Iruplinalkib

We utilized an integrated approach for model‐informed dose selection to predict the recommended phase 2 dose (RP2D) of iruplinalkib, a selective oral ALK and ROS1 tyrosine kinase inhibitor. The efficacy and pharmacokinetics data obtained from ROS1 or ALK‐overexpressing cell‐derived xenograft models were used for pharmacokinetics pharmacodynamics (PKPD) modeling and calculating human iruplinalkib tumor static concentration (TSC). The plasma concentration‐time profile based on pooled clinical data was included in population PK (PopPK) analysis. The steady‐state plasma concentration‐time profile of iruplinalkib was predicted based on 1000 simulated replicates of the analysis dataset overlaid with data from 54 patients who received iruplinalkib at 120, 180, or 240 mg QD. A two‐compartment PopPK model with first‐order absorption and linear elimination successfully delineated iruplinalkib PK characteristics in mice, with good precision (relative standard error [RSE] < 30%). TSC in humans, estimated using a modified Simeoni model, was 98 and 78 ng/mL for ROS1‐positive and ALK‐positive tumors, respectively. A two‐compartment PopPK model with first‐order absorption and first‐order elimination was established based on data collected from previous clinical studies, and the model described iruplinalkib PK properties well (RSE < 30%). Iruplinalkib 180 mg QD was predicted to benefit over 90% of the population and recommended as the RP2D. This dose regimen was further validated by results of advanced clinical trials and ultimately incorporated into the prescribing information as the recommended dosage. A translational model‐based approach using integrated preclinical PK/PD and PopPK modeling in patients with non‐small cell lung cancer is a reliable method to predict RP2D.Trial Registration:ChiCTR.org.cn number: ChiCTR20170871; ClinicalTrials.gov identifier: NCT03389815; ChinaDrugTrials.org.cn number: CTR20190737

Immune checkpoint blockage (ICB) therapy has shown minimal effectiveness in anaplastic lymphoma kinase (ALK)-positive nonsmall cell lung cancer (NSCLC) regardless of Programmed death-ligand 1 expression. ALK fusion accompanied by mismatch repair deficiency or microsatellite instability-high (MMRd/MSI-H) and high tumor mutation burden (TMB-H) are extremely rare in NSCLC, and the efficacy of ALK inhibitors or ICB-based therapies is unclear. Here, we report the case of a 60-year-old female patient with metastatic lung adenocarcinoma accompanied by EML4-ALK fusion, TMB-H, MMRd/MSI-H, and pathogenic mutations in TP53, MLH1, and STK11. The patient experienced progression on initial iruplinalkib and subsequent alectinib therapy within 5 months. After the failure of third-line therapy with cisplatin-pemetrexed combined with bevacizumab, she received sintilimab plus anlotinib which led to a progression-free survival of 6.5 months. She received sintilimab combined with albumin-paclitaxel plus carboplatin and achieved partial response after 6 months. She developed adverse events after one cycle of sintilimab plus albumin-paclitaxel treatment. Then she was continued with sintilimab plus anlotinib as a maintenance therapy due to intolerance to chemotherapy. After progression on ICB-based therapy, the patient was treated with lorlatinib and still under follow-up with overall survival of more than 3 years. Our findings highlight the therapeutic potential of ICB-based regimens in patients with MSI-H and ALK-rearranged NSCLC.