ROS1 therapy among patients with advanced non-small cell lung cancer: an endless road to rediscover?

Background

Non-small cell lung cancer (NSCLC) is a heterogeneous disease, with a subset driven by oncogenic alterations, including fusions involving the proto-oncogene tyrosine-protein kinase 1 (ROS1) (1,2). ROS1 encodes a receptor tyrosine kinase (RTK) whose precise physiological function in humans remains largely unknown (3). However, chromosomal rearrangements involving ROS1 lead to the production of chimeric oncoproteins that aberrantly activate downstream signaling pathways, promoting oncogenesis across various cancer types in both adult and pediatric populations (3). In NSCLC, ROS1 gene fusions are identified in approximately 1–2% of cases, establishing them as a distinct molecular subtype and an actionable therapeutic target (4). The identification of ROS1 fusions in NSCLC was first reported in 2007 through a phosphoproteomic screen that characterized tyrosine kinase signaling in NSCLC cell lines and tumors (3).

ROS1 fusion-positive NSCLC typically presents in younger patients, often with a never-smoking or light-smoking history, like other oncogene-driven NSCLCs like those with ALK or EGFR mutations (5). While specific demographic data varies, the incidence of central nervous system (CNS) metastases in stage IV ROS1-rearranged NSCLC has been a notable area of study, with rates of CNS progression on crizotinib being a significant clinical consideration (5).

The TRUST trials overview

The TRUST trials were phase II trials in which taletrectinib was used among patients with positive ROS1 NSCLC (6) with a dose of 600 mg daily. Taletrectinib is a novel ROS-1 tyrosine kinase inhibitor (TKI) with lower neurologic adverse events (AEs) when compared to other next-generation ROS-1 TKI (6). TRUST I trial was conducted in China and TRUST II sought external validation with global centers. The primary endpoints were objective rate response (ORR), while secondary endpoints included intracranial (IC)-ORR, progression-free survival (PFS), duration of response (DOR), and safety.

Population characteristics and results

It is notable that the number of patients selected for phase II trials (n=273 for efficacy analysis, with n=172 from TRUST I and n=101 from TRUST II), considering this rare profile mutation (4). Among those patients, 160 were TKI-naïve and 113 were treated with at least one prior line before starting taletrectinib. Overall, the median age was 56 years, females were predominant (57.1%), as well as non-smokers (66.7%). However, solely 17% were from Western countries (n=47) (6).

The study met its main endpoint. For TKI-naïve the ORR rate response was 88.8%, while disease control rate (DCR) of 95%, median DOR of 44.2 months, IC-ORR of 76.5%, and median PFS was 45.6 months. As for those pre-treated patients, the ORR was 55.8%, with a DCR of 87.6%, median DOR of 16.6 months, IC-ORR of 65.6%, and median PFS of 9.7 months. Overall, the median time to response was 1.4 months, and 33.0% of treatment-related AE were reported. The most common treatment-related AE were increased aspartate aminotransferase (AST) (70.2%), increased alanine aminotrasnferase (ALT) (66.5%), and diarrhea (61.4%), with only a 3% rate of treatment discontinuation. The most common neurologic events included dizziness (21.6%), dysgeusia (15%), and headache (11%), with the majority being grade 1. Median overall survival (OS) was not reached in all cohorts (6).

Discussion

Accurate identification of ROS1 fusions is critical for guiding treatment decisions, as targeted therapies are highly effective in this subset of patients (3,4). Various diagnostic methodologies are employed for ROS1 rearrangement detection. Fluorescence in situ hybridization (FISH) has been a traditional method for detecting ROS1 rearrangements (1). Immunohistochemistry (IHC) for ROS1 protein expression can serve as a screening tool, with positive cases requiring confirmation by other methods. Next-generation sequencing (NGS), particularly RNA-based NGS, is increasingly recognized as a comprehensive diagnostic approach, capable of identifying diverse ROS1 fusion partners and overcoming challenges associated with DNA-based methods (3). The identification of novel ALK and ROS fusion proteins in NSCLC has further emphasized the importance of broad molecular profiling (3).

The advent of oral small-molecule TKIs targeting the ROS1 fusion oncoprotein has significantly transformed the treatment landscape for metastatic ROS1 fusion-positive NSCLC, leading to improved patient outcomes (4).

Crizotinib, a first-generation multikinase inhibitor, was the first TKI to demonstrate substantial clinical activity in ROS1-rearranged NSCLC (7). Its efficacy led to regulatory approval for this indication (3). Entrectinib is another FDA-approved first-line therapy for ROS1⁺ NSCLC, offering systemic and CNS efficacy (4,8). Based on current guidelines, repotrectinib is a preferred choice because of its relative efficacy, CNS activity, and resistance coverage. Entrectinib and crizotinib may be considered when the neurological side effect profile of repotrectinib is a concern.

Despite the effectiveness of first-generation TKIs, resistance invariably develops, limiting clinical benefit and leading to disease relapse (3). This has spurred the development of next-generation ROS1 TKIs designed to overcome resistance mutations and enhance CNS penetration (3,4). In that matter, novel molecules that target ROS1 include Repotrectinib (9,10), taletrectinib (5), ceritinib (11), and zidesamtinib (12,13). The selection among first-line therapeutic options requires careful consideration of systemic and CNS efficacy, tolerability profiles, and accessibility (4).

Taletrectinib achieved an optimal DCR and ORR, regardless of offered line of treatment, with promising results and low treatment discontinuation rates (where most of laboratory with no clinical symptoms).

Although authors suggested that taletrectinib may be used globally, it is important to mention that TRUST I had a higher population than TRUST II, and that may be a pitfall for the aimed external validity, since sampling can be diluted and underrepresented. Also, it is highly unrecommended to perform comparisons to the data presented in other trials, highlighting ORR and survival data, since these are not phase III trials. Another concern was based on the comments that among White and Asian populations, a global scale could be applied based on the presented results, but the data presented in the final paper do not present the race variable or the results for it.

There is a phase III trial of taletrectinib versus crizotinib in the first-line setting (Clinical-Trials.gov identifier: NCT06564324), aiming to evaluate efficacy and safety. However, it raises the discussion whether phase III clinical trials are crucial for rare mutations among patients with NSCLC, since besides the difficulties in recruitment, the resources and costs applied here may not imply different data from phase II trials, hence, this can be a reason to delay changes in clinical practice.

While ongoing efforts seek to validate taletrectinib’s clinical benefit, one of the most pressing issues in the long-term management of ROS1 fusion-positive NSCLC remains resistance to ROS1 TKIs. Understanding the molecular mechanisms behind resistance—whether intrinsic or acquired—is key to informing subsequent treatment strategies (4).

Key resistance mechanisms include:

• On-target ROS1 mutations: these are alterations within the ROS1 kinase domain that reduce the binding affinity of TKIs. Specific mutations, such as the ROS1 G2032R solvent front mutation, are well-characterized resistance mutations that next-generation TKIs aim to overcome (9);
• Bypass signaling pathways: activation of alternative oncogenic pathways can allow cancer cells to bypass ROS1 inhibition (3);
• Histological transformation: in some cases, NSCLC can undergo histological transformation into small cell lung cancer (SCLC) or other neuroendocrine carcinomas, leading to TKI resistance (3).

The approach to subsequent therapy in patients with progressive disease on an initial ROS1 TKI depends on the pace and pattern of progression and, ideally, the identified mechanisms of resistance (4). Next-generation ROS1 TKIs offer broader coverage of resistance mutations and superior CNS penetration compared to first-generation agents, highlighting the utility of sequential TKI therapy (3,4).

Finally, future data on molecular assessment may assist physicians in clinical decision making, with better understanding of how co-mutations impact tumor’s response rate and how the current resistant mechanisms can be avoided.

Future directions

Ongoing research aims to further improve outcomes for patients with ROS1⁺ NSCLC. This includes exploring novel therapeutic strategies to address TKI resistance, optimizing the sequencing of ROS1 TKIs, and investigating the role of these agents in earlier-stage, non-metastatic disease (4). Further understanding of the polyclonal nature of resistance and development of selective ROS1 inhibitors that allow for deconvoluting specific adverse effects are also important areas of investigation (3,4).

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-79/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-79/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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