Augtyro (repotrectinib)

P2, N=6, Terminated, M.D. Anderson Cancer Center | N=58 --> 6 | Trial completion date: Dec 2027 --> Dec 2025 | Recruiting --> Terminated | Trial primary completion date: Dec 2027 --> Dec 2025; <75% Participation

Currently, selpercatinib, larotrectinib, and repotrectinib are approved by the FDA for the treatment of certain solid tumors harboring specific gene fusions. Recent studies on zenocutuzumab resulted in the FDA-accelerated approval for NGR1 fusion-positive NSCLC and PDAC. Germline mutations may specifically increase responsiveness to poly(ADP-ribose) polymerase (PARP) inhibitors or platinum-based treatments. Comprehensive genomic profiling, incorporating fusion detection and germline testing, is essential to identify patients who may benefit from precision-based approaches.

This includes work that led to the FDA approvals of immune checkpoint inhibitors in multiple rare pediatric tumor types, the NTRK inhibitors larotrectinib, entrectinib, and repotrectinib for children and adults with solid tumors with NTRK fusions, the ALK inhibitor crizotinib in children and adults with ALK-positive inflammatory myofibroblastic tumors, and the radioligand LUATHERA for adolescents and adults with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Despite these advances, the study of rare pediatric cancers faces multiple challenges including a limited number of patients for efficient and well-powered clinical trials and a dearth of financial incentives. Ongoing, coordinated efforts are needed to continue the advancement of novel treatments and improve survival and minimize late effects.

Crizotinib, entrectinib, and repotrectinib have been approved by the US Food and Drug Administration for treatment of ROS1-positive NSCLC. In this nonrandomized clinical trial, lorlatinib demonstrated durable efficacy and manageable safety in TKI-naive advanced ROS1-positive NSCLC, supporting the potential for using lorlatinib in earlier treatment settings. ClinicalTrials.gov Identifier: NCT03612154.

Crizotinib first demonstrated substantial clinical benefit, but its limitations, including poor central nervous system (CNS) penetration and acquired resistance, highlighted the need for next-generation inhibitors. Several agents have since been developed, including entrectinib, lorlatinib, repotrectinib, taletrectinib, and zidesamtinib, each offering improved intracranial (IC) activity and efficacy against resistance mutations, notably ROS1^G2032R. Despite these advances, optimal sequencing strategies remain undefined, and resistance ultimately emerges in most patients. This review provides an updated overview of ROS1 biology, diagnostic approaches, clinical outcomes with currently available TKIs, mechanisms of resistance, and ongoing challenges, emphasizing the rapidly evolving therapeutic landscape.

P3, N=190, Active, not recruiting, Bristol-Myers Squibb | Trial primary completion date: Mar 2027 --> Mar 2026

P1, N=32, Not yet recruiting, Bristol-Myers Squibb

Several ALK inhibitors, like crizotinib, ceritinib, lorlatinib, repotrectinib, and alectinib, have shown different levels of success, but resistance to these treatments is still a big challenge. While ALK inhibitors have shown promise, resistance mechanisms necessitate the development of combination therapies and next-generation inhibitors. Future research should focus on optimizing targeted treatment strategies to improve survival outcomes in pediatric patients with ALK-positive neuroblastoma.

P1, N=18, Completed, Bristol-Myers Squibb | Recruiting --> Completed

P3, N=190, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting

Current evidence suggests that these therapies show promise in treating NTRK gene fusions (larotrectinib, entrectinib, repotrectinib), BRAF V600E mutation (dabrafenib and trametinib), and RET fusions (selpercatinib) in lung cancer. However, available data are limited by small sample sizes (ranging from 4 to 247 participants per trial-cohort) and the absence of control groups. Larger, controlled studies and real-world evaluations are needed to confirm these findings and inform broader clinical use.