Pan-cancer efficacy of pralsetinib in patients with RET fusion–positive solid tumors from the phase 1/2 ARROW trial

Pharmacodynamics; Prognostic markers; Target validationFarmacodinámica; Marcadores pronósticos; Validación de objetivosFarmacodinàmica; Marcadors pronòstics; Validació d'objectiusOncogenic RET fusions occur in diverse cancers. Pralsetinib is a potent, selective inhibitor of RET receptor tyrosine kinase. ARROW (NCT03037385, ongoing) was designed to evaluate pralsetinib efficacy and safety in patients with advanced RET-altered solid tumors. Twenty-nine patients with 12 different RET fusion–positive solid tumor types, excluding non-small-cell lung cancer and thyroid cancer, who had previously received or were not candidates for standard therapies, were enrolled. The most common RET fusion partners in 23 efficacy-evaluable patients were CCDC6 (26%), KIF5B (26%) and NCOA4 (13%). Overall response rate, the primary endpoint, was 57% (95% confidence interval, 35–77) among these patients. Responses were observed regardless of tumor type or RET fusion partner. Median duration of response, progression-free survival and overall survival were 12 months, 7 months and 14 months, respectively. The most common grade ≥3 treatment-related adverse events were neutropenia (31%) and anemia (14%). These data validate RET as a tissue-agnostic target with sensitivity to RET inhibition, indicating pralsetinib’s potential as a well-tolerated treatment option with rapid, robust and durable anti-tumor activity in patients with diverse RET fusion–positive solid tumors.The authors would like to thank the patients, their families and all investigators involved in this study. V.S. is an Andrew Sabin Family Foundation Fellow at The University of Texas MD Anderson Cancer Center. V.S. acknowledges support of the Jacquelyn A. Brady Fund. V.S. is supported by US National Institutes of Health grants R01CA242845 and R01CA273168. MD Anderson Cancer Center Department of Investigational Cancer Therapeutics is supported by the Cancer Prevention and Research Institute of Texas (RP1100584), the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (1U01 CA180964), a National Center for Advancing Translational Sciences grant (UL1 TR000371) and the MD Anderson Cancer Center Support grant (P30 CA016672). Medical writing support, including assisting authors with the development of the outline as well as initial draft and incorporation of comments, was provided by N. Tracey and W. Wheddon; editorial support, including submission, was provided by E. Sims and T. Taylor, all of Paragon (Knutsford, United Kingdom), supported by Blueprint Medicines, according to Good Publication Practice guidelines. The sponsor was involved in the study design and collection, analysis and interpretation of data, as well as data checking of information provided in the article. However, ultimate responsibility for opinions, conclusions and data interpretation lies with the authors. E.G. is supported by the Caixa Research Advanced Oncology Research Program (supported by Fundació La Caixa, LCF/PR/CE07/50610001). E.N. is supported by the Carlos III National Health Institute grant (PI21/00789) and Horizon 2020 (H2020-SC1-2019-Single-Stage-RTD). M. Schuler is supported by the Oncology Center of Excellence Grant/German Cancer Aid (70112273) and the German Cancer Consortium, partner site: University Hospital Essen (BMBF 613-71043-1). G.C. is supported by an OPTIMA (optimal treatment for patients with solid tumors in Europe through artificial intelligence) grant (101034347). The ARROW study (NCT03037385) was supported by Blueprint Medicines and F. Hoffmann-La Roche

Phase 1 Study of Molibresib (GSK525762), a Bromodomain and Extra-Terminal Domain Protein Inhibitor, in NUT Carcinoma and Other Solid Tumors

Carcinoma; Concentració de fàrmac en plasma; FarmacocinèticaCarcinoma; Concentración de fármaco en plasma; FarmacocinéticaCarcinoma; Plasma drug concentration; PharmacokineticsBackground Bromodomain and extra-terminal domain proteins are promising epigenetic anticancer drug targets. This first-in-human study evaluated the safety, recommended phase II dose, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the bromodomain and extra-terminal domain inhibitor molibresib (GSK525762) in patients with nuclear protein in testis (NUT) carcinoma (NC) and other solid tumors. Methods This was a phase I and II, open-label, dose-escalation study. Molibresib was administered orally once daily. Single-patient dose escalation (from 2 mg/d) was conducted until the first instance of grade 2 or higher drug-related toxicity, followed by a 3 + 3 design. Pharmacokinetic parameters were obtained during weeks 1 and 3. Circulating monocyte chemoattractant protein-1 levels were measured as a pharmacodynamic biomarker. Results Sixty-five patients received molibresib. During dose escalation, 11% experienced dose-limiting toxicities, including six instances of grade 4 thrombocytopenia, all with molibresib 60–100 mg. The most frequent treatment-related adverse events of any grade were thrombocytopenia (51%) and gastrointestinal events, including nausea, vomiting, diarrhea, decreased appetite, and dysgeusia (22%–42%), anemia (22%), and fatigue (20%). Molibresib demonstrated an acceptable safety profile up to 100 mg; 80 mg once daily was selected as the recommended phase II dose. Following single and repeat dosing, molibresib showed rapid absorption and elimination (maximum plasma concentration: 2 hours; t1/2: 3–7 hours). Dose-dependent reductions in circulating monocyte chemoattractant protein-1 levels were observed. Among 19 patients with NC, four achieved either confirmed or unconfirmed partial response, eight had stable disease as best response, and four were progression-free for more than 6 months. Conclusions Once-daily molibresib was tolerated at doses demonstrating target engagement. Preliminary data indicate proof-of-concept in NC.This study (BET115521; NCT01587703) was supported by GlaxoSmithKline (GSK). Financial support for this work was also provided by National Institutes of Health (NIH) Cancer Center Support Grants P30 CA016672 and P30 CA006516, as well as NIH grant R01 CA124633 to CAF