TTR by BIRC and local radiology assessment for participants whose tumors harbor an STK11 mutation regardless of PD-L1 expression status (pooled from both cohorts) | TTR is defined as the time from the date of enrollment to the date of first documented response of either CR or PR per RECIST 1.1 by local review assessment and by BIRC. TTR will be calculated for all participants whose tumors harbor an STK11 mutation by pooling participants from both cohorts | From enrollment to first documented response, up to approximately 24 months | 
| PFS by BIRC and local radiology assessment for participants whose tumors harbor an STK11 mutation regardless of PD-L1 expression status (pooled from both cohorts) | PFS is defined as the time from the date of first dose of study treatment to the date of the first documented disease progression per RECIST 1.1 by local review assessment and BIRC or date of death due to any cause. PFS will be calculated for all participants whose tumors harbor an STK11 mutation by pooling participants from both cohorts | From first study treatment to first documented progression or death, up to 24 months | 
| OS for participants whose tumors harbor an STK11 mutation regardless of PD-L1 expression status (pooled from both cohorts) | OS is defined as the time from the date of enrollment to the date of death due to any cause. OS will be calculated for all participants whose tumors harbor an STK11 mutation by pooling participants from both cohorts | From enrollment to death, up to approximately 36 months | 
| Maximum concentration (Cmax) of JDQ443 in plasma | Blood samples will be collected for pharmacokinetics characterization. | Up to approximately 24 months | 
| Time to reach maximum concentration at steady-state (Tmax,ss) of JDQ443 in plasma | Blood samples will be collected for pharmacokinetics characterization. | Up to approximately 24 months | 
| Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of JDQ443 in plasma | Blood samples will be collected for pharmacokinetics characterization. | Up to approximately 24 months | 
| Area Under the Curve From Time Zero to the last measurable concentration sampling time at steady-state (AUClastss) of JDQ443 in plasma | Blood samples will be collected for pharmacokinetics characterization. | Up to approximately 24 months | 
| Observed concentration at the end of a dosing interval at steady-state (Cmin,ss) of JDQ443 in plasma | Blood samples will be collected for pharmacokinetics characterization. | Up to approximately 24 months | 
| Total body clearance (CL/F) of JDQ443 from the plasma | Blood samples will be collected for pharmacokinetics characterization. | Up to approximately 24 months | 
| Time to definitive deterioration (TTDD) in NSCLC-SAQ total score | The Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ) is a 7-item, patient-reported outcome measure which assess patient-reported symptoms associated with advanced NSCLC: cough, pain, dyspnea, fatigue, and appetite. | From baseline up to approximately 24 months | 
| TTDD in the physical functioning scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30 | The EORTC QLQ-C30 includes 5 functional scales (physical, role, cognitive, emotional and social functioning), 3 symptom scales (fatigue, pain and nausea/vomiting), a GHS/QoL scale, and six single items (constipation, diarrhea, insomnia, shortness of breath, appetite loss and financial difficulties). | From baseline up to approximately 24 months | 
| Chain from baseline in NSCLC-SAQ | The NSCLC-SAQ is a 7-item, patient-reported outcome measure which assess patient-reported symptoms associated with advanced NSCLC: cough, pain, dyspnea, fatigue, and appetite. | From baseline up to approximately 24 months | 
| Change from baseline in EORTC QLQ-C30 | The EORTC QLQ-C30 includes 5 functional scales (physical, role, cognitive, emotional and social functioning), 3 symptom scales (fatigue, pain and nausea/vomiting), a GHS/QoL scale, and six single items (constipation, diarrhea, insomnia, shortness of breath, appetite loss and financial difficulties). | From baseline up to approximately 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lung cancer, NSCLC, KRAS G12C, STK11, PD-L1, JDQ443