This is a multicenter, randomized, open-label, phase III clinical study, to evaluate the efficacy and safety of IN10018 in combination with D-1553 as compared to anti-PD-1 monoclonal antibody (mAb) in combination with platinum and pemetrexed as the first-line treatment for the locally advanced or metastatic KRASG12C mutation-positive non-squamous non-small cell lung cancer (NSCLC).

Preclinical studies indicate that IN10018 synergizes with D-1553 to enhance antitumor activity and delay resistance through multiple mechanisms, including suppression of FAK-YAP signaling pathway activation, reduction of tumor stromal fibrosis, and induction of immunogenic cell death (ICD). IN10018-602/D1553-106 is an ongoing Phase Ib/II clinical study evaluating the synergistic antitumor activity and safety of IN10018 combined with D-1553 in patients with KRAS G12C-mutant solid tumors. Preliminary results have demonstrated notable antitumor activity and a favorable safety and tolerability profile in patients with advanced KRAS G12C-mutant NSCLC and metastatic colorectal cancer. Based on the available clinical data, the sponsor plans to initiate a Phase III study in previously untreated patients with advanced KRAS G12C-mutant NSCLC to further evaluate the efficacy and safety of IN10018 in combination with D-1553 compared with first-line standard treatment.

Inclusion Criteria:

• Able and willing to provide informed consent and comply with study requirements
• Has histologically confirmed locally advanced (Stage IIIB/C) or metastatic (Stage IV) non-squamous NSCLC
• Aged 18-80 years at the time of consent
• Has KRAS G12C mutation confirmed by central laboratory
• Has not received prior systemic therapy for advanced or metastatic NSCLC
• Has at least one measurable lesion per RECIST v1.1
• ECOG performance status of 0-1
• Has adequate organ function
• Life expectancy ≥3 months in the opinion of the Investigator
• Male and female subjects of reproductive potential must agree to use effective contraception during and for 6 months after treatment

Exclusion Criteria:

• Has other histological subtypes of NSCLC (e.g., small cell or neuroendocrine)
• Has active or untreated CNS metastases or carcinomatous meningitis
• Prior treatment with KRAS G12C inhibitors, FAK inhibitors, or immune checkpoint inhibitors
• Has another known driver mutation with approved targeted therapy (e.g., EGFR, ALK, ROS1)
• Has uncontrolled cardiovascular disease, active severe infection, interstitial lung disease, or autoimmune disease requiring systemic therapy
• Has history of another malignancy within 5 years, except those curatively treated and considered low risk (e.g., basal cell carcinoma, cervical carcinoma in situ)
• Has gastrointestinal conditions that may interfere with absorption of oral drugs (if applicable)
• Has known active hepatitis B, hepatitis C, or HIV infection
• Has received a live vaccine within 30 days before first dose of study drug
• Pregnant or breastfeeding women
• Has psychiatric or substance abuse disorders that would interfere with study compliance
• Is participating in another interventional clinical study
• Any condition that, in the opinion of the Investigator, would interfere with participation or study results