TABLE 1.
The clinical trials in patients with LKB1-mutated tumors.
| NCT # | Drug | Study design | Study result | Study phase | Status |
|---|---|---|---|---|---|
| NCT02352844 (Devarakonda et al., 2021) | everolimus | This study evaluates the response to everolimus, a mTORC1 inhibitor in advanced solid tumors with TSC1, TSC2, NF1, NF2, or LKB1 mutations | Of 8 patients who could be evaluated, one patient experienced complete response and another experienced stable disease. The patient with stable disease had lung adenocarcinoma with LKB1 mutation | II | Completed |
| NCT03600883 (Skoulidis et al., 2021) | sotorasib | This study evaluates the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of sotorasib (AMG 510), a KRAS G12C inhibitor, in advanced solid tumors with KRAS G12C mutation, in monotherapy and combination therapy. LKB1 mutation was assessed as co-occurring genomic alteration with KRAS G12C | Of the 124 patients with NSCLC who could be evaluated, 46 patients (37.1%) I/II showed an objective response, including 4 patients (3.2%) having a complete response and 42 (33.9%) having a partial response. The median progressionfree survival was 6.8 months, and the median overall survival was 12.5 months. Among the 104 patients who were assessed for co-occurring genomic alterations, a response was seen in 50% of the patients in the subgroup with mutated LKB1 and wild-type KEAP1. Among patients with mutated KEAP1, a response was seen in 23% of those with both mutated LKB1 and KEAP1 and in 14% of those with wild-type LKB1 and mutated KEAP1 | I/II | active, not recruiting |
| NCT04933695 (ClinicalTrials, 2021) | sotorasib | This study evaluates the clinical activity of sotorasib (AMG 510), a KRAS G12C inhibitor in stage IV NSCLC tumors with KRAS G12C mutation and <1% PD-L1 and/or LKB1 co-mutation in need of first line treatment | N/A | II | active, not recruiting |
| NCT03785249 (Pant et al., 2023) | MRTX849 | This study evaluates the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of MRTX849 (adagrasib), a KRAS G12C inhibitor, in advanced solid tumors with a KRAS G12C mutation. Advanced solid tumor malignancies with KRAS G12C mutation stratified by co-mutation status (e.g., LKB1) | Of 51 patients with KRAS G12C–mutant advanced NSCLC, a partial response rate was 45% (23/51) and 51% had stable disease (26/51). The objective response rate in patients with LKB1 co-mutations was 64% (9/14). Patients with LKB1 co-mutations showed increase of CD4 and CD8 expression after treatment, indicating a potential immune response to therapy | I/II | recruiting |
| NCT05276726 (ClinicalTrials, 2022) | Glecirasib | This study evaluates the safety, tolerability and preliminary antitumor activity of Glecirasib (JAB-21822), a KRAS G12C inhibitor, in locally advanced or metastatic NSCLC with concurrent KRAS G12C and LKB1 mutation and KEAP wild type either treatment naive or at least one-line prior therapy for advance disease | N/A | Ib/II | recruiting |
| NCT03872427 (ClinicalTrials, 2019) | telaglenastat | This study evaluates the clinical activity of telaglenastat (CB-839), a glutaminase inhibitor, in solid tumors or malignant peripheral nerve sheath tumors with NF1, KEAP1/NRF2, or LKB1 mutations | N/A | II | active, not recruiting |
| NCT06188208 (ClinicalTrials, 2023b) | VVD-130850 | This study evaluates the safety, tolerability, pharmacokinetics, pharmacodynamics, and anti-tumor activity of VVD-130850, a STAT3 Inhibitor, as monotherapy and in combination with immunotherapy in advanced solid and hematologic tumors. LKB1 mutated NSCLC was recruited for combination therapy | N/A | I | recruiting |
| NCT05807048 (ClinicalTrials, 2023a) | daratumumab | This study evaluates the clinical activity of daratumumab, an anti-PD-L1 monoclonal antibody in metastatic NSCLC with LKB1 mutation who have received previous standard treatment. An overall response rate ≥20% is considered clinically meaningful | N/A | II | recruiting |
| NCT04265534 (ClinicalTrials, 2020) | telaglenastat with pembrolizumab and chemotherapy | This study evaluates the safety and clinical activity of telaglenastat (CB-839), a glutamase inhibitor, with pembrolizumab and chemotherapy, for first line treatment of metastatic NSCLC with NF1, KEAP1/NRF2, or LKB1 mutations | Lack of clinical benefit and terminated | II | Terminated |
| NCT04173507 (Skoulidis et al., 2022) | talazoparib plus avelumab | This study (a LUNG-MAP treatment trial) evaluates the efficacy and safety of talazoparib, a PARP inhibitor in combination with avelumab, a PD-L1 monoclonal antibody, for stage IV or recurrent non-squamous NSCLC with LKB1 mutations | Of 42 patients, the objective response rate was 2% (1/42), the disease control rate at 12 weeks was 40% (17/42). 62% patients (26/42) had stable disease as best objective response. The median progression free survival was 2.7 months, and the median overall survival was 7.6 months. However, the combination therapy did not meet the pre-specified threshold for efficacy | II | Completed |
| NCT05887492 (ClinicalTrials, 2023c) | TNG260 plus pembrolizumab | This study evaluates the safety and tolerability, pharmacokinetics, and clinical activity of TNG260, a CoREST-selective deacetylase inhibitor, in combination with pembrolizumab, a PD-1 monoclonal antibody, in locally advanced or metastatic LKB1 mutated solid tumors | N/A | I/II | recruiting |
| NCT06124963 (ClinicalTrials, 2023d) | WX390 plus toripalimab | This study evaluates the safety, tolerability and preliminary antitumor activity of WX390, a PI3K-mTOR dual inhibitor, in combination with toripalimab, a PD-1 monoclonal antibody in advanced gastric-type endocervical adenocarcinoma with LKB1 mutations | N/A | II | recruiting |
| NCT03184571 (ClinicalTrials, 2017) | bemcentinib plus pembrolizumab | This study evaluates the safety and anti-tumor activity of bemcentinib, an AXK inhibitor, in combination with pembrolizumab, a PD-1 monoclonal antibody in advanced NSCLC, some of which have LKB1 mutations | Of the 24 chemo-refractory and 30 PD-1 inhibitor refractory NSCLC, three patients had LKB1 mutations and all experienced clinical benefit. One patient had a partial response for 10 months and two patient had stable disease for 3.5 and 6.2 months, respectively | II | Completed |
| NCT06219174 (ClinicalTrials, 2024b) | DFMO plus pembrolizumab | This study evaluates the safety and clinical activity of Difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, as an immunotherapeutic target, in combination with pembrolizumab, a PD-1 monoclonal antibody, in advanced/metastatic NSCLC with LKB1 mutations | N/A | I/II | recruiting |
| NCT06331650 (ClinicalTrials, 2024a) | carbognilumab plus chemotherapy | This study evaluates the safety and clinical activity of carbognilumab (DB16680), a PD-1 and CTLA-4 bispecific antibody, in combination with standard chemotherapy in advanced or postoperative recurrent NSCLC with LKB1 mutations | N/A | II | recruiting |
| NCT03334617 (Besse et al., 2024) | durvalumab plus targeted therapy | This study evaluates the efficacy, safety and tolerability of durvalumab, a PD-L1 monoclonal antibody, in combination with targeted anticancer agents in refractory NSCLC. Patients with LKB1 mutations were enrolled to receive durvalumab plus the PARP inhibitor olaparib | The objective response rate with durvalumab–olaparib was 4.8% in LKB1 biomarker matched cohort, suggesting limited vulnerability from targeting this mutation. | II | active, not recruiting |