A Phase 3 Study of IN10018 in Combination With D-1553 Versus Standard Therapy for First Line Non-squamous Non-small Cell Lung Cancer With KRAS G12C Mutation

Official title

A Phase 3 Multicenter, Randomized, Controlled, and Open-Label Study of IN10018 in Combination With D-1553 Versus Standard Therapy for the Treatment of First Line Locally-advanced or Metastatic Non-squamous Non-small Cell Lung Cancer With KRAS G12C Mutation

Overview

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).

Detailed description

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.

Interventions

• Drug IN10018 in combination with D-1553
  IN10018 100mg QD PO and D-1553 600mg BID PO, 21days per cycle
• Drug anti-PD-1 monoclonal antibody in combination with platinum and pemetrexed
  Tislelizumab 200mg Q3W IV + Carboplatin AUC 5 mg/mL/min or Cisplatin 75mg/m² Q3W IV+ Pemetrexed 500mg/m² Q3W IV

Primary outcome measures

• Progression-Free Survival (PFS) [Time frame: up to 36 months]

Secondary outcome measures (9)

• Objective Response Rate (ORR) [Time frame: up to 36 months]
• Overall Survival (OS) [Time frame: up to 60 months]
• Disease Control Rate (DCR) [Time frame: Up to 36 months]
• Duration of Response (DoR) [Time frame: up to 36 months]
• PFS [Time frame: up to 36 months]
• ORR [Time frame: up to 36 months]
• DCR [Time frame: up to 36 months]
• DOR [Time frame: Up to 36 months]
• Number of subjects with adverse event [Time frame: up to 36 months]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 11 centers

• Beijing Cancer Hospital — Beijing
• The First Affiliated Hospital, Sun Yat-sen University — Guangzhou
• Henan Cancer Hospital — Zhengzhou
• The First Affiliated Hospital of Zhengzhou University — Zhengzhou
• Union Hospital Tongji Medidcal College Huazhong University of Science and Technology — Wuhan
• Hunan Cancer Hospital — Changsha
• Jiangsu Cancer Hospital — Nanjing
• First Affiliated Hospital of Gannan Medical University — Gannan
• … and 3 more centers

Publications

• Song Z, Li X, Lin R, Shi H, Yuan Y, Liu Y, Luo Y, Lv T, Zhang Y, Zhu L, Zhu Y, Zhang L, Wang Z. Ifebemtinib plus garsorasib as first-line treatment for KRASG12C-mutated non-small-cell lung cancer in China: a multicentre, single-arm expansion cohort from a phase 1b/2 trial. Lancet Respir Med. 2026 Jul 7:S2213-2600(26)00142-6. doi: 10.1016/S2213-2600(26)00142-6. Online ahead of print. PMID 42413526

Identifiers

NCT: NCT07174908 · IN10018-023

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗