Phase II Evaluation of JDQ443 Monotherapy in KRAS G12C-Mutated NSCLC with Variable PD-L1 Expression and STK11 Co-Mutation

The primary objective of this study is to evaluate the **antitumor activity** of JDQ443 as a single-agent first-line treatment in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring a KRAS G12C mutation and a PD-L1 expression of less than 1%, irrespective of STK11 mutation status (cohort A). This is clinically relevant as it aims to determine the efficacy of JDQ443 in a specific genetic subset of NSCLC, potentially offering a targeted therapeutic option for patients with limited treatment alternatives.

Secondary objectives include:

• Assessing the antitumor activity of JDQ443 as a single-agent first-line treatment for participants with locally advanced or metastatic NSCLC whose tumors have a KRAS G12C mutation, a PD-L1 expression of 1% or greater, and an STK11 co-mutation (cohort B).
• Evaluating the duration of response (DOR) in both cohorts, which is crucial for understanding the sustainability of the treatment's efficacy over time.

The clinical trial involves a total of **63 participants** diagnosed with **locally advanced or metastatic KRAS G12C-mutated non-small cell lung cancer**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically includes adults and older adults. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of locally advanced or metastatic non-small cell lung cancer (NSCLC) without prior systemic treatment for metastatic disease. The trial includes individuals with a **PD-L1 expression** of less than 1% or those with a PD-L1 expression of 1% or greater and an STK11 co-mutation. All participants must have at least one measurable lesion per RECIST 1.1 and an ECOG performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population is capable of swallowing study medication, and prior treatments such as chemotherapy, immunotherapy, or radiotherapy are permissible if completed more than 12 months before enrollment. The study does not exclude vulnerable populations, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

The clinical trial is designed to evaluate the **efficacy** and safety of JDQ443 as a single-agent treatment for patients with locally advanced or metastatic **KRAS G12C-mutated non-small cell lung cancer**. This is a Phase II, open-label trial with a focus on patients whose tumors exhibit specific **PD-L1 expression** levels and **STK11 co-mutation** status. The trial employs a randomized, controlled design to ensure robust data collection and analysis. The estimated duration of the trial is from December 2022 to October 2025, with participant involvement expected to last up to 1060 days, depending on individual response and disease progression.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as **ECOG performance status** and the presence of measurable lesions per RECIST 1.1. Following successful screening, participants will be enrolled and commence treatment with JDQ443, administered orally in tablet form. Regular follow-up visits will be scheduled to monitor treatment response, assess safety, and collect pharmacokinetic data. These visits will include evaluations of overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), among other endpoints.

The end-of-study visit will occur upon completion of the treatment period or earlier if disease progression or unacceptable toxicity is observed. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any other medical reasons deemed necessary by the investigator. Throughout the trial, data will be reviewed by a blinded independent review committee to ensure objective assessment of treatment outcomes. The trial aims to provide valuable insights into the potential of JDQ443 as a first-line treatment option for this specific patient population.

The clinical trial involves the administration of the experimental medication **JDQ443**, which is formulated as a **tablet**. The active substance in JDQ443 is chemically derived and identified as 1-{6-[(4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one. The medication is administered **orally**. The maximum daily dose is 400 mg, with a total maximum dose of 424 g over the treatment period. The maximum treatment period is 1060 days. JDQ443 is not a pediatric formulation and is not classified as an orphan drug. The pharmaceutical form is a tablet, and the product is manufactured by Novartis Pharma AG.

In this study, JDQ443 is used as a single-agent treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring a **KRAS G12C mutation**. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial aims to evaluate the antitumor activity and safety of JDQ443 in this specific patient population.

Efficacy in this clinical trial will be assessed using several key endpoints. The primary endpoint is the **Overall Response Rate (ORR)**, which is defined as the proportion of participants achieving a confirmed complete response (CR) or partial response (PR) as the best overall response (BOR) according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), evaluated by a blinded independent review committee (BIRC). Secondary endpoints include the ORR per RECIST 1.1 by BIRC, Duration of Response (DOR), Progression-Free Survival (PFS), Overall Survival (OS), and Disease Control Rate (DCR). DOR is measured from the first occurrence of a PR or CR to disease progression or death. PFS is defined as the time from enrollment to the first documented disease progression or death. OS is the time from enrollment to death from any cause. DCR is the proportion of participants with a BOR of confirmed CR, PR, and stable disease (SD).

Additional assessments include Time to Response (TTR), which is the time from enrollment to the first documented response of CR or PR, and various patient-reported outcomes such as changes in the Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ) total score and the physical functioning scale of the EORTC QLQ-C30. The trial will also monitor the type, frequency, and severity of adverse events, changes in laboratory values, vital signs, and electrocardiograms (ECGs). The concentration of JDQ443 in plasma and derived pharmacokinetic (PK) parameters will be evaluated as appropriate. These efficacy parameters will be measured and analyzed at scheduled assessments throughout the trial, including at baseline, during treatment, and at the end of treatment (EOT).