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Background: In preliminary findings from the recurrent or metastatic cervical cancer cohort of CheckMate 358, nivolumab showed durable anti-tumour responses, and the combination of nivolumab plus ipilimumab showed promising clinical activity. Here, we report long-term outcomes from this cohort., Methods: CheckMate 358 was a phase 1-2, open-label, multicohort trial. The metastatic cervical cancer cohort enrolled patients from 30 hospitals and cancer centres across ten countries. Female patients aged 18 years or older with a histologically confirmed diagnosis of squamous cell carcinoma of the cervix with recurrent or metastatic disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and up to two previous systemic therapies were enrolled into the nivolumab 240 mg every 2 weeks group, the randomised groups (nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks [NIVO3 plus IPI1] or nivolumab 1 mg/kg every 3 weeks plus ipilimumab 3 mg/kg every 3 weeks for four cycles then nivolumab 240 mg every 2 weeks [NIVO1 plus IPI3]), or the NIVO1 plus IPI3 expansion group. All doses were given intravenously. Patients were randomly assigned (1:1) to NIVO3 plus IPI1 or NIVO1 plus IPI3 via an interactive voice response system. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal, or for up to 24 months. The primary endpoint was investigator-assessed objective response rate. Anti-tumour activity and safety were analysed in all treated patients. This study is registered with ClinicalTrials.gov (NCT02488759) and is now completed., Findings: Between October, 2015, and March, 2020, 193 patients were recruited in the recurrent or metastatic cervical cancer cohort of CheckMate 358, of whom 176 were treated. 19 patients received nivolumab monotherapy, 45 received NIVO3 plus IPI1, and 112 received NIVO1 plus IPI3 (45 in the randomised group and 67 in the expansion group). Median follow-up times were 19·9 months (IQR 8·2-44·8) with nivolumab, 12·6 months (7·8-37·1) with NIVO3 plus IPI1, and 16·7 months (7·2-27·5) with pooled NIVO1 plus IPI3. Objective response rates were 26% (95% CI 9-51; five of 19 patients) with nivolumab, 31% (18-47; 14 of 45 patients) with NIVO3 plus IPI1, 40% (26-56; 18 of 45 patients) with randomised NIVO1 plus IPI3, and 38% (29-48; 43 of 112 patients) with pooled NIVO1 plus IPI3. The most common grade 3-4 treatment-related adverse events were diarrhoea, hepatic cytolysis, hyponatraemia, pneumonitis, and syncope (one [5%] patient each; nivolumab group), diarrhoea, increased gamma-glutamyl transferase, increased lipase, and vomiting (two [4%] patients each; NIVO3 plus IPI1 group), and increased lipase (nine [8%] patients) and anaemia (seven [6%] patients; pooled NIVO1 plus IPI3 group). Serious treatment-related adverse events were reported in three (16%) patients in the nivolumab group, 12 (27%) patients in the NIVO3 plus IPI1 group, and 47 (42%) patients in the pooled NIVO1 plus IPI3 group. There was one treatment-related death due to immune-mediated colitis in the NIVO1 plus IPI3 group., Interpretation: Nivolumab monotherapy and nivolumab plus ipilimumab combination therapy showed promise in the CheckMate 358 study as potential treatment options for recurrent or metastatic cervical cancer. Future randomised controlled trials of nivolumab plus ipilimumab or other dual immunotherapy regimens are warranted to confirm treatment benefit in this patient population., Funding: Bristol Myers Squibb and Ono Pharmaceutical., Competing Interests: Declaration of interests AO reports receiving grants from AbbVie, Ability Pharmaceuticals, Advaxis, Agenus, Aprea Therapeutics, AstraZeneca, Beigene, Belgian Gynaecological Oncology Group (BGOG), Bristol Myers Squibb, Clovis Oncology, Corcept Therapeutics, Eisai, F Hoffmann-La Roche, Grupo Español de Investigación en Cáncer de Ovario (GEICO), Immunogen, Iovance Biotherapeutics, Lilly, Medimmune, Merck Healthcare, Merck Sharp & Dohme, Millennium Pharmaceuticals, Mundipharma Research, Novartis Farmacéutica, Regeneron Pharmaceuticals, Seagen, Seattle Genetics, Sutro Biopharma, Tesaro, University Health Network, and Werastem; consultant or advisory fees from Agenus, AstraZeneca Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceutical, Eisai Europe, EMD Serono, F Hoffmann-La Roche, GlaxoSmithKline (GSK), GOG, Immunogen, Medison Pharma, Merck Sharp & Dohme de España, Mersana Therapeutics, Novocure, Pharma Mar, prIME Oncology, Roche Farma, Sattucklabs, and Sutro Biopharma; honoraria from Edizioni Minerva Medica, ESMO, and Doctaforum Servicios; and travel accommodations from AstraZeneca, Clovis, GSK, PharmaMar, and Roche. KM reports receiving research grants from Clovis, Genentech, GSK, Lilly, PTC Therapeutics, and Verastem; consultant or advisory fees from AstraZeneca, Aravive, Alkermes, Addi, Blueprint Pharma, Clovis, Eisai, GSK, Genentech/Roche, Hengrui, Immunogen, Inxmed, IMab, Lilly, Mereo, Mersana, Merck, Myriad, Novartis, Novocure, OncXerna, Onconova, Tarveda, VBL Therapeutics, and Verastem; honoraria from AstraZeneca, Great Debates and Updates, GSK, Immunogen, Medscape, PRIME, and RTP; travel accommodations from AstraZeneca; and is a GOG Partners Associate Director. TM reports receiving grants from Bayer Biocompatibles, MSD; and consulting fees from Adaptimmune, AstraZeneca, Bristol Myers Squibb, Eisai, Ipsen, and Roche. LAD reports receiving consultant or advisory fees from MSD. AA reports receiving speaker fees from Bristol Myers Squibb. CDL reports receiving speaker fees from Bristol Myers Squibb, Genentech, Novartis, and Oncosec; and research funding from BMS, Genentech, Novartis, and Oncosec. VB reports receiving institutional financial support for clinical trials from AbbVie, ACEO, Adaptimmune, Amcure, Amgen, Amunix, Astellas, AstraZeneca, BeiGene, Bicycle, BMS, Boehringer Ingelheim, Boston Therapeutics, CytomX, Daiichi, DebioPharm, Dynavax, Genentech/Roche, Genmab, GSK, Incyte, Innovio, Ipsen, Janssen, Kura, Lilly, Loxo, Macrogenics, Menarini, Merck, Mersana, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, ORCA, Pfizer, PharmaMar, Principia, PsiOxus, PUMA, Ribbon, Ryvu, Sanofi, Seattle Genetics, Taiho, Takeda, Tesaro, Transgene, Regeneron, Rigontec, Seagen, Spectrum, Synthon, Urogen, and Zenith; consultant or advisory fees from CytomX Therapeutics, Guidepoint, Ideaya Biosciences, Janssen, Lilly, Loxo Therapeutics, Oncoart, and Puma Biotechnology; honoraria from Eli Lilly, Gedefo, Getthi, MSD, SOLTI, and TACTICS; and travel or accommodation support from Bayer. WHS reports receiving grants from AstraZeneca, Bristol Myers Squibb, Genentech, Merck, and Novartis; and consultant or advisory fees from Bristol Myers Squibb, ION, Merck, Pfizer, and Regeneron. MT reports receiving grants from Bayer and Ono Pharmaceuticals; consultant or advisory fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eisai, Genmab, Janssen, Lilly, MSD, Merck Biopharma, Ono Pharmaceuticals, and Pfizer; and honoraria from Bayer, Bristol Myers Squibb, Eisai, Lilly, Merck Biopharma, Ono Pharmaceuticals, and Rakuten Medical. SLT reports receiving grants from Bristol Myers Squibb; and consultant or advisory fees from AstraZeneca and PathAI; and reports receipt of research grants from Compugen, and consulting fees from Amgen, Bristol Myers Squibb, Compugen, and Janssen Pharmaceuticals for an immediate family member. MM reports leadership role fees from Centro Oncologico Internacional. AMA reports receiving consultant or advisory fees from Amgen, AstraZeneca, and Eli Lilly; being a Principal Investigator for Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, Janssen, and MSD; and speaker's bureau fees from GSK; and other fees from Roche. TAK is an employee and stockholder of Bristol Myers Squibb. CC is an employee and stockholder of Bristol Myers Squibb. ML is an employee of Syneos Health, which provides consulting services to Bristol Myers Squibb. CG-B is an employee and stockholder of Bristol Myers Squibb. XW was previously an employee of Bristol Myers Squibb and reports receiving stock options from Bristol Myers Squibb. RWN reports receiving research funding from Bristol Myers Squibb, GSK/Tesaro, Gynecologic Oncology Group, Mersana, and OncoMed Sutro Bio; speaker's bureau from Seagen; and consultant or advisory fees from Agenus, AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Eisai, Genelux, GOG Partners, GSK/Tesaro, Immunogen, Laekna, MSD, OncoMed, Seagen, and Sutro Bio. JL-PG and JCP declare no competing interests., (© 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background DR5 is a transmembrane receptor that transduces extracellular ligand-binding to activate apoptosis signaling cascades. This phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of a new monoclonal antibody potent DR5 agonist, DS-8273a, in subjects with advanced solid tumors. Methods The study comprised dose escalation and dose expansion cohorts. The dose escalation cohorts intended to determine the safety and to identify the maximum tolerated dose (MTD) or maximum administered dose (MAD) and to characterize the pharmacokinetics and pharmacodynamics by a conventional 3 + 3 design (starting at 2 mg/kg and escalating through 8, 16 and 24 mg/kg once every 3 weeks). In the dose expansion cohort, additional subjects were treated at the MAD for further evaluation of PK and safety. Results Thirty two subjects were enrolled and treated, 16 in the dose escalation cohorts and 16 in the dose expansion cohort. No subjects experienced a dose limiting toxicity (DLT). Treatment emergent adverse events were observed in 29 (91%) subjects, 14 (44%) of which were attributed to study-drug; all drug-related events were grade 1 and 2 in severity, and were mainly fatigue, nausea, vomiting and diarrhea. Measures of plasma exposure increased dose-proportionally and the mean terminal elimination half-life was 11 days. Blood samples available from a subset of patients treated at 24 mg/kg revealed declines in myeloid derived suppressor cells (MDSC) at 2 weeks. No objective responses were observed in any subjects. Conclusions DS-8273a was well tolerated and demonstrated linear pharmacokinetics. Decreases in MDSC were temporally associated with DS-8273a exposure. This agent could be studied further in combination with other agents, pending further proof-of-target-engagement.

Objectives: Patritumab is a fully human anti-human epidermal growth factor receptor 3 (HER3) antibody that blocks activation by its ligand, heregulin (HRG). Preclinical studies have demonstrated the efficacy of patritumab in aberrantly high HRG-expressing non-small cell lung cancer (NSCLC). In the phase II randomized, placebo-controlled double-blind study HERALD (n=212 patients with NSCLC), patritumab plus erlotinib did not improve progression-free survival (PFS) compared with placebo plus erlotinib. The current study examined whether soluble HRG (sHRG) level in serum correlated with the efficacy of patritumab plus erlotinib., Materials and Methods: Serum was obtained from participants prior to treatment (n=202). sHRG level was measured using a validated quantitative immune assay, and correlations with survival were blindly assessed., Results: sHRG level was various (-1346-11,772pg/mL). Participants were divided into the sHRG-high or -low subgroups at the concentration defining near the third quartile, 980pg/mL. Patritumab plus erlotinib significantly improved PFS relative to placebo in the sHRG-high subgroup (n=46, hazard ratio 0.42 [0.19-0.96], p=0.0327). In contrast, the HRG-low subgroup (n=148) had no improvement in PFS with patritumab., Conclusion: sHRG seems to be a predictive biomarker for the efficacy of patritumab plus erlotinib in NSCLC patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: During early clinical development, prospective identification of a predictive biomarker and validation of an assay method may not always be feasible. Dichotomizing a continuous biomarker measure to classify responders also leads to challenges. We present a case study of a prospective-retrospective approach for a continuous biomarker identified after patient enrollment but defined prospectively before the unblinding of data. An analysis of the strengths and weaknesses of this approach and the challenges encountered in its practical application are also provided., Methods: HERALD (NCT02134015) was a double-blind, phase 2 study in patients with non-small cell lung cancer (NSCLC) randomized to erlotinib with placebo or with high or low doses of patritumab, a monoclonal antibody targeted against human epidermal growth factor receptor 3 (HER3). While the primary objective was to assess safety and progression-free survival (PFS), a secondary objective was to determine a single predictive biomarker hypothesis to identify subjects most likely to benefit from the addition of patritumab. Although not identified as the primary biomarker in the study protocol, on the basis of preclinical results from 2 independent laboratories, expression levels of the HER3 ligand heregulin (HRG) were prospectively declared the predictive biomarker before data unblinding but after subject enrollment. An assay to measure HRG mRNA was developed and validated. Other biomarkers, such as epidermal growth factor receptor (EGFR) mutation status, were also evaluated in an exploratory fashion. The cutoff value for high vs. low HRG mRNA levels was set at the median delta threshold cycle. A maximum likelihood analysis was performed to evaluate the provisional cutoff. The relationship of HRG values to PFS hazard ratios (HRs) was assessed as a measure of internal validation. Additional NSCLC samples were analyzed to characterize HRG mRNA distribution., Results: The subgroup of patients with high HRG mRNA levels ("HRG-high") demonstrated clinical benefit from patritumab treatment with HRs of 0.37 (P = 0.0283) and 0.29 (P = 0.0027) in the high- and low-dose patritumab arms, respectively. However, only 102 of the 215 randomized patients (47.4%) had sufficient tumor samples for HRG mRNA measurement. Maximum likelihood analysis showed that the provisional cutoff was within the optimal range. In the placebo arm, the HRG-high subgroup demonstrated worse prognosis compared with HRG-low. A continuous relationship was observed between increased HRG mRNA levels and lower HR. Additional NSCLC samples (N = 300) demonstrated a similar unimodal distribution to that observed in this study, suggesting that the defined cutoff may be applicable to future NSCLC studies., Conclusions: The prospective-retrospective approach was successful in clinically validating a probable predictive biomarker. Post hoc in vitro studies and statistical analyses permitted further testing of the underlying assumptions. However, limitations of this analysis include the incomplete collection of adequate tumor tissue and a lack of stratification. In a phase 3 study, findings are being confirmed, and the HRG cutoff value is being further refined., Clinicaltrialsgov Number: NCT02134015.

Purpose: HER3 is a key dimerization partner for other HER family members, and its expression is associated with poor prognosis. This first-in-human study of U3-1287 (NCT00730470), a fully human anti-HER3 monoclonal antibody, evaluated its safety, tolerability, and pharmacokinetics in patients with advanced solid tumor., Experimental Design: The study was conducted in 2 parts: part 1--sequential cohorts received escalating doses (0.3-20 mg/kg) of U3-1287 every 2 weeks, starting 3 weeks after the first dose; part 2--additional patients received 9, 14, or 20 mg/kg U3-1287 every 2 weeks, based on observed tolerability and pharmacokinetics from part 1. Recommended phase II dose, adverse event rates, pharmacokinetics, and tumor response were determined., Results: Fifty-seven patients (part 1: 26; part 2: 31) received U3-1287. As no dose-limiting toxicities were reported, the maximum-tolerated dose was not reached. The maximum-administered dose was 20 mg/kg every 2 weeks. The most frequent adverse events related to U3-1287 were fatigue (21.1%), diarrhea (12.3%), nausea (10.5%), decreased appetite (7.0%), and dysgeusia (5.3%). No patient developed anti-U3-1287 antibodies. In these heavily pretreated patients, stable disease was maintained 9 weeks or more in 19.2% in part 1 and 10 weeks or more in 25.8% in part 2., Conclusion: U3-1287 treatment was well tolerated, and some evidence of disease stabilization was observed. Pharmacokinetic data support U3-1287 dosing of 9 to 20 mg/kg every 2 to 3 weeks. Combination studies of U3-1287 are ongoing., (©2013 AACR)

Background: Efatutazone (CS-7017), a novel peroxisome proliferator-activated receptor gamma (PPARγ) agonist, exerts anticancer activity in preclinical models. The authors conducted a phase 1 study to determine the recommended phase 2 dose, safety, tolerability, and pharmacokinetics of efatutazone., Methods: Patients with advanced solid malignancies and no curative therapeutic options were enrolled to receive a given dose of efatutazone, administered orally (PO) twice daily for 6 weeks, in a 3 + 3 intercohort dose-escalation trial. After the third patient, patients with diabetes mellitus were excluded. Efatutazone dosing continued until disease progression or unacceptable toxicity, with measurement of efatutazone pharmacokinetics and plasma adiponectin levels., Results: Thirty-one patients received efatutazone at doses ranging from 0.10 to 1.15 mg PO twice daily. Dose escalation stopped when maximal impact on PPARγ-related biomarkers had been reached before any protocol-defined maximum-tolerated dose level. On the basis of a population pharmacokinetic/pharmacodynamic analysis, the recommended phase 2 dose was 0.5 mg PO twice daily. A majority of patients experienced peripheral edema (53.3%), often requiring diuretics. Three episodes of dose-limiting toxicities, related to fluid retention, were noted in the 0.10-, 0.25-, and 1.15-mg cohorts. Of 31 treated patients, 27 were evaluable for response. A sustained partial response (PR; 690 days on therapy) was observed in a patient with myxoid liposarcoma. Ten additional patients had stable disease (SD) for ≥60 days. Exposures were approximately dose proportional, and adiponectin levels increased after 4 weeks of treatment at all dose levels. Immunohistochemistry of archived specimens demonstrated that PPARγ and retinoid X receptor expression levels were significantly greater in patients with SD for ≥60 days or PR (P = .0079), suggesting a predictive biomarker., Conclusions: Efatutazone demonstrates acceptable tolerability with evidence of disease control in patients with advanced malignancies., (Copyright © 2012 American Cancer Society.)