BOS172738: a next-generation rearranged during transfection inhibitor enters the evolving landscape of rearranged during transfection-targeted therapy

Introduction

The therapeutic landscape of rearranged during transfection (RET)-altered malignancies has undergone a profound transformation over the past five years. The development of highly selective RET inhibitors has replaced chemotherapy and multikinase inhibitors as the preferred approach for patients with RET fusion-positive non-small-cell lung cancer (NSCLC) and RET-mutant medullary thyroid cancer (MTC), respectively. Against this backdrop, the phase I study of BOS172738 reported by Schöffski et al. in ESMO Open represents an important step in the continued evolution of selective RET targeting (1).

This multicenter dose-escalation and expansion trial enrolled 117 heavily pretreated patients with RET-fusion-positive NSCLC and RET-mutant MTC, demonstrating preliminary efficacy with objective response rates of 28% in NSCLC and 30% in MTC, alongside disease control rates of 59% and 74%, respectively. Median progression-free survival (mPFS) was 6.18 months in NSCLC and 12.75 months in MTC.

While these results are encouraging, they must be contextualized within the rapidly evolving landscape of RET-targeted therapy, where two highly selective RET inhibitors—selpercatinib and pralsetinib—have already established themselves as standard-of-care agents with superior efficacy profiles.

Placing BOS172738 in clinical context

The current standards of care in RET-driven malignancies were established through pivotal trials of selpercatinib and pralsetinib. In the LIBRETTO-001 trial, selpercatinib demonstrated objective response rates of 64% in previously treated RET-fusion-positive NSCLC patients and 85% in treatment-naive patients, with mPFS of 16.5 months in the pretreated cohort (2). Similarly, pralsetinib showed response rates of 61% in previously treated and 70% in treatment-naive RET-fusion-positive NSCLC (3). For RET-mutant MTC, selpercatinib achieved response rates of 69% in previously treated patients and 73% in treatment-naive patients (4).

These outcomes were subsequently reinforced in randomized phase III trials. The phase III LIBRETTO-431 trial demonstrated selpercatinib’s superiority over platinum-based chemotherapy with pembrolizumab in first-line RET-fusion-positive NSCLC [mPFS, 24.8 vs. 11.2 months; hazard ratio (HR), 0.46], establishing it as the preferred initial therapy for this molecularly defined population (5). Similarly, the LIBRETTO-531 trial showed selpercatinib’s superiority over multikinase inhibitors (cabozantinib or vandetanib) in RET-mutant MTC, with mPFS not reached with selpercatinib versus 16.8 months with multikinase inhibitors (HR 0.28, P<0.001), demonstrating consistent benefit across all patient subgroups (6). These data have reshaped guidelines, with selective RET inhibitors now recommended as preferred first-line therapy in both disease settings (7).

However, cross-trial comparisons must be interpreted cautiously. The BOS172738 study enrolled a heavily pretreated population, with patients having received a median of 2 to 3 prior lines of therapy and 21% of patients harboring brain metastases at baseline (1).

Notably, while the Part B expansion included a cohort (n=23) designated for patients with “other RET gene-altered advanced tumors or NSCLC/MTC with prior specific RET gene-targeted therapy”, this cohort combined two distinct populations, and the study does not report the specific number of patients who had received prior selective RET inhibitors. Furthermore, although 45% of patients overall received prior targeted small molecule therapy, no granular breakdown distinguishing multikinase inhibitors from selective RET inhibitors was provided. This limits the ability to draw conclusions about BOS172738’s activity in the post-selpercatinib or post-pralsetinib setting—arguably the most clinically relevant question for a next-generation RET inhibitor. Early-phase trials are intended to identify preliminary signals of activity, characterize safety profiles, and determine optimal dosing rather than to establish definitive comparative efficacy. Within that framework, the activity observed with BOS172738 confirms meaningful RET pathway inhibition in refractory disease and supports continued investigation.

Translational pharmacology and molecular differentiation

As newer RET inhibitors enter clinical development, their ultimate positioning will depend on mechanistic differentiation. BOS172738 is described as a potent and selective RET inhibitor with a prolonged half-life of approximately 65 hours (8). Sustained target engagement may theoretically allow continuous pathway suppression, though the clinical implications of this pharmacokinetic profile remain to be defined.

Subtle differences in kinase-binding interactions may influence susceptibility to resistance mutations, drug-drug interactions, and central nervous system (CNS) penetration. Notably, preclinical data provide an early signal of mechanistic differentiation: in a Ba/F3 cell line model expressing KIF5B-RET with the G810S secondary mutation, cells were resistant to both selpercatinib and pralsetinib but retained sensitivity to BOS172738 (9). If validated clinically, this differential activity against the most prevalent solvent-front resistance mutation would represent a meaningful translational advantage. Further characterization across broader panels of resistance mutations, including gatekeeper alterations, will be essential to fully define the mechanistic profile of BOS172738 relative to established selective RET inhibitors.

Safety profile and clinical manageability

In the phase I study, treatment-related adverse events occurred in 85% of patients, with 54% experiencing grade ≥3 toxicities (1). The most common grade ≥3 events were creatine phosphokinase (CPK) elevation (25%), neutropenia (10%), and anemia (9%). These toxicities were reported as manageable with dose modification.

The frequency of high-grade CPK elevation is notable. Although asymptomatic CPK elevations are observed with several kinase inhibitors, the clinical implications, particularly with long term therapy, merit careful monitoring in subsequent trials. Whether this represents a compound-specific effect or reflects patient selection requires further clarification. Importantly, early data suggested minimal hypertension or hepatotoxicity, potentially differentiating BOS172738 from multikinase inhibitors (8).

Comparative tolerability assessments across trials are inherently limited, but ongoing evaluation in larger and potentially less heavily pretreated populations will better define its safety profile. Pharmacokinetic characteristics, including prolonged half-life, may offer sustained exposure but could also influence toxicity management strategies. These considerations underscore the importance of integrated pharmacologic and clinical assessment in future development.

Resistance biology: the central translational challenge

Acquired resistance to selective RET inhibition represents one of the most pressing unmet needs in RET-driven cancers. On-target resistance mutations within the RET kinase domain, including solvent-front G810 substitutions, hinge-site alterations (Y806C/N), and gatekeeper alterations such as V804M/L, have emerged as mechanisms of acquired resistance to selpercatinib and pralsetinib (10-12). X-ray crystallography has confirmed that these mutations create steric clashes at the drug-binding site, impairing inhibitor binding while preserving kinase activity (13). Consistent with these structural findings, molecular profiling of post-progression biopsies from 18 patients who developed resistance to selective RET inhibitors revealed both on-target alterations—including G810 residue mutations (11%)—and off-target bypass mechanisms such as mesenchymal epithelial transition (MET) amplification (17%) and kirsten rat sarcoma viral oncogene homolog (KRAS) amplification (6%) as recurrent drivers of resistance (14).

Off-target bypass mechanisms also contribute to resistance, including activation of alternative receptor tyrosine kinases [such as epidermal growth factor receptor (EGFR), MET, or human EGFR 2 (HER2)], downstream pathway activation [such as KRAS or B-Raf proto-oncogene (BRAF) mutations], and histologic transformation (10,12). Addressing these mechanisms will likely require either next-generation inhibitors capable of overcoming on-target mutations or rational combination strategies targeting bypass pathways.

Although the BOS172738 trial design permitted enrollment of patients with prior RET gene-targeted therapy in the Part B expansion cohort, the study does not report the number of patients who had received prior selective RET inhibitors or their specific outcomes, limiting our ability to assess its activity against acquired resistance mutations (1). However, emerging preclinical data provide an important translational signal. In a Ba/F3 cell line model expressing KIF5B-RET with the G810S secondary mutation, cells were resistant to both selpercatinib and pralsetinib but retained sensitivity to BOS172738, suggesting a potential mechanistic advantage against the most clinically prevalent solvent-front resistance mutation (9). If validated clinically, this differential activity would provide a compelling rationale for investigation in the post-selpercatinib/pralsetinib setting. Comprehensive evaluation across broader panels of solvent-front and gatekeeper mutations, coupled with future expansion cohorts specifically enrolling patients with molecularly characterized resistance, would meaningfully strengthen the translational positioning of BOS172738.

CNS disease: a critical clinical variable

CNS disease represents another important clinical challenge in RET-fusion-positive NSCLC. Brain metastases occur in approximately 40–50% of patients during their disease course, and CNS penetration of RET inhibitors is critical for optimal outcomes (11). Selpercatinib has demonstrated intracranial activity, with CNS objective response rates exceeding 80% in patients with measurable brain metastases in the LIBRETTO-001 trial (2).

In the BOS172738 study, 21% of patients had brain metastases at baseline, with 43% reduction in target lesions in the brain seen in 1 patient on study treatment; however, intracranial response rates overall were not specifically reported (1). Dedicated evaluation of CNS efficacy, including radiographic intracranial response, duration of CNS control, and pharmacokinetic CNS penetration studies, will be important in defining the agent’s clinical profile.

Optimal sequencing and combination strategies

With selective RET inhibitors now firmly established as first-line therapy in RET-altered malignancies, clinical focus has increasingly shifted toward optimal sequencing strategies after disease progression. At present, no standardized second-line approach exists following failure of selpercatinib or pralsetinib.

Management decisions are therefore individualized and, when feasible, informed by molecular profiling to identify underlying resistance mechanisms. In this evolving landscape, several potential clinical roles for BOS172738 can be envisioned. It may hold value in the post-selective RET inhibitor setting—specifically after progression on selpercatinib or pralsetinib—particularly if future translational and clinical data demonstrate activity against solvent-front or other acquired resistance mutations. However, as noted, the current study does not provide sufficient data to evaluate this hypothesis, underscoring the need for dedicated expansion cohorts enrolling patients with molecularly characterized resistance to selective RET inhibitors. Alternatively, if differentiated safety or pharmacologic advantages emerge, it could serve as an alternative frontline option in selected patients with specific comorbidities. Additionally, BOS172738 may function as a platform agent in rational combination strategies, provided its tolerability profile and pharmacokinetic characteristics support such development. The investigation of combination strategies, including the pairing of RET inhibition with mitogen-activated protein kinase MEK inhibitors, MET inhibitors, or immune checkpoint blockade, represents a rational extension of resistance biology and pathway cross-talk (12,13). However, careful consideration of additive efficacy alongside the risk of overlapping toxicities will be essential in designing future trials.

Future development considerations

For BOS172738 to establish a meaningful role within the contemporary treatment landscape, several critical issues must be addressed through ongoing clinical development. First, comprehensive preclinical assessment of activity against common RET resistance mutations is essential. Demonstration of retained efficacy against solvent-front mutations such as G810 or other acquired resistance alterations would provide a compelling rationale for evaluation in the post-selpercatinib or pralsetinib setting (15,16). Second, given the substantial incidence of brain metastases in RET fusion-positive NSCLC, dedicated investigation of CNS penetration and intracranial activity is necessary. This should include pharmacokinetic analyses confirming CNS exposure as well as prospective clinical cohorts evaluating intracranial response rates and durability. Third, identification of predictive biomarkers may help define patient subgroups most likely to benefit, potentially including specific RET fusion partners, co-occurring genomic alterations, or tumor microenvironment characteristics. Fourth, although direct comparative trials against established selective RET inhibitors may be impractical, contextualizing clinical benefit through real-world datasets or propensity-adjusted analyses could clarify relative efficacy. Finally, rational combination strategies grounded in preclinical synergy and complementary mechanisms of action should be explored, with careful attention to the tolerability profile of BOS172738 to ensure feasibility of combination regimens.

Conclusions

The phase I evaluation of BOS172738 confirms the continued viability of selective RET inhibition in RET-altered malignancies and provides important early clinical data in a heavily pretreated population. As standards of care continue to evolve, the development of next-generation RET inhibitors should be informed by translational insights, particularly with respect to resistance mutation coverage, CNS activity, and rational combination strategies. Continued translational integration will be essential to realize that potential.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Thyroid. The article has undergone external peer review.

Peer Review File: Available at https://aot.amegroups.com/article/view/10.21037/aot-2026-0017/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aot.amegroups.com/article/view/10.21037/aot-2026-0017/coif). B.K. reports grant funding to her institution (the Ohio State University) from Eli Lilly & Co, Eisai, Merck, and RayzeBio; and consulting fees from Exelixis. The other 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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