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Nanrilkefusp alfa (nanril; SOT101) is an interleukin (IL)-15 receptor βγ superagonist that stimulates natural killer (NK) and CD8 + T cells, thereby promoting an innate and adaptive anti-tumor inflammatory microenvironment in mouse tumor models either in monotherapy or combined with an anti-programmed cell death protein 1 (PD-1) antibody. In cynomolgus monkeys, a clinical schedule was identified, which translated into the design of a phase 1/1b clinical trial, AURELIO-03 (NCT04234113). In 51 patients with advanced/metastatic solid tumors, nanril increased the proportions of CD8 + T cells and NK cells in peripheral blood and tumors. It had a favorable safety profile when administered subcutaneously on days 1, 2, 8, and 9 of each 21-day cycle as monotherapy (0.25-15 μg/kg) or combined (1.5-12 μg/kg) with the anti-PD-1 pembrolizumab (200 mg). The most frequent treatment-emergent adverse events were pyrexia, injection site reactions, and chills. Furthermore, early clinical efficacy was observed, including in immune checkpoint blockade-resistant/refractory patients., Competing Interests: Declaration of interests S.C. reports personal fees from AbbVie, Adaptimmune, Adlai Nortye USA Inc., Aduro Biotech, Agios Pharmaceuticals, Alderaan Biotechnology, Amgen, Astellas, Astex Pharmaceuticals, AstraZeneca Ab, AstraZeneca, Avacta, Aveo, Basilea Pharmaceutica International Ltd., Bayer Healthcare Ag, BBB Technologies Bv, BeiGene, BicycleTx Ltd., Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol-Myers Squibb Ca, Casi Pharmaceuticals Inc., Celanese, Celgene Corporation, Cellcentric, Chugai Pharmaceutical Co., Cullinan-Apollo, CureVac, Cytovation, Daiichi Sankyo, Debiopharm, Domain Therapeutics, Eisai, Eisai Limited, Eli Lilly, Ellipses Pharma, Exelixis, Faron Pharmaceuticals Ltd., Forma Therapeutics, GamaMabs, Genentech, Genmab, Genomics, GlaxoSmithKline, H3 Biomedicine, Hoffmann La Roche Ag, ImCheck Therapeutics, Immunicom Inc., Incyte Corporation, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, iTeos Belgium SA, Janssen, Janssen Cilag, Janssen R&D LLC, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Medimmune, Menarini Ricerche, Merck, Merck Serono, Merck, Sharp & Dohme Chibret, OSE Pharma, Merrimack Pharmaceuticals, Merus, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis, Novartis Pharma, Octimet Oncology Nv, OncoEthix, Oncopeptides, Oncovita, Orion Pharma, OSE Pharma, Pfizer, PharmaMar, Pierre Fabre, Pierre Fabre Medicament, Relay Therapeutics Inc., Roche, Sanofi Aventis, Seagen, Seattle Genetics, SOTIO Biotech A.S., Syros Pharmaceuticals, Taiho Pharma, Tatum Bioscience, Tesaro, Tollys SAS, Transgene, Transgene S.A, Turning Point Therapeutics, Ultrahuman8, and Xencor; grants from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, GSK, INCA, Janssen Cilag, Merck, Pfizer, Roche, and Sanofi; and non-financial support (drug supplied) from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, GSK, Medimmune, Merck, NH TherAguix, Pfizer, and Roche. E.G. reports personal fees from Agios Pharmaceuticals, Alkermes, Amgen, Anaveon, Bayer, BeiGene USA, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Cellestia Biotech, Debiopharm, Ellipses Pharma, F. Hoffmann La Roche Ltd., Forma Therapeutics, F-Star Therapeutics, Genentech Inc., Genmab B.V., Glycotope GmbH, GSK, Hengrui, ICO, Incyte Biosciences, Incyte Corporation, Janssen Global Services, Kura Oncology Inc., Lilly, Lilly S.A., Loxo Oncology Inc., MAB Discovery, Macrogenics Inc., Menarini Ricerche Spa, Merck, Sharp & Dohme, Merck, Sharp & Dohme de Espana, S.A, Nanobiotix, S.A, Neomed Therapeutics 1 Inc., Novartis, Novartis Farmaceutica, S.A, Pfizer, SLU, PharmaMar, S.A.U, Pierre Fabre Medicament, Principia Biopharma Inc., PsiOxus Therapeutics Ltd., Roche, Roche/Genentech, Sanofi, Sierra Oncology, Inc., Seagen, SOTIO Biotech A.S., Symphogen A/S, TFS, Thermo Fisher and grants from AstraZeneca, BeiGene, Novartis, Roche, Taiho, and Thermo Fisher outside the submitted work. V.G. reports institutional support from Affimed GmbH, Anaveon AG, BicycleTx Ltd, BioNTech SE, Boehringer Ingelheim, Celgene Corporation, Debiopharm International S.A., Epizyme Inc., F. Hoffmann-La Roche Ltd., F-star Therapeutics Limited, Genmab, ImCheck Therapeutics, Janssen Research & Development LLC, Novartis, Pieris Pharmaceuticals Inc., Regeneron Pharmaceuticals Inc., Seagen Inc., Shattuck Labs Inc., SOTIO Biotech AG, and T-knife GmbH. P.A.C. has received personal fees from Amgen, Bristol Myers Squibb, Boehringer Ingelheim, Janssen Oncology, OSE Immunotherapeutics, and Roche. C.G.-R. reports personal fees from Bristol Myers Squibb, Eisai, Foundation Medicine, Macomics, Pierre Fabre, and Roche/Genentech. P.G. reports consulting or advisory fees and travel expenses from Servier and consulting or advisory fees from Roche outside the submitted work. A.N. reports personal fees from AbbVie, AKH Inc., Alfaisal University, ARMO BioSciences, ASCO Direct Oncology Highlights, CME Outfitters, CytomX Therapeutics, Deka Biosciences, European Society for Medical Oncology, Genome & Company, Horizon Therapeutics USA Inc., Immune-Onc Therapeutics, Korean Society of Medical Oncology, Lynx Health, Merck Sharp & Dohme Corp., NeoImmuneTech, NGM Bio, Nouscom, OncoNano, OncoSec KEYNOTE-695, Pharming Healthcare Inc., PsiOxus Therapeutics, Scripps Cancer Care Symposium, Servier, Society for Immunotherapy of Cancer, STCube Pharmaceuticals, Takeda, and The Lynx Group and grants from Amplimmune, Arcus Biosciences, ARMO BioSciences, Atterocor/Millendo, Baxalta US Inc., BioNTech SE, Bristol Myers Squibb, Calithera Biosciences, Chao Physician-Scientist Foundation, CytomX Therapeutics, Eli Lilly, EMD Serono, Healios Onc. Nutrition, Immune Deficiency Foundation, Immune-Onc Therapeutics, Incyte, Jeffery Modell Foundation, Karyopharm Therapeutics, Kymab, MedImmune, Merck, Monopteros Therapeutics, NCI, NeoImmuneTech, Neon Therapeutics, Novartis, Pfizer, PsiOxus, Regeneron, Seven & Eight Biopharma, SOTIO Biotech AG, Surface Oncology, The Texas Medical Center Digestive Diseases Center, and TopAlliance Biosciences outside the submitted work. P.L. reports personal fees from AbbVie, ABL Bio, Agenus, Agios, Astellas, AstraZeneca, BAKX Therapeutics, Bayer, Black Diamond, Compass BADX, Cybrexa, CytomX, EMD Serono, Five Prime, Genentech, Genmab, Glaxo-Smith Kline, Halozyme, I-Mab, imCheck, ImmunoMet, IQVIA, Kineta Inc., Kyowa Kirin Pharmaceutical Development, MacroGenics, Mekanist, Mersana Therapeutics, Molecular Templates, NeuroTrials, Pfizer, QED Therapeutics, Qualigen, Relay Therapeutics, Roche/Genentech, Roivant Sciences, Salarius, Scenic Biotech, Seagen, Shattuck, Silverback, SK Life Science, SOTIO Biotech A.S., STCube Pharmaceuticals, Stemline, Takeda, TRIGR, Tyme, and Zentalis Pharmaceuticals. R.M. reports support from SOTIO Biotech A.S. N.P. is an employee of SOTIO Biotech A.S. and reports international patents/patent applications (WO 2020/234387, WO 2022/090202, and WO 2022/090203) with Cytune Pharma. M.R. reports support from SOTIO Biotech A.S. A.S. is an employee of SOTIO Biotech A.S. J.K.-K. is an employee of SOTIO Biotech AG. S.T. is an employee of SOTIO Biotech AG. R. Sachse is an employee of SOTIO Biotech AG. U.M. is an employee of SOTIO Biotech A.S. and reports the following international patents/patent applications (WO 2020/234387, WO 2022/090202, WO 2022/090203, PCT/EP2022/067253, PCT/EP2022/067236, and PCT/EP2022/072845) with Cytune Pharma. R. Spisek is an employee of SOTIO Biotech A.S. D.B. reports international patents/patent applications (WO 2012/175222, WO 2014/170032, WO 2015/018528, WO 2015/131994, WO 2015/018529, WO 2020/234387, WO 2022/090202, WO 2022/090203, PCT/EP2022/067253, PCT/EP2022/067236, and PCT/EP2022/072845) with Cytune Pharma. L.P.G. is an employee of SOTIO Biotech A.S. I.A. is an employee of SOTIO Biotech A.S. and reports international patents/patent applications (WO 2020/234387, WO 2022/090202, WO 2022/090203, PCT/EP2022/067253, PCT/EP2022/067236, and PCT/EP2022/072845) with Cytune Pharma. A.M. was the principal investigator for the AURELIO-03 (ClinicalTrials.gov identifier: NCT04234113) trial of nanril. He was compensated for providing expertise to SOTIO Biotech AG and Cytune Pharma through scientific advisory boards and consulting time. He received expense reimbursements for travel and housing and fees for presenting nanril data at international scientific meetings. He is currently part of the scientific advisory board of other companies developing immunocytokines: Deka Biosciences and Marengo Therapeutics., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

The reporting of adverse events (AEs) is fundamental to characterize safety profiles of novel therapeutic drug classes, however, conventional analysis strategies are suboptimal tools for this task. We therefore attempted to contribute to the modernization of AE analysis by encompassing the dimension of time, the duration and the recurrent nature of AEs induced by these extended treatment durations. This paper presents and highlights the benefits of alternative approaches to modernize AE analysis based on the MOTIVATE prospective study modeling immune-related AEs (irAEs) in patients with solid tumors (regardless of the primary site) treated with immune checkpoint inhibitor irrespective of disease stage. The probability of presenting an irAE over time was estimated using the prevalence function. The time-to-onset (TTO) and the mean number of recurrent irAEs were also assessed. Among the 147 patients analyzed, 39.7% had a melanoma, 37.7% a non-small cell lung cancer (NSCLC) and 74.8% were treated for metastatic disease. Despite a higher proportion of melanoma patients presenting at least one irAE, the prevalence of irAEs was lower in melanoma than in NSCLC patients over time. TTO analysis showed that irAEs occurred earlier in NSCLC patients whereas melanoma patients experienced more recurrent irAEs over the long-term. The prevalence function of non-metastatic and metastatic patients revealed different long-term toxicity profiles. These alternative methodologies capture different toxicity patterns (time-to-onset, recurrent, acute episodic or long-term moderate AEs) and provide a more consistent safety assessment for new therapeutics, thereby assisting clinicians and health authorities in their therapeutic decision-making processes., Competing Interests: Declarations. Ethics approval: The protocol was approved by a French Ethical Research Committee (CPP) and registered in Clinical-Trials.gov (NCT03447483). The study was conducted in accordance with the Declaration of Helsinki and ICH guidelines for Good Clinical Practice. Written informed consent was obtained from all patients prior to inclusion. Consent to participate: Informed consent was obtained from all individual participants included in the study. Competing interests: CGR reported receiving personal fees from BMS, Macomics, Pharmamar, Pierre Fabre, Roche / Genentech outside the submitted work; institutional fees from Amunix, BMS, Hookipa, IDEAYA, Kazia Therapeutics outside the submitted work; research grant from Roche / Genentech outside the submitted work. MV reported receiving personal fees from Lilly, BMS outside the submitted work. DL reported receiving personal fees from Roche, AstraZeneca, Pfizer, Novartis, MSD, Daiichi Sankyo, Lilly, Amgen, EISAI, Exact Sciences, Gilead, Daiichi outside the submitted work; support for attending meetings and/or travel from Roche, AstraZeneca, Pfizer, Novartis, MSD, Gilead outside the submitted work. VS reported receiving personal fees from BMS, MSD, Sanofi, Janssen, Astellas, Incyte, Bayer, Pierre Fabre outside the submitted work. JPD reported receiving institutional fees from BMS, Merck Serono, MSD, Pierre Fabre, Roche ouside the submitted work; research grant from Amgen, AstraZeneca, BMS, Genentech, MSD, Transgene outside the submitted work. TF reported receiving personal fees from Jansen outside the submitted work; institutional fees from Roche, Lilly outside the submitted work. All other authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Novel treatments are needed for patients with advanced, triple-negative breast cancer (TNBC) that progresses or recurs after first-line treatment with chemotherapy. The authors report results from the TNBC cohort of the multicohort, open-label, single-arm, phase 2 LEAP-005 study of lenvatinib plus pembrolizumab in patients with advanced solid tumors (ClinicalTrials.gov identifier NCT03797326)., Methods: Eligible patients had metastatic or unresectable TNBC with disease progression after one or two lines of therapy. Patients received lenvatinib (20 mg daily) plus pembrolizumab (200 mg every 3 weeks; up to 35 cycles). The primary end points were the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1, and safety (adverse events graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0). Duration of response, progression-free survival, and overall survival were secondary end points., Results: Thirty-one patients were enrolled. The objective response rate by investigator assessment was 23% (95% confidence interval [CI], 10%-41%). Overall, the objective response rate by blinded independent central review (BICR) was 32% (95% CI, 17%-51%); and, in patients who had programmed cell death ligand 1 combined positive scores ≥10 (n = 8) and <10 (n = 22), the objective response rate was 50% (95% CI, 16%-84%) and 27% (95% CI, 11%-50%), respectively. The median duration of response by BICR was 12.1 months (range, from 3.0+ to 37.9+ months). The median progression-free survival by BICR was 5.1 months (95% CI, 1.9-11.8 months) and the median overall survival was 11.4 months (95% CI, 4.1-21.7 months). Treatment-related adverse events occurred in 94% of patients (grade 3, 52%; grade 4, 0%). One patient died due to a treatment-related adverse event of subarachnoid hemorrhage., Conclusions: The combination of lenvatinib plus pembrolizumab demonstrated antitumor activity with a manageable safety profile in patients with previously treated, advanced TNBC., (© 2024 Merck Sharp & Dohme LLC and The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Selective rearranged during transfection (RET) tyrosine kinase inhibitor, pralsetinib, demonstrated clinical efficacy and was well tolerated in lung and thyroid cancers with RET gene mutations or fusions in clinical trials. While the latter focused on the risk of pneumonitis, there is a lack of data regarding other types of infectious risks associated with pralsetinib. Herein, we report the case of a 53-year-old patient with a CCDC6-RET fusion neuroendocrine tumor, who achieved a partial response with pralsetinib as the fifth-line therapy. Of particular note, during pralsetinib therapy, the clinical course was complicated by five severe infectious events, namely, two oxygen-requiring pneumonias, two distinct spondylodiscitis, and one pneumocystis. Our study highlights the increased risk of any type of opportunistic infectious event with pralsetinib, but not selpercatinib, which is probably caused by off-target JAK1/2 inhibition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Poumeaud, Jaffrelot, Gomez-Roca, Korakis, Leonardi, Joly, Mazières, Guimbaud, Fares and Alouani.)

Tumor-associated macrophages (TAMs) are a critical determinant of resistance to PD-1/PD-L1 blockade. This phase 1 study (MEDIPLEX, NCT02777710) investigated the safety and efficacy of pexidartinib, a CSF-1R-directed tyrosine kinase inhibitor (TKI), and durvalumab (anti-PD-L1) in patients with advanced colorectal and pancreatic carcinoma with the aim to enhance responses to PD-L1 blockade by eliminating CSF-1-dependent suppressive TAM. Forty-seven patients were enrolled. No unexpected toxicities were observed, one (2%) high microsatellite instability CRC patient had a partial response, and seven (15%) patients experienced stable disease as their best response. Increase of CSF-1 concentrations and decrease of CD14 low CD16 high monocytes in peripheral blood mononuclear cells (PBMCs) confirmed CSF-1R engagement. Treatment decreased blood dendritic cell (DC) subsets and impaired IFN-λ/IL-29 production by type 1 conventional DCs in ex vivo TLR3-stimulated PBMCs. Pexidartinib also targets c-KIT and FLT3, both key growth factor receptors of DC development and maturation. In patients, FLT3-L concentrations increased with pexidartinib treatment, and AKT phosphorylation induced by FLT3-L ex vivo stimulation was abrogated by pexidartinib in human blood DC subsets. In addition, pexidartinib impaired the FLT3-L- but not GM-CSF-dependent generation of DC subsets from murine bone marrow (BM) progenitors in vitro and decreased DC frequency in BM and tumor-draining lymph node in vivo. Our results demonstrate that pexidartinib, through the inhibition of FLT3 signaling, has a deleterious effect on DC differentiation, which may explain the limited antitumor clinical activity observed in this study. This work suggests that inhibition of FLT3 should be considered when combining TKIs with immune checkpoint inhibitors.

Nivolumab and cabozantinib are approved agents in mRCC patients after sunitinib/pazopanib (TKI) failure. However, the optimal sequence, cabozantinib then nivolumab (CN) or nivolumab then cabozantinib (NC), is still unknown. The CABIR study aimed to identify the optimal sequence between CN and NC after frontline VEGFR-TKI. In this multicenter retrospective study, we collected data from mRCC pts receiving CN or NC, after frontline VEGFR-TKI. A propensity score (PrS) was calculated to manage bias selection, and sequence comparisons were carried out with a cox model on a matched sample 1:1. The primary endpoint was progression-free survival (PFS) from the start of second line to progression in third line (PFS 2-3 ). Key secondary endpoints included overall survival from second line (OS 2 ). Out of 139 included mRCC patients, 38 (27%) and 101 (73%) received CN and NC, respectively. Overlap in PrS allowed 1:1 matching for each CN pts, with characteristics well balanced. For both PFS 2-3 and OS 2 , NC sequence was superior to CN (PFS 2-3 : HR = 0.58 [0.34-0.98], P = .043; OS 2 : 0.66 [0.42-1.05], P = .080). Superior PFS 2-3 was in patients treated between 6 and 18 months with prior VEGFR-TKI (P = .019) and was driven by a higher PFS L3 with cabozantinib when given after nivolumab (P < .001). The CABIR study shows a prolonged PFS of the NC sequence compared to CN in mRCC after first line VEGFR-TKI failure. The data suggest that cabozantinib may be more effective than nivolumab in the third-line setting, possibly related to an ability of cabozantinib to overcome resistance to PD-1 blockade., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Regorafenib has shown substantial clinical activity in patients with advanced biliary tract cancers (BTCs). Preclinical data suggested that this drug modulates antitumour immunity and is synergistic with immune checkpoint inhibition., Patients and Methods: This is a single-arm, multicentric phase II trial. Regorafenib was given 3 weeks/4, 160 mg quaque die (once a day) (QD); avelumab 10 mg/kg IV was given every two weeks, beginning at C1D15 until progression or unacceptable toxicity. The primary end-point was the confirmed objective response rate under treatment, as per Response Evaluation Criteria in Solid Tumours 1.1. The secondary end-points included the following: 1-year non-progression rate; progression-free survival (PFS) and overall survival; safety and biomarkers studies performed on sequential tumour samples obtained at baseline and at cycle 2 day 1., Results: Thirty-four patients were enrolled in four centres. Twenty-nine patients were assessable for efficacy after central radiological review. The best response was partial response for four patients (13.8%), stable disease for 11 patients (37.9%) and progressive disease for 14 patients (48.3%). The median PFS and overall survival were 2.5 months (95% confidence interval [CI] [1.9-5.5]) and 11.9 months (95%CI [6.2-NA]) respectively. The most common grade 3 or 4 clinical adverse events related to treatment were hypertension (17.6%), fatigue (14.7%) and maculopapular rash (11.8%). High baseline levels of programmed cell death ligand 1 and of indoleamine 2, 3-dioxygénase expression were associated with improved outcomes., Conclusions: Regorafenib combined with avelumab has antitumour activity in a subset of heavily pretreated biliary tract cancer population. Further investigations are needed in patients selected based on tumour microenvironment features., Clinical Trial Registration: NCT03475953., Competing Interests: Conflict of interest statement AB, CR and JPG: employees from Immusmol/Explicyte. AI: research grants MSD, BMS, ROCHE and personal fees: Epizyme, Bayer, Lilly, Roche, Springworks; non-financial support: Merck. All remaining authors have declared no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

We compared the performance of six prognostic scores (Royal Marsden Hospital, MDACC: MD Anderson Clinical Center and MDACC + NLR: neutrophil-to-lymphocyte ratio, MD Anderson - immune checkpoint inhibitors (MDA-ICI), GRIm: Gustave Roussy Immune Score and LIPI: Lung Immune Prognostic Index) in predicting overall survival (OS) in phase I trial patients treated with immune checkpoint inhibitors (ICI). Medical records of patients with advanced solid tumors enrolled in ICI phase I trials between 2015 and 2018 at Institut Universitaire du Cancer de Toulouse-Oncopole were reviewed. The performance of prognostic scores on OS was compared using different criteria. A total of 259 patients were included. Median age was 63 years (range: 18-83). Main primary cancers were melanoma (19%), head and neck (16%), lung (13%) and bladder (10%). With a median follow-up of 15 months (95% confidence interval [CI] = [11.6;17.5]), median OS was 12.5 months (95% CI = [10.3;16.0]). All scores were associated with OS. The MDACC, LIPI and GRIm scores performed better than the others. Concordance of risk group assignment between the scoring systems was poor. According to our results, the MDACC, GRIm and LIPI scores better suited to ICI phase I settings. Adequate scoring would allow better patient selection in early ICI trials, especially during the critical period of dose escalation, and in proof-of-concept expansion cohorts., (© 2020 UICC.)