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FGFR-1 upregulation has been associated with endocrine therapy resistance in breast cancer patients. Here the authors report the results of a phase IIa study to assess the safety and efficacy of AZD454, an inhibitor of FGFR-1, 2 and 3 receptor tyrosine kinases, in combination with anastrozole or letrozole, in estrogen receptor positive breast cancer patients.

Objective: Imlunestrant is a next-generation oral selective estrogen receptor degrader designed to deliver continuous estrogen receptor (ER) target inhibition. EMBER is a phase 1a/b trial of imlunestrant, as monotherapy and combined with targeted therapy, in patients with ER+ advanced breast cancer or endometrioid endometrial cancer (EEC). This report focuses on patients with ER+ EEC., Methods: EMBER used an i3 + 3 dose-escalation design to determine the recommended phase 2 dose (RP2D) followed by dose-expansion cohorts (1:1 randomization): imlunestrant monotherapy and imlunestrant plus abemaciclib (150 mg twice daily). Eligible patients had measurable disease and progression or recurrence after platinum-containing chemotherapy. Prior fulvestrant or aromatase inhibitor was not allowed. Secondary endpoints included safety, pharmacokinetics and antitumor activity., Results: In total, 72 patients with a median of 2 prior anticancer therapies were treated. Among the 39 patients who received imlunestrant (400 mg [RP2D], n = 33; 800 mg, n = 6), the most common treatment-emergent adverse events (TEAEs) were grade 1-2 nausea (35.9 %), diarrhea (25.6 %), urinary tract infection (25.6 %), and abdominal pain (20.5 %). Overall response rate (ORR) was 10.3 %, clinical benefit rate (CBR) was 33.3 %, and median progression-free survival (mPFS) was 3.8 months (95 % CI, 1.8-6.7). Among the 33 patients who received imlunestrant (400 mg [RP2D], n = 29; 800 mg, n = 4) plus abemaciclib, the most common TEAEs were diarrhea (87.9 %), nausea (66.7 %), fatigue (48.5 %), and anemia (45.5 %). ORR was 18.2 %, CBR was 42.4 %, and mPFS was 6.8 months (95 % CI, 2.1-12)., Conclusion: Imlunestrant, as monotherapy and combined with abemaciclib, has a manageable safety profile with preliminary evidence of antitumor activity in patients with ER+ EEC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kan Yonemori: Institutional research support:MSD, Daiichi-Sankyo, Merck Biopharma, AstraZeneca, Taiho, Pfizer, Novartis, Takeda, Chugai, Ono, Sanofi, Seattle genetics, Eisai, Eli Lilly and company, Genmab, Boeringer Ingelheim, Kyowa Hakko Kirin, Nihon Kayaku, Haihe. Honoraria: Pfizer, Eisai, AstraZeneca, Eli Lilly and Company, Takeda, Chugai, Fuji Film Pharma, PDR pharma, MSD, Boeringer Ingelheim, Ono, Daiichi-Sankyo, Bayer, Jansen, Asteras, Bristol Myers Squibb, Novartis, Sanofi, Merk Biopharma. Advisory board: Eisai, Astra Zeneca, Sanofi, Genmab, Gliad, OncXerna, Takeda, Novartis, MSD, Henlius. Other: Principal investigator (to institution): MSD, Daiichi-Sankyo, Genmab, Seagen, AstraZeneca, Taiho, Merk Biopharma Pfizer, Novartis, Takeda, Chugai, Ono, Sanofi, Seattle genetics, Eisai, Eli Lilly and company, Genmab, Boeringer Ingelheim, Kyowa Hakko Kirin, Nihon Kayaku, Haihe. Valentina Boni: Institutional research support: Abbvie; ACEO; Adaptaimmune; Amcure; AMGEN; Amunix, AstraZeneca; Bycicle; BMS CytomX; GSK; Genentech/Roche; Genmab; Incyte; Ipsen; Janssen; Kura; Lilly; Loxo Therapeutics; Nektar; Macrogenics; Menarini; Merck; Merus; Nanobiotix; Novartis; Pfizer; PharmaMar; Principia; Puma; Ryvu; Ribbon; Sanofi; Taiho; Tesaro; BeiGene; Transgene; Takeda; Incyte; Innovio; MSD; PsiOxus; Seattle Genetics; Mersana; Daiichi; Nektar; Astellas; ORCA; Boston Therapeutics; Dynavax; DebioPharm; Boehringer Ingelheim; Regeneron; Rigontec; Millennium; Seagen; Synthon; Spectrum; Urogen; Zenith. Consulting fees: Puma Biotechnology; Ideaya Biosciences; Loxo Therapeutics, CytomX Therapeutics; Guidepoint; Oncoart, Lilly; Janssen; EMD Serono; IDMC Nanobiotix NANORAY-312/Novartis; Steering Committee CytomX Therapeutics. Honoraria (speaking): Eli Lilly and Company; MSD; SOLTI; TACTICS; Getthi; Gedefo. Attending meeting and/or travel: Bayer (ESMO GI). Stock/Ownership: 1TRIALSP. Tarek M. Meniawy: Research funding: Bristol Myers Squibb, AstraZeneca, Merck Serono, Roche, BeiGene, MSD, Regeneron, Incyte, GSK. Advisory board: Novartis, GSK, MSD, Sanofi, Eisai, BMS. Attending meeting and/or travel: Bristol Myers Squibb. Peter A. Kaufman: Consulting fees: Eli Lilly and Company. Honoraria: Eli Lilly and Company. Attending meeting and/or travel: Eli Lilly and Company. Debra L. Richardson: Advisory board: Mersana, AstraZeneca, GSK, Immunogen, Eisai, ProfoundBio, Daiichi-Sankyo. Koji Matsumoto: Research funding: Daichi-Sankyo, MSD, Eli Lilly and Company, Gilead Sciences, Eisai. Honoraria: MSD, Kyowa Kirin, Daichi-Sankyo, Eli Lilly and Company, Chugai. Karthik V. Giridhar: Research funding: Guardant Health; Advisory board: AstraZeneca, Eli Lilly and Company, Novartis, Neogenomics, TerSera Therapeutics, Puma Biotechnology. Attending meeting and/or travel: Eli Lilly and Company, Grail Inc. José Angel García-Sáenz: Grants or contracts: Stemline Menarini, Jazz Pharmaceutical. Consulting fees: Stemline Menarini, Eli Lilly and Company. Advisory Board: Daiichi Sankyo, AstraZeneca, Eli Lilly and Company, Novartis, Gilead. Speaker's bureau: Eli Lilly and Company, Novartis, Astrofarma. Research funding: AstraZeneca. Attending meeting and/or travel: Roche, Novartis, Daiichi-Sankyo. Don S. Dizon: Consulting fees: GSK, Clovis and Pharma, Astra Zeneca, Kronos Biotech. Stock: Doximity, Midi Health. Els Van Nieuwenhuysen: Research funding: Eli Lilly and Company. Yujia Li; Shawn T. Estrem; Bastien Nguyen; Francesca Bacchion; Roohi Ismail-Khan are employees and stock owners of Eli Lilly and Company. Komal Jhaveri: Institutional research funding:Novartis, Genentech, Debiopharm group, ADC therapeutics, Pfizer, Novita Pharmaceuticals, Clovis oncology, Eli Lilly and Company, Zymeworks, Immunomedics, Puma Biotechnology, VelosBio/Merck, AstraZeneca, Context Therapeutics, Scorpion Therapeutics, Blueprint Medicines. Consulting fees: Novartis, Pfizer, AstraZeneca, Jounce Therapeutics, Synthon, Intellisphere, Bristol Myers Squibb, Genetench, Abbvie, Eli Lilly and Company, BluePrint Medicines, Seagen, Daiichi-Sankyo, Biotheranostics, Sun Pharma Advanced Research Company, Taiho Oncology, Sanofi, Gilead Sciences, Scorpion Therapeutics. Attending meeting and/or travel: Taiho Pharmaceutical, Jounce therapeutics, Pfizer, AstraZeneca, Intellisphere, Eli Lilly and Company, Gilead Sciences, Genetench/Roche. Kalyan Banda: Institutional research funding: Eli Lilly and Company, MorphoSys, Regeneron, Kineta, Pfizer; Honoraria: American Society for Clinical Oncology; Advisory Board: Astra Zeneca, Immunogen; Attending meeting and/or travel: American Society for Clinical Oncology. The other authors have completed conflict of interest forms and do not have potential conflicts of interest related to subject matter discussed in this manuscript to declare., (Copyright © 2024. Published by Elsevier Inc.)

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.)

Purpose: Data from population-based studies have shown an increased incidence of certain types of neoplasms in patients younger than 50 years (early-onset cancer [EOC]); however, little information is derived from other real-world data sources. In a nonpopulation registry, we analyzed changes in the incidence of several neoplasms in successive generations., Methods: This cross-sectional study included all patients with a cancer diagnosis registered in one university hospital in Málaga, Spain, between 1998 and 2021, and 18 neoplasms were analyzed. For each neoplasm, the proportion of patients younger than 50 years and age 50 years and older (late-onset cancer [LOC]) of the total number of patients diagnosed each year was determined. In addition, the age limit was lowered to 45-40 years. Changes in these proportions between each year and the following year were assessed by calculating the annual percentage change (APC), and a final assessment of these changes was performed by determining the average APC (AAPC)., Results: Of the 24,596 patients, 5,466 (22.2%) had EOC, and 19,130 (77.8%) had LOC. The incidence of all tumors increased throughout the study period in both age groups. The AAPC increase was higher in patients with EOC than in those with LOC for the following neoplasms: head and neck (6.1% v 4.6%), colon (11.0% v 8.2%), testicular (16.3% v -13.1%), non-Hodgkin lymphoma (8.4% v 5.9%), rectum (16.1% v 6.8%), kidney (27.8% v 20.1%), and sarcoma (43.4% v 28.6%). This increase was confirmed in patients younger than 45 years and 40 years., Conclusion: Our results are consistent with the data published for most tumor sites analyzed. This global public health problem requires the utmost attention to decrease excess cancer in young patients.

Purpose: Praluzatamab ravtansine (CX-2009) is a conditionally activated Probody drug conjugate (PDC) comprising an anti-CD166 mAb conjugated to DM4, with a protease-cleavable linker and a peptide mask that limits target engagement in normal tissue and circulation. The tumor microenvironment is enriched for proteases capable of cleaving the linker, thereby releasing the mask, allowing for localized binding of CX-2009 to CD166. CX-2009 was evaluated in a phase I/II clinical trial for patients with advanced solid tumors., Patients and Methods: Eligible patients had metastatic cancer receiving ≥2 prior treatments. CX-2009 was administered at escalating doses every 3 weeks (0.25-10 mg/kg) or every 2 weeks (4-6 mg/kg). Primary objective was to determine the safety profile and recommended phase II dose (RP2D)., Results: Of 99 patients enrolled, the most prevalent subtype was breast cancer (n = 45). Median number of prior therapies was 5 (range, 1-19). Dose-limiting toxicities were observed at 8 mg/kg every 3 weeks and 6 mg/kg every 2 weeks. On the basis of tolerability, the RP2D was 7 mg/kg every 3 weeks. Tumor regressions were observed at doses ≥4 mg/kg. In the hormone receptor-positive/HER2-nonamplified breast cancer subset (n = 22), 2 patients (9%) had confirmed partial responses, and 10 patients (45%) had stable disease. Imaging with zirconium-labeled CX-2009 confirmed uptake in tumor lesions and shielding of major organs. Activated, unmasked CX-2009 was measurable in 18 of 22 posttreatment biopsies., Conclusions: CD166 is a novel, ubiquitously expressed target. CX-2009 is the first conditionally activated antibody-drug conjugate to CD166 to demonstrate both translational and clinical activity in a variety of tumor types., (©2022 The Authors; Published by the American Association for Cancer Research.)

Current evidence suggests that plasma cell-free DNA (cfDNA) is fragmented around a mode of 166 bp. Data supporting this view has been mainly acquired through the analysis of double-stranded cfDNA. The characteristics and diagnostic potential of single-stranded and damaged double-stranded cfDNA in healthy individuals and cancer patients remain unclear. Here, through a combination of high-affinity magnetic bead-based DNA extraction and single-stranded DNA sequencing library preparation (MB-ssDNA), we report the discovery of a large proportion of cfDNA fragments centered at ∼50 bp. We show that these "ultrashort" cfDNA fragments have a greater relative abundance in plasma of healthy individuals (median = 19.1% of all sequenced cfDNA fragments, n = 28) than in plasma of patients with cancer (median = 14.2%, n = 21, P < 0.0001). The ultrashort cfDNA fragments map to accessible chromatin regions of blood cells, particularly in promoter regions with the potential to adopt G-quadruplex (G4) DNA secondary structures. G4-positive promoter chromatin accessibility is significantly enriched in ultrashort plasma cfDNA fragments from healthy individuals relative to patients with cancers ( P < 0.0001), in whom G4-cfDNA enrichment is inversely associated with copy number aberration-inferred tumor fractions. Our findings redraw the landscape of cfDNA fragmentation by identifying and characterizing a novel population of ultrashort plasma cfDNA fragments. Sequencing of MB-ssDNA libraries could facilitate the characterization of gene regulatory regions and DNA secondary structures via liquid biopsy. Our data underline the diagnostic potential of ultrashort cfDNA through classification for cancer patients., (© 2022 Hudecova et al.; Published by Cold Spring Harbor Laboratory Press.)

The immune checkpoint inhibitor atezolizumab is approved for PD-L1-positive triple-negative breast cancer (TNBC). However, no activity of atezolizumab in PD-L1-negative TNBC has been reported to date. Here, we present the case study of a woman with TNBC with low tumor infiltrating lymphocytes and PD-L1-negative disease, which achieved a significant response to atezolizumab monotherapy and durable response after the combination of atezolizumab and nab-paclitaxel. The comprehensive genomic analysis that we performed in her tumor and plasma samples revealed high tumor mutational burden (TMB), presence of the APOBEC genetic signatures, high expression of the tumor inflammation signature, and a HER2-enriched subtype by the PAM50 assay. Some of these biomarkers have been shown to independently predict response to immunotherapy in other tumors and may explain the durable response in our patient. Our work warrants further translational studies to identify biomarkers of response to immune checkpoint inhibitors in TNBC beyond PD-L1 expression and to better select patients that will benefit from immunotherapy., Competing Interests: Potential conflicts of interest are the following: AP reports consulting fees from Nanostring Technologies, Roche, Pfizer, Novartis, AstraZeneca, Foundation Medicine, Guardant Health, and Daiichi Sankyo outside the submitted work. AV reports consulting fees from Sysmex, Novartis, Merck, Bristol Meyers Squibb, Guardant Health, and Incyte; research funding from Bristol Meyers Squibb; and royalties from Ferrer outside the submitted work. VP has received fees as consultant, participated in advisory boards, or received travel grants from Sysmex, Roche, MSD, AstraZeneca, Bayer, and Exact Sciences outside the submitted work. CS has declared personal fees as consultant and advisory board or travel grants of AstraZeneca, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann–La Roche Ltd, MediTech, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Piere Fabre, Puma, Roche Farma, Sanofi-Aventis, SeaGen, and Zymeworks and institutional financial interests from AstraZeneca, Daiichi Sankyo, Eli Lilly and Company, Genentech, Immunomedics, Macrogenics, Merck, Sharp and Dhome España S.A., Novartis, Pfizer, Piqur Therapeutics, Puma, Roche, Synthon, and Zenith Pharma. CS and AP are Board Members of SOLTI Cooperative Group and are employed by Institut Oncològic Baselga (IOB), Quironsalud Group. The remaining 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 © 2021 Brasó-Maristany, Sansó, Chic, Martínez, González-Farré, Sanfeliu, Ghiglione, Carcelero, Garcia-Corbacho, Sánchez, Soy, Jares, Peg, Saura, Muñoz, Prat and Vivancos.)

Purpose: PROCLAIM-CX-2029 is a phase I first-in-human study of CX-2029, a Probody-drug conjugate targeting CD71 (transferrin receptor 1) in adults with advanced solid tumors. Although the transferrin receptor is highly expressed across multiple tumor types, it has not been considered a target for antibody-drug conjugates (ADCs) due to its broad expression on normal cells. CX-2029 is a masked form of a proprietary anti-CD71 antibody conjugated to monomethyl auristatin E, designed to be unmasked in the tumor microenvironment by tumor-associated proteases, therefore limiting off-tumor toxicity and creating a therapeutic window for this previously undruggable target., Patients and Methods: This was a dose-escalation, multicenter trial to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of CX-2029. The primary endpoint was to determine the maximum tolerated dose (MTD) and cycle 1 dose-limiting toxicity (DLT). CX-2029 was administered i.v. every 3 weeks., Results: Forty-five patients were enrolled in eight dose levels. No DLTs were reported in the dose escalation through 4 mg/kg. At 5 mg/kg, there were two DLTs (febrile neutropenia and pancytopenia). Following expansion of the 4 mg/kg dose to six patients, two additional DLTs were observed (infusion-related reaction and neutropenia/anemia). Both the 4 and 5 mg/kg doses were declared above the maximum tolerated dose. The recommended phase II dose is 3 mg/kg. The most common dose-dependent hematologic toxicities were anemia and neutropenia. Confirmed partial responses were observed in three patients, all with squamous histologies., Conclusions: The Probody therapeutic platform enables targeting CD71, a previously undruggable ADC target, at tolerable doses associated with clinical activity. See related commentary by Oberoi and Garralda, p. 4459 ., (©2021 American Association for Cancer Research.)

Background: Probody ® therapeutics are antibody prodrugs that are activated in the tumor microenvironment by tumor-associated proteases, thereby restricting the activity to the tumor microenvironment and minimizing 'off-tumor' toxicity. We report dose-escalation and single-agent expansion phase data from the first-in-human study of CX-072 (pacmilimab), a Probody checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1)., Methods: In the dose-escalation phase of this multicenter, open-label study (NCT03013491), adults with advanced solid tumors (naive to programmed-death-1/PD-L1 or cytotoxic T-lymphocyte-associated antigen 4 inhibitors) were enrolled into one of seven dose-escalation cohorts, with pacmilimab administered intravenously every 14 days. The primary endpoints were safety and determination of the maximum tolerated dose (MTD). In the expansion phase, patients with one of six prespecified malignancies (triple-negative breast cancer [TNBC]; anal squamous cell carcinoma [aSCC]; cutaneous SCC [cSCC]; undifferentiated pleomorphic sarcoma [UPS]; small bowel adenocarcinoma [SBA]; and thymic epithelial tumor [TET]); or high tumor mutational burden (hTMB) tumors were enrolled. The primary endpoint was objective response (Response Evaluation Criteria In Solid Tumors v.1.1)., Results: An MTD was not reached with doses up to 30 mg/kg. A recommended phase 2 dose (RP2D) of 10 mg/kg was chosen based on pharmacokinetic and pharmacodynamic findings in the expansion phase. Ninety-eight patients enrolled in the expansion phase: TNBC (n=14), aSCC (n=14), cSCC (n=14), UPS (n=20), SBA (n=14), TET (n=8), and hTMB tumors (n=14). Of 114 patients receiving pacmilimab at the RP2D, grade ≥3 treatment-related adverse events (TRAEs) were reported in 10 patients (9%), serious TRAEs in six patients (5%), and treatment discontinuation due to TRAEs in two patients (2%). Grade ≥3 immune-related AEs occurred in two patients (rash, myocarditis). High PD-L1 expression (ie, >50% Tumor Proportion Score) was observed in 22/144 (19%) patients. Confirmed objective responses were observed in patients with cSCC (n=5, including one complete response), hTMB (n=4, including one complete response), aSCC (n=2), TNBC (n=1), UPS (n=1), and anaplastic thyroid cancer (n=1)., Conclusions: Pacmilimab can be administered safely at the RP2D of 10 mg/kg every 14 days. At this dose, pacmilimab had a low rate of immune-mediated toxicity and showed signs of antitumor activity in patients not selected for high PD-L1 expression., Trial Registration Number: NCT03013491., Competing Interests: Competing interests: AN: Research funding from Amplimmune, Arcus Biosciences, ARMO BioSciences, Atterocor, BMS, Calithera Biosciences, CytomX Therapeutics, Eli Lilly, EMD, HealiosOnc, ImmuneOncia, Incyte, Karyopharm Therapeutics, Kymab, MedImmune, Merck, NCI, NeoimmuneTech, Neon Therapeutics, Novartis, Nutrition, Pfizer, PsiOxus, Regeneron, Serono, Surface Oncology, and TopAlliance Biosciences. Advisory boards for CytomX Therapeutics, Genome & Company, Kymab, Novartis, OncoSec KEYNOTE-695, and STCube Pharmaceuticals. Travel expenses from ARMO BioSciences. AN’s spouse has received research funding from Baxalta, Chao physician-scientist, Immune Deficiency Foundation, and Jeffery Modell Foundation; and has served on advisory boards for Behring, CSL, Horizon, Pharming, and Takeda. FT: Research funding and conference registration from Novartis. Consultancy/advisory role for Achilles Therapeutics, Bayer, BMS, Enara Bio, GSK, T-Knife, and Zelluna. EGEDV: Institutional financial support for clinical trials or contracted research from Amgen, AstraZeneca, Bayer, Chugai Pharma, G1 Therapeutics, Genentech, Nordic Nanovector, Radius Health, Regeneron, Roche, Servier, and Synthon. Institutional financial support for advisory boards from Daiichi Sankyo, Merck, NSABP, Pfizer, and Sanofi; all outside the submitted work. FALME: Consultancy/advisory role for Servier, Novartis, Eisai, and Ipsen. NU: Consultant for AstraZeneca, Eli Lilly, Ipsen, QED, and Taiho. Research support from EMD, Ipsen, Serono, and Taiho. Holds stock in Exact Sciences and Natera. PAO: Research funding from and advisory role for Amgen, Armo BioSciences, Array, AstraZeneca/MedImmune, Bristol-Meyers Squibb, Celldex, CytomX, Merck, Neon Therapeutics, Novartis, Pfizer, and Roche/Genentech. PL: Consultant/advisory board for AbbVie, ABL Bio, Agenus, Agios, Astellas, AstraZeneca, Black Diamond, Cybrexa, CytomX, EMD Serono, GenMab, Genentech, Glaxo-Smith Kline, ImmunoMet, IQVIA, Kineta Inc., Kyowa Kirin Pharmaceutical Development, MacroGenics, Molecular Templates, Pfizer, QED Therapeutics, Salarius, Shattuck, Silverback, SK Life Science, SOTIO, STCube Pharmaceuticals, Takeda, TRIGR, and Zentalis Pharmaceuticals. Data safety monitoring committee for Five Prime, Halozyme, and Tyme. Participant in imCORE Alliance (Roche/Genentech). JG-C: Speaker’s bureau for Bayer; fees to support registration and attending scientific meetings from BMS and Novartis. VB: Consulting/advisory role for CytomX Therapeutics, Guidepoint, Ideaya Biosciences, Loxo Therapeutics, Oncoart, and Puma Biotechnology. Institutional financial support for clinical trials from Abbvie, ACEO, Adaptaimmune, Amcure, AMGEN, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Boston Therapeutics, Cytomx Therapeutics, Daiichi, DebioPharm, Dynavax, GSK, Genentech/Roche, H3, Incyte, Innovio, Janssen, Kura, Lilly, Loxo, Macrogenics, Menarini, Merck, Mersana, Merus, Millenium, MSD, Nanobiotix, Nektar, Novartis, ORCA, Pfizer, PharmaMar, Principia, PsiOxus, PUMA, Regeneron, Rigontec, Sanofi, Seattle Genetics, Spectrum, Synthon, Taiho, Tesaro, Transgene, Takeda, and Zenith. JB: Institutional financial support for clinical trials or contracted research from AbbVie, Acerta Pharma, ADC, Agios, Amgen, Apexigen, Arch Oncology, Arcus Bio, ARMO, Array, Arrys, AstraZeneca, AtlasMedx, Bayer, Beigene, Bellicum, BI, Bicycle Therapeutics, Blueprint, BMS, Boston Biomedical, CALGB, Calithera, Celgene, Celldex, Cyteir Therapeutics, Cytomx, Daiichi Sankyo, Effector, Eisai, EMD Serono, Evelo, Five Prime, FORMA, Forty Seven, Foundation Bio, Genentech/Roche, Gilead, Gossamer Bio, GSK, Harpoon, Hutchinson MediPharma, IGM Biosciences, Imclone, Incyte, Innate, Innate Pharma, Ipsen, Jacobio, Koltan, LEAP, Lilly, Mabspace, Macrogenics, Marshall Edwards, MedImmune, Merck, Merrimack, Mersana, Merus, Millennium, Morphotex, Nektar, NeoImmune Tech, NGM Biopharma, Novartis, Novocare, NuMab, Oncogenex, OncoMed, Ongologie, Onyx, Pfizer, Pieris, Prelude Oncology, PureTech Health, Regeneron, Relay Therapeutics, REPARE Therapeutics, Revolution Medicines, Rgenix, Sanofi, Scholar Rock, Seattle Genetics, Shattuck Labs, Sierra, Stemcentrx, SynDevRex, Synthorx, Taiho, Takeda, Tarveda, TempestTx, TG Therapeutics, Tracon, Treadwell Therapeutics, Tyrogenex, Unum Therapeutics, Vyriad, and Zymeworks. Institutional financial support for advisory boards/consulting from Array, Agios, Amgen, Apexigen, Arch Oncology, ARMO, AstraZeneca, Bayer, Beigene, BI, Bicycle Therapeutics, BMS, Celgene, Continuum Clinical, Cyteir, Daiichi Sankyo, Evelo, Five Prime, FORMA, Fusion Therapeutics, Genentech/Roche, Gilead, GSK, Incyte, Innate, Ipsen, Janssen, LEAP, Lilly, Macrogenics, MedImmune, Merck, Merrimack, Moderna Therapeutics, Molecular Partners, Novartis, Oncogenex, OncoMed, Pfizer, Phoenix Bio, Piper Biotech, Prelude Therapeutics, Relay Therapeutics, Samsung Bioepios, Sanofi, Seattle Genetics, Taiho, Tanabe Research Laboratories, TD2 (Translational Drug Development), TG Therapeutics, Tizona, Tolero, and Torque. Food, beverages and/or travel expenses from ARMO, BI, BMS, Celgene, FORMA, Genentech/Roche, Gilead, Ipsen, Lilly, MedImmune, Merck, Novartis, Oncogenex, OncoMed, and Taiho. KAA: Advisory board for CytomX (unpaid). Institutional financial support for clinical trials or contracted research from Amgen, AstraZeneca, CytomX, GSK, Merck, Pfizer, and Tizona. MR: Honoraria from Bayer. GD: Research funding from AstraZeneca, Bristol Myers Squibb, and Merck. Honoraria from AstraZeneca. Advisory board for Curio Science. MG-M: Speaker’s bureau for Astra Zeneca, Pharmamar, and Roche. Financial support for registration and attendance at scientific meetings from MDS, Pharmamar, and Roche. MS is a former employee and ALH is a current employee of CytomX Therapeutics, Inc. Both are stockowners in CytomX Therapeutics Inc. H-TA: Advisor for Bayer, Beigene, Bicycle, Engitix, Guardant, iOnctura, Roche, and Servier. Employed by HCA Healthcare UK and Sarah Cannon Research Institute. AS: Consultant for Amgen, AstraZeneca, BMS, Merck, Mirati, and Novartis. Institutional financial support for clinical trials or contracted research from CytomX., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Probody® therapeutics are antibody prodrugs designed to be activated by tumor-associated proteases. This conditional activation restricts antibody binding to the tumor microenvironment, thereby minimizing 'off-tumor' toxicity. Here, we report the phase 1 data from the first-in-human study of CX-072 (pacmilimab), a Probody immune checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1), in combination with the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab., Methods: Adults (n=27) with advanced solid tumors (naive to PD-L1/programmed cell death protein 1 or CTLA-4 inhibitors) were enrolled in the phase 1 combination therapy dose-escalation portion of this multicenter, open-label, phase 1/2 study (NCT03013491). Dose-escalation pacmilimab/ipilimumab followed a standard 3+3 design and continued until the maximum tolerated dose (MTD) was determined. Pacmilimab+ipilimumab was administered intravenously every 3 weeks for four cycles, followed by pacmilimab administered every 2 weeks as monotherapy. The primary objective was identification of dose-limiting toxicities and determination of the MTD. Other endpoints included the rate of objective response (Response Evaluation Criteria In Solid Tumors v.1.1)., Results: Twenty-seven patients were enrolled in pacmilimab (mg/kg)+ipilimumab (mg/kg) dose-escalation cohorts: 0.3+3 (n=6); 1+3 (n=3); 3+3 (n=3); 10+3 (n=8); 10+6 (n=6); and 10+10 (n=1). Dose-limiting toxicities occurred in three patients, one at the 0.3+3 dose level (grade 3 dyspnea/pneumonitis) and two at the 10+6 dose level (grade 3 colitis, grade 3 increased aspartate aminotransferase). The MTD and recommended phase 2 dose was pacmilimab 10 mg/kg+ipilimumab 3 mg/kg administered every 3 weeks. Pacmilimab-related grade 3-4 adverse events (AEs) and grade 3-4 immune-related AEs were reported in nine (33%) and six (22%) patients, respectively. Three patients (11%) discontinued treatment because of AEs. The overall response rate was 19% (95% CI 6.3 to 38.1), with one complete (anal squamous cell carcinoma) and four partial responses (cancer of unknown primary, leiomyosarcoma, mesothelioma, testicular cancer). Responses lasted for >12 months in four patients., Conclusions: The MTD and recommended phase 2 dose of pacmilimab (10 mg/kg)+ipilimumab (3 mg/kg) every 3 weeks is active and has a favorable tolerability profile., Competing Interests: Competing interests: RES: Honoraria from Amgen and AstraZeneca. Advisory boards for AstraZeneca, Blueprint Medicines, Celldex, Daiichi Sankyo, EMD Serono, Genentech/Roche, Janssen, and Seagen. Research support from AstraZeneca and Merck. OH: Consulting/advisory boards for Aduro, Akeso, Amgen, Beigene, Bioatla, BMS, Roche Genentech, GSK, lmmunocore, ldera, lncyte, Janssen, Merck, Nextcure, Novartis, Pfizer, Sanofi/Regeneron, Seattle Genetics, Tempus, and Zelluna. Speakers’ bureau for BMS, Novartis, Pfizer, and Sanofi/Regeneron. Institutional financial support for contracted research from Arcus, Aduro, Akeso, Amgen, Bioatla, BMS, CytomX, Exelixis, Roche Genentech, GSK, lmmunocore, ldera, lncyte, lovance, Merck, Moderna, Merck-Serano, NextCure, Novartis, Pfizer, Sanofi/Regeneron, Seattle Genetics, Torque, and Zelluna. EGEdV: Institutional financial support for clinical trials or contracted research from Amgen, AstraZeneca, Bayer, Chugai Pharma, G1 Therapeutics Genentech, Nordic Nanovector, Radius Health, Regeneron, Roche, Servier, and Synthon. Institutional financial support for advisory boards from Daiichi Sankyo, Merck, NSABP, Pfizer, and Sanofi; all outside the submitted work. PAO: Research funding from and has advisory role for Neon Therapeutics, Bristol-Meyers Squibb, Merck, CytomX, Pfizer, Novartis, Celldex, Amgen, Array, AstraZeneca/MedImmune, Armo BioSciences and Roche/Genentech. JG-C: Speaker’s bureau for Bayer; Fees to support registration and attending scientific meetings from BMS, Novartis. VB: Consulting/advisory role for CytomX Therapeutics, Guidepoint, Ideaya Biosciences; Loxo Therapeutics, Oncoart, and Puma Biotechnology. Institutional financial support for clinical trials from Abbvie, ACEO, Adaptaimmune, Amcure, Amgen, Astellas, AstraZeneca, BeiGene, BMS, Boehringer Ingelheim, Boston Therapeutics, CytomX Therapeutics, Daiichi, DebioPharm, Dynavax, GSK, Genentech/Roche, H3, Incyte, Innovio, Janssen, Kura, Lilly, Loxo, Mersana, Nektar, Macrogenics, Menarini, Merck, Merus, Millenium, MSD, Nanobiotix, Novartis, ORCA, Pfizer, PharmaMar, Principia, PsiOxus, PUMA, Regeneron, Rigontec, Sanofi, Seattle Genetics, Spectrum, Synthon, Taiho, Tesaro, Transgene, Takeda, and Zenith. JB: Institutional financial support for clinical trials or contracted research from AbbVie, Acerta Pharma, ADC, Agios, Amgen, Apexigen, Arch Oncology, Arcus Bio, ARMO, Array, Arrys, AstraZeneca, AtlasMedx, Bayer, Beigene, Bellicum, BI, Bicycle Therapeutics, Blueprint, BMS, Boston Biomedical, CALGB, Calithera, Celgene, Celldex, Cyteir Therapeutics, Cytomx, Daiichi Sankyo, Effector, Eisai, EMD Serono, Evelo, Five Prime, FORMA, Forty Seven, Foundation Bio, Genentech / Roche, Gilead, Gossamer Bio, GSK, Harpoon, Hutchinson MediPharma, IGM Biosciences, Imclone, Incyte, Innate, Innate Pharma, Ipsen, Jacobio, Koltan, LEAP, Lilly, Mabspace, Macrogenics, Marshall Edwards, MedImmune, Merck, Merrimack, Mersana, Merus, Millennium, Morphotex, Nektar, NeoImmune Tech, NGM Biopharma, Novartis, Novocare, NuMab, Oncogenex, OncoMed, Ongologie, Onyx, Pfizer, Pieris, Prelude Oncology, PureTech Health, Regeneron, Relay Therapeutics, REPARE Therapeutics, Revolution Medicines, Rgenix, Sanofi, Scholar Rock, Seattle Genetics, Shattuck Labs, Sierra, Stemcentrx, SynDevRex, Synthorx, Taiho, Takeda, Tarveda, TempestTx, TG Therapeutics, Tracon, Treadwell Therapeutics, Tyrogenex, Unum Therapeutics, Vyriad, and Zymeworks. Institutional financial support for advisory boards/consulting from Array, Agios, Amgen, Apexigen, Arch Oncology, ARMO, AstraZeneca, Bayer, Beigene, BI, Bicycle Therapeutics, BMS, Celgene, Continuum Clinical, Cyteir, Daiichi Sankyo, Evelo, Five Prime, FORMA, Fusion Therapeutics, Genentech / Roche, Gilead, GSK, Incyte, Innate, Ipsen, Janssen, LEAP, Lilly, Macrogenics, MedImmune, Merck, Merrimack, Moderna Therapeutics, Molecular Partners, Novartis, Oncogenex, OncoMed, Pfizer, Phoenix Bio, Piper Biotech, Prelude Therapeutics, Relay Therapeutics, Samsung Bioepios, Sanofi, Seattle Genetics, Taiho, Tanabe Research Laboratories, TD2 (Translational Drug Development), TG Therapeutics, Tizona, Tolero, and Torque. Food, beverages and/or travel expenses from ARMO, BI, BMS, Celgene, FORMA, Genentech / Roche, Gilead, Ipsen, Lilly, MedImmune, Merck, Novartis, Oncogenex, OncoMed, and Taiho. KAA: Advisory board for CytomX (unpaid). Institutional financial support for clinical trials or contracted research from Amgen, AstraZeneca, CytomX, GSK, Merck, Pfizer, and Tizona. DCC: Consultant for Nektar Therapeutics, GSK, Torque, PureTech, and HUYA. RP: Honoria for attending advisory boards from Pierre Faber, Bayer, Octimet, Clovis Oncology, Novartis, Karus Therapeutics, Biosceptre, BMS, Cybrexa, Ellipses, CV6 Therapeutics, Astex Therapeutics and Sanofi Aventis. Fees for delivery of educational talks or chairing educational meetings by AstraZeneca, Novartis, Bayer, Tesaro and BMS. Funds to support attendance at conferences from BMS and MSD. MS is a former employee and Lawrence Lu is a current employee of CytomX Therapeutics and both own stock in CytomX Therapeutics. FT: Research funding and conference registration from Novartis. Consultancy/advisory role for GSK, Achilles Therapeutics, BMS, Zelluna, Enara Bio, Bayer, T-Knife., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Therapies targeting the programmed cell death 1 (PD-1) receptor or its ligand (PD-L1), such as the humanized monoclonal antibody durvalumab, have shown durable clinical responses in several tumor types. However, concerns about the safety and feasibility of PD-1/PD-L1 blockade in HIV-1-infected individuals have led to the exclusion of these patients from clinical trials on cancer immunotherapies., Objective: To evaluate the feasibility and safety of durvalumab treatment in patients with advanced cancer and virologically controlled HIV-1 infection., Design, Setting, and Participants: The DURVAST study was a nonrandomized, open-label, phase 2 clinical trial in patients with any solid tumor type in which anti-PD-1 or anti-PD-L1 antibodies have approved indications or for which there are data of antitumoral activity with no other available curative therapy. All patients had basal undetectable plasma viremia while undergoing combination antiretroviral therapy., Interventions: Treatment consisted of intravenous infusion of durvalumab (1500 mg every 4 weeks) until disease progression or unacceptable toxic effects., Main Outcomes and Measures: Adverse events were graded with the use of the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. Tumor response was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1., Results: A total of 20 HIV-1-infected patients with advanced cancer were enrolled; 16 (80%) were male, the median (range) age was 54 (30-73) years, and 12 (60%) had progressed with previous cancer treatment lines. A median (range) of 4 (1-16) cycles of durvalumab were administered. Drug-related adverse events were observed in 50% of patients, and all were grade 1 and 2 (mainly diarrhea, asthenia, and arthromyalgia). Four of 16 response-evaluable patients (25%) had a partial response. Five patients (31%) had stable disease, including 4 with durable stable disease (disease control rate of 50%). CD4+ and CD8+ T-cell counts and plasma HIV-1 viremia remained stable throughout the study., Conclusions and Relevance: Durvalumab treatment was feasible and safe in HIV-1-infected patients with cancer receiving combination antiretroviral therapy. HIV-1-infected patients on suppressive antiretroviral therapy with advanced cancer should have access to cancer immunotherapy treatments., Trial Registration: ClinicalTrials.gov Identifier: NCT03094286.

Background: Epertinib (S-222611) is a potent reversible inhibitor of HER2, EGFR and HER4. This trial evaluated the safety, tolerability, pharmacokinetics and antitumour activity of daily oral epertinib combined with trastuzumab (arm A), with trastuzumab plus vinorelbine (arm B) or with trastuzumab plus capecitabine (arm C), in patients with HER2-positive metastatic breast cancer (MBC)., Methods: Eligible patients, with or without brain metastases, had received prior HER2-directed therapy. A dose-escalation phase determined the tolerability of each combination and established a dose for further study. Further, patients were recruited to expansion cohorts in each of the 3 arms to further explore efficacy and safety., Results: The recommended doses of epertinib were 600 mg, 200 mg and 400 mg in arms A, B and C, respectively. The most frequent grade 3/4 adverse event (AE) was diarrhoea in all arms, which was manageable with medical intervention and dose modification. The objective response rate (complete response [CR] plus partial response [PR]) in heavily pre-treated HER2-positive MBC patients at the recommended doses of epertinib combined with trastuzumab was 67% (N = 9), with trastuzumab plus vinorelbine was 0% (N = 5) and with trastuzumab plus capecitabine was 56% (N = 9). Notably, 4 of 6 patients previously treated with T-DM1 responded in the arm A expansion cohort (epertinib plus trastuzumab). In the arm C expansion cohort (epertinib plus trastuzumab plus capecitabine), 4 of 7 patients responded despite previous exposure to capecitabine. Measurable regression of brain metastases was observed in patients with CNS target lesions treated in both arms A and C., Conclusion: We observed safety, tolerability and encouraging antitumour activity of epertinib combined with trastuzumab, or with trastuzumab plus capecitabine. This supports further evaluation of these combinations in patients with pre-treated HER2-positive MBC, with or without brain metastases., Trial Registration: EudraCT Number: 2013-003894-87; registered 09-September-2013.

Purpose: The strategy of combining endocrine therapy with PI3K-mTOR inhibition has shown promise in estrogen receptor (ER)-positive breast cancer, but new agents and combinations with a better therapeutic index are urgently needed. Taselisib is a potent, selective, beta-isoform-sparing PI3 kinase inhibitor., Patients and Methods: 30 patients with ER-positive, metastatic breast cancer who had failed prior endocrine therapy were treated with escalating doses of taselisib (2 or 4 mg in an intermittent or continuous schedule) combined with tamoxifen 20 mg once daily in this phase 1b study using a "rolling six" design., Results: Taselisib combined with tamoxifen was generally well tolerated, with treatment-emergent adverse events as expected for this class of drugs, including diarrhea (13 patients, 43%), mucositis (10 patients, 33%), and hyperglycemia (8 patients, 27%). No dose-limiting toxicities were observed. Objective responses were seen in 6 of 25 patients with RECIST-measurable disease (ORR 24%). Median time to disease progression was 3.7 months. Twelve of 30 patients (40%) had disease control for 6 months or more. Circulating tumor (ct)DNA studies using next-generation tagged amplicon sequencing identified early indications of treatment response and mechanistically relevant correlates of clinical drug resistance (e.g., mutations in KRAS, ERBB2 ) in some patients., Conclusions: Taselisib can be safely combined with tamoxifen at the recommended phase 2 dose of 4 mg given once daily on a continuous schedule. Preliminary evidence of antitumor activity was seen in both PIK3CA mutant and wild-type cancers. The randomized phase 2 part of POSEIDON (testing tamoxifen plus taselisib or placebo) is currently recruiting., (©2019 American Association for Cancer Research.)

Existing methods to improve detection of circulating tumor DNA (ctDNA) have focused on genomic alterations but have rarely considered the biological properties of plasma cell-free DNA (cfDNA). We hypothesized that differences in fragment lengths of circulating DNA could be exploited to enhance sensitivity for detecting the presence of ctDNA and for noninvasive genomic analysis of cancer. We surveyed ctDNA fragment sizes in 344 plasma samples from 200 patients with cancer using low-pass whole-genome sequencing (0.4×). To establish the size distribution of mutant ctDNA, tumor-guided personalized deep sequencing was performed in 19 patients. We detected enrichment of ctDNA in fragment sizes between 90 and 150 bp and developed methods for in vitro and in silico size selection of these fragments. Selecting fragments between 90 and 150 bp improved detection of tumor DNA, with more than twofold median enrichment in >95% of cases and more than fourfold enrichment in >10% of cases. Analysis of size-selected cfDNA identified clinically actionable mutations and copy number alterations that were otherwise not detected. Identification of plasma samples from patients with advanced cancer was improved by predictive models integrating fragment length and copy number analysis of cfDNA, with area under the curve (AUC) >0.99 compared to AUC <0.80 without fragmentation features. Increased identification of cfDNA from patients with glioma, renal, and pancreatic cancer was achieved with AUC > 0.91 compared to AUC < 0.5 without fragmentation features. Fragment size analysis and selective sequencing of specific fragment sizes can boost ctDNA detection and could complement or provide an alternative to deeper sequencing of cfDNA., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: We hypothesized that the abundance of PD1 mRNA in tumor samples might explain the differences in overall response rates (ORR) observed following anti-PD1 monotherapy across cancer types., Patients and Methods: RNASeqv2 data from 10 078 tumor samples representing 34 different cancer types was analyzed from TCGA. Eighteen immune-related gene signatures and 547 immune-related genes, including PD1, were explored. Correlations between each gene/signature and ORRs reported in the literature following anti-PD1 monotherapy were calculated. To translate the in silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 773 formalin-fixed paraffin embedded (FFPE) tumor samples across 17 cancer types. To test the direct relationship between PD1 mRNA, PDL1 immunohistochemistry (IHC), stromal tumor-infiltrating lymphocytes (sTILs) and ORR, we evaluated an independent FFPE-based dataset of 117 patients with advanced disease treated with anti-PD1 monotherapy., Results: In pan-cancer TCGA, PD1 mRNA expression was found strongly correlated (r > 0.80) with CD8 T-cell genes and signatures and the proportion of PD1 mRNA-high tumors (80th percentile) within a given cancer type was variable (0%-84%). Strikingly, the PD1-high proportions across cancer types were found strongly correlated (r = 0.91) with the ORR following anti-PD1 monotherapy reported in the literature. Lower correlations were found with other immune-related genes/signatures, including PDL1. Using the same population-based cutoff (80th percentile), similar proportions of PD1-high disease in a given cancer type were identified in our in-house 773 tumor dataset as compared with TCGA. Finally, the pre-established PD1 mRNA FFPE-based cutoff was found significantly associated with anti-PD1 response in 117 patients with advanced disease (PD1-high 51.5%, PD1-intermediate 26.6% and PD1-low 15.0%; odds ratio between PD1-high and PD1-intermediate/low = 8.31; P < 0.001). In this same dataset, PDL1 tumor expression by IHC or percentage of sTILs was not found associated with response., Conclusions: Our study provides a clinically applicable assay that links PD1 mRNA abundance, activated CD8 T-cells and anti-PD1 efficacy.

Improvements in genomic and molecular methods are expanding the range of potential applications for circulating tumour DNA (ctDNA), both in a research setting and as a 'liquid biopsy' for cancer management. Proof-of-principle studies have demonstrated the translational potential of ctDNA for prognostication, molecular profiling and monitoring. The field is now in an exciting transitional period in which ctDNA analysis is beginning to be applied clinically, although there is still much to learn about the biology of cell-free DNA. This is an opportune time to appraise potential approaches to ctDNA analysis, and to consider their applications in personalized oncology and in cancer research.

Purpose: Limited data are available on cabazitaxel pharmacokinetics in patients with renal impairment. This open-label, multicenter study assessed cabazitaxel in patients with advanced solid tumors and normal or impaired renal function., Methods: Cohorts A (normal renal function: creatinine clearance [CrCL] >80 mL/min/1.73 m 2 ), B (moderate renal impairment: CrCL 30 to <50 mL/min/1.73 m 2 ) and C (severe impairment: CrCL <30 mL/min/1.73 m 2 ) received cabazitaxel 25 mg/m 2 (A, B) or 20 mg/m 2 (C, could be escalated to 25 mg/m 2 ), once every 3 weeks. Pharmacokinetic parameters and cabazitaxel unbound fraction (F U ) were assessed using linear regression and mixed models. Geometric mean (GM) and GM ratios (GMRs) were determined using mean CrCL intervals (moderate and severe renal impairment: 40 and 15 mL/min/1.73 m 2 ) versus a control (90 mL/min/1.73 m 2 )., Results: Overall, 25 patients received cabazitaxel (median cycles: 3 [range 1-20]; Cohort A: 5 [2-13]; Cohort B: 3 [1-15]; and Cohort C: 5 [1-20]), of which 24 were eligible for pharmacokinetic analysis (eight in each cohort). For moderate and severe renal impairment versus normal renal function, GMR estimates were: clearance normalized to body surface area (CL/BSA) 0.95 (90% CI 0.80-1.13) and 0.89 (0.61-1.32); area under the curve normalized to dose (AUC/dose) 1.06 (0.88-1.27) and 1.14 (0.76-1.71); and F U 0.99 (0.94-1.04) and 0.97 (0.87-1.09), respectively. Estimated slopes of linear regression of log parameters versus log CrCL (renal impairment) were: CL/BSA 0.06 (-0.15 to 0.28); AUC/dose -0.07 (-0.30 to 0.16); and F U 0.02 (-0.05 to 0.08). Cabazitaxel safety profile was consistent with previous reports., Conclusions: Renal impairment had no clinically meaningful effect on cabazitaxel pharmacokinetics., Competing Interests: Compliance with ethical standardsConflict of interestThis study was sponsored by Sanofi. Analía Azaro, Jordi Rodón, Silvia Damian, Javier Garcia-Corbacho and Maja de Jonge have no conflicts of interest to disclose. Jean-Pascal Machiels has been a member of advisory boards for Boehringer Ingelheim (without compensation) and MSD, and received research grants from Novartis, Bayer and Janssen. Sylvie Rottey has been a member of advisory boards and received research funding from Sanofi. Richard Baird and Ron Mathijssen have received research funding from Sanofi. Pierre-François Clot, Claudine Wack, and Liji Shen are employees of Sanofi. Liji Shen is a stock holder of Sanofi.Ethical approvalAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.