BOS172738 and the continuing evolution of precision therapy for RET-altered cancers

REarranged during Transfection (RET) was discovered as an oncogene activated by DNA rearrangement in 1985 through the transfection of NIH3T3 cells with human lymphoma DNA (1). The RET proto-oncogene encodes a transmembrane receptor tyrosine kinase with a unique extracellular domain consisting of four cadherin-like domains and a cysteine-rich region (2). The identification of oncogenic RET alterations has transformed the therapeutic landscape of several solid tumors, most notably medullary thyroid carcinoma (MTC), papillary thyroid carcinoma (PTC), and a subset of non-small cell lung carcinomas (NSCLC) (3,4). Over the past decade, RET has emerged as a paradigmatic example of how molecularly defined oncogenic drivers can be successfully targeted, translating fundamental discovery into substantial and durable clinical benefit. In this context, the phase I dose-escalation and expansion study of BOS172738 reported by Patrick Schöffski and colleagues in ESMO Open represents an important addition to the selective RET inhibitor landscape (5).

Early efforts to therapeutically target RET relied on multikinase inhibitors (MKIs) such as vandetanib, cabozantinib, lenvatinib, and sorafenib. Although these agents demonstrated meaningful efficacy in advanced RET-mutant MTC—leading to regulatory approval—their clinical activity in RET fusion–positive NSCLC was limited, as reflected by relatively modest objective response rates, progression-free survival, and overall survival (6,7). These shortcomings were largely attributable to limited kinase selectivity, resulting in off-target inhibition of vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor, and related kinases, and consequent dose-limiting toxicities.

The development of highly selective RET inhibitors, most notably selpercatinib and pralsetinib, marked a decisive inflection point. Both agents achieved high and durable response rates across advanced RET fusion-positive NSCLC and PTC, as well as RET-mutant MTC, while substantially improving tolerability relative to MKIs (8-15). As a result, selpercatinib and pralsetinib rapidly became standard-of-care therapies in RET-driven malignancies. However, clinical experience has also revealed residual challenges, including treatment-emergent toxicities, limitations in dose optimization, and the emergence of both on-target resistance mutations—particularly solvent-front alterations at G810—and off-target bypass mechanisms (16,17). These considerations have motivated the continued development of next-generation RET inhibitors with refined selectivity and resistance coverage, among which BOS172738 represents a compelling candidate.

The BOS172738-01 study reported by Schöffski et al. describes the first-in-human evaluation of BOS172738, a next-generation selective RET tyrosine kinase inhibitor, in a molecularly enriched population of patients with RET-altered tumors (5). This phase I, open-label, multicenter trial incorporated both dose-escalation (Part A) and dose-expansion (Part B) cohorts. In addition to defining safety, tolerability, pharmacokinetics, and the recommended phase II dose, the study provided an early but informative assessment of antitumor activity across diverse RET-driven malignancies.

A key differentiating feature of BOS172738 is its safety and tolerability profile when viewed in the context of existing selective RET inhibitors. Treatment-emergent adverse events (TEAEs) were largely manageable and consistent with highly selective RET inhibition, with a notably low incidence of toxicities commonly associated with residual anti-angiogenic activity. The most frequent grade ≥3 BOS172738-related TEAEs were increased blood creatine phosphokinase (25%), neutrophil count decrease (10%), and anemia (9%), while serious treatment-related TEAEs were infrequent, including muscular weakness (3%) and myositis (2%). Importantly, grade ≥3 hypertension and hepatotoxicity—adverse events that remain clinically relevant with selpercatinib and pralsetinib—were observed in only 2% of patients receiving BOS172738. The differences in safety and tolerability could be primarily explained by differences in kinome selectivity patterns, particularly relative inhibition of VEGFR2 and certain hematopoietic kinases (18-20). Although cross-study comparisons should be interpreted cautiously, these findings suggest that BOS172738 may offer a differentiated tolerability profile, potentially enabling sustained target inhibition and improved dose intensity in selected patient populations.

From an efficacy standpoint, BOS172738 demonstrated encouraging antitumor activity, particularly in RET fusion-positive cancers and RET-mutant MTC. Objective responses were observed in 28% of patients with RET fusion-positive NSCLC and 30% of those with RET-mutant MTC, with disease control achieved in 59% and 74% of patients in each cohort, respectively. Median durations of response were 10.17 and 19.15 months. While these response rates are numerically lower than those reported for selpercatinib and pralsetinib in later-phase trials, such cross-trial comparisons are inherently confounded by differences in trial phase, patient selection, and dose optimization. The lower response rate and shorter duration of response of BOS172738 may reflect differences in RET binding potency, residence time, and overall target coverage. Importantly, the activity observed with BOS172738—despite the maximum tolerated dose not being reached—suggests that its antitumor efficacy may be less constrained by tolerability, potentially allowing more sustained target inhibition over prolonged treatment periods.

Beyond efficacy and safety, the potential role of BOS172738 in addressing resistance represents a particularly important consideration. Solvent-front mutations at RET G810 have emerged as a clinically relevant mechanism of acquired resistance to first-generation selective RET inhibitors. Preclinical data suggest that BOS172738 retains modest activity against multiple G810 substitutions, raising the possibility that it may be effective in specific resistance settings (19-21). Although the present study was not designed to systematically evaluate resistance, these features highlight a potential niche for BOS172738 in sequential treatment strategies following progression on selpercatinib or pralsetinib. Future studies incorporating molecularly annotated resistance cohorts and longitudinal sampling will be critical to clarify this potential advantage.

The inclusion of a heterogeneous population of RET-altered tumors further underscores the relevance of this study. RET fusions occur across a broad spectrum of malignancies, often at low frequency, necessitating basket-style trial designs (22,23). However, because the manuscript does not detail the single-nucleotide variants identified in several cancers with progressive disease shown in Figure S5 (5), it remains unclear whether these variants represent pathogenic RET alterations; thus, caution is warranted when interpreting these specific data. Nevertheless, the overall results reinforce the feasibility and importance of molecularly driven basket trials for advancing therapies in rare oncogenic subsets.

Despite these encouraging findings, key questions remain. The durability of responses, intracranial efficacy, and comparative performance relative to established selective RET inhibitors will ultimately define the clinical positioning of BOS172738. In particular, its role may be shaped less by frontline efficacy and more by activity in pretreated or resistant disease settings, where unmet clinical needs persist. Accordingly, well-designed phase II and III trials will be essential to determine how BOS172738 can be optimally integrated into the evolving RET-targeted treatment paradigm.

In conclusion, the phase I study of BOS172738 reported by Schöffski et al. highlights the continued refinement of selective RET inhibition. By combining encouraging antitumor activity with a potentially differentiated safety and resistance profile, BOS172738 expands the therapeutic options for patients with RET-altered cancers. As the field moves beyond first-generation selective inhibitors, such next-generation agents may play an increasingly important role in sustaining long-term disease control and overcoming resistance in RET-driven malignancies.

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-2026-1-0009/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://aot.amegroups.com/article/view/10.21037/aot-2026-1-0009/coif). The author has no conflicts of interest to declare.

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