P2, N=29, Active, not recruiting, Tianjin Medical University Cancer Institute and Hospital | Recruiting --> Active, not recruiting

The translation potential of this scaffold is also supported by the clinical success of indole-based EGFR inhibitors, including the third-generation drug osimertinib. This paper summarizes the relevant literature of indole EGFR inhibitors published between 2021 and 2025, which may include mechanistic insights, biological screening, and therapeutic potential. The indole scaffold can be a useful starting point to push forward the next generation of targeted cancer therapies.

In vivo, anlotinib reduced tumor growth in Sh-PD-L1-OR models (P < 0.01), with decreased expression of EGFR, PD-L1, YAP, and β-catenin. These findings suggest that high PD-L1 expression promotes osimertinib resistance through activation of YAP and Wnt/β-catenin, and that anlotinib combined with osimertinib can reverse resistance by restoring GSK3β activity, activating the Hippo pathway, and inhibiting β-catenin signaling.

Patients were treated in first-line (1L) with osimertinib or other TKIs (non-osimertinib). This study demonstrates that real-world treatment patterns and outcomes of TKIs are comparable with those found in both clinical trials and other real-world studies. RWE studies can support clinicians in investigating the best treatment strategy and decision makers to drive new health policies.

P2, N=15, Recruiting, M.D. Anderson Cancer Center | Trial primary completion date: Feb 2026 --> Feb 2028

P2, N=21, Recruiting, Sun Yat-sen University

Recent studies indicate that multiple Ubiquitin-Specific Proteases (USP) family members play pivotal roles in lung cancer: Ubiquitin-Specific Peptidase 7 (USP7) promotes proliferation and osimertinib resistance in non-small cell lung cancer by stabilising proteins such as ERβ, c-Abl, and KRAS; Ubiquitin-Specific Peptidase 9, X-linked (USP9X) mediates radiotherapy resistance by regulating KDM4C and REV1; USP10 influences cellular metabolism and chemotherapy sensitivity via PTEN/AKT/mTOR and HDAC6 pathways; Ubiquitin-Specific Peptidase 14 (USP14) enhances tumour migration by regulating β-catenin and Acf7 stability; Ubiquitin-Specific Peptidase 22 (USP22) amplifies tumour stem cell properties and suppresses ferroptosis via EGFR and BMI1 signalling; Ubiquitin-Specific Peptidase 35 (USP35) and Ubiquitin-Specific Peptidase 38 (USP38) respectively modulate apoptosis resistance and proliferation through BIRC3 and KLF5; while Ubiquitin-Specific Peptidase 39 (USP39) influences mitochondrial metabolism via PDHA, thereby promoting tumour growth...It further explores the potential value of small-molecule inhibitors targeting USPs (such as P5091, IU1, and gentiopicroside) in reversing drug resistance, inducing apoptosis, and enhancing immunotherapy...This paper reviews the molecular mechanisms and targeting strategies of USPs in lung cancer based on a systematic literature search of PubMed and Web of Science databases. It further explores their potential applications in precision lung cancer therapy, providing theoretical foundations and directional guidance for future research.

We also explored clinical phosEGFR reduction induced by the 3rd generation TKI osimertinib, suggesting that limited target engagement may explain modest response achieved in EGFR Exon20Ins at the clinically investigated doses. The developed model is a valuable tool to understand the impact of kinetic characteristics on phosEGFR reduction and related efficacy, select a target engagement-based criterion for therapeutic dose predictions, and provide interpretation and insights on observed clinical efficacy of irreversible inhibitors in EGFR Exon20Ins.

The efficacy of TKIs was consistent across SQC forms (including de novo or adenocarcinoma-transformed cases) and EGFR mutation types. The findings indicate that, compared with early-generation TKIs, third-generation TKIs are effective against de novo SQCs and should be considered a plausible treatment option for transformed SQCs.

P2, N=64, Not yet recruiting, Chinese University of Hong Kong

P2, N=36, Recruiting, Guangzhou Medical University | Not yet recruiting --> Recruiting | Trial completion date: Mar 2026 --> Mar 2027

For classical EGFR mutations such as exon 19 deletion and exon 21 L858R mutation, combination strategies in the first-line setting, based on the results of the MARIPOSA (lazertinib and amivantamab) and FLAURA 2 (platinum-based doublet chemotherapy and osimertinib) trials, provide promising outcomes. Optimising the treatment sequence in advanced EGFR-mutated NSCLC is crucial to ensure the best survival outcomes along with the best treatment tolerance and quality of life. Predictive biomarkers are strongly needed as well as biomarker-based escalation and de-escalation clinical trials.