Search

Purpose: Advanced urothelial cancer generally has high mortality despite modern anti-PD-1/L1 antibody-based combinations. Augmenting checkpoint inhibitor-mediated immune responses with lymphocyte growth factors may improve outcomes. We conducted a randomized phase II study (Cancer Immunotherapy Trials Network-14) in 47 patients to explore whether human recombinant IL-7 (CYT107) could be safely combined with PD-L1 inhibition to enhance responses., Patients and Methods: Patients with urothelial cancer after platinum chemotherapy were randomized to atezolizumab alone or with CYT107 weekly for four doses. The primary objective was clinical efficacy by the objective response rate (ORR). Secondary objectives included safety, toxicity, and other clinical outcomes. Correlative endpoints included peripheral immunophenotyping and quantification of cytokines., Results: CYT107 plus atezolizumab was well-tolerated, without dose-limiting toxicities and lower grade 3 to 4 treatment-related adverse events compared with atezolizumab monotherapy. The ORR was 26.3% for the combination therapy versus 23.8% for atezolizumab alone (P = 0.428). The complete response rate was 10.5% for the combination therapy versus 4.8% for monotherapy. Three patients on combination therapy had responses >21 months versus one with monotherapy. CD4+ and CD8+ T-lymphocyte expansion occurred in patients with response to combination therapy, with the greatest effect in T memory stem cells. Patients who responded to treatment exhibited elevated baseline levels of CCL4 and reduced levels of VEGFA and TNF., Conclusions: Combining CYT107 with atezolizumab was safe and resulted in lymphocyte expansion, a doubling of the complete response rate, and durable responses exceeding 2 years. However, the ORR was similar to atezolizumab alone. Increased and sustained doses of CYT107 coupled with patient selection strategies should be further investigated., (©2024 American Association for Cancer Research.)

Importance: The oral pan-fibroblast growth factor receptor inhibitor rogaratinib previously demonstrated encouraging safety and efficacy in a phase 1 study of patients with urothelial cancer (UC) overexpressing FGFR messenger RNA (mRNA)., Objective: To evaluate the safety, pharmacokinetics, and preliminary efficacy of rogaratinib in combination with the programmed cell death 1 ligand 1 (PD-L1) inhibitor atezolizumab in cisplatin-ineligible patients with FGFR mRNA-positive, locally advanced/metastatic UC., Design Setting and Participants: The FORT-2 nonrandomized clinical trial was an open-label, single-arm, multicenter study conducted between May 15, 2018, and July 16, 2021, in 30 centers across Asia, Europe, and North America. Eligible patients had locally advanced/metastatic UC with FGFR1 / 3 mRNA overexpression and were ineligible for cisplatin-based chemotherapy. The data analysis was completed from July 2022 to September 2022., Interventions: Patients received rogaratinib 600 mg or rogaratinib 800 mg twice daily in combination with intravenous atezolizumab 1200 mg every 21 days., Main Outcomes and Measures: Primary end points included safety, tolerability, and the recommended phase 2 dose (RP2D) of rogaratinib in combination with atezolizumab., Results: Among 153 patients screened, 73 (48%) had tumors with FGFR1/3 mRNA overexpression, and 37 patients were enrolled and treated (median [range] age, 75.0 [47.0-85.0] years; 32 [87%] male). The most common treatment-emergent adverse events (TEAEs) included diarrhea in 23 patients (62%), hyperphosphatemia in 19 (51%), and fatigue in 15 (41%). Grade 3 or higher TEAEs were reported in 27 patients (73%), and 4 grade 5 TEAEs were reported, though unrelated to treatment. The RP2D was rogaratinib 600 mg in combination with atezolizumab 1200 mg. At the RP2D, the overall response rate was 53.8% in the rogaratinib 600 mg group, including 4 patients (15%) with complete responses; 12 responders (86%) did not have an FGFR3 gene alteration, and 11 (79%) had low PD-L1 expression., Conclusions and Relevance: In this phase 1b nonrandomized clinical trial, rogaratinib plus atezolizumab demonstrated a manageable safety profile, with no unexpected safety signals. Efficacy for this combination at the RP2D was observed in tumors with low PD-L1 and was not dependent on FGFR3 gene alterations, suggesting broad potential benefit for patients with locally advanced/metastatic UC and FGFR mRNA overexpression., Trial Registration: ClinicalTrials.gov Identifier: NCT03473756., Competing Interests: Conflict of Interest Disclosures: Dr Sweis reported grants paid to institution from Ascendis, AstraZeneca, Astellas, ALX Oncology, Bayer, BMS, CytomX, Eisai, Genentech/Roche, Gilead, Immunocore, Jounce, Loxo Oncology, Lilly, Merck, Moderna, Mirati, Novartis, Pfizer, Pionyr, Pyxis, QED, Regeneron, and Scholar Rock outside the submitted work; personal fees from AbbVie, Aveo, Eisai, Exelixis, Gilead, Janssen, and Lilly outside the submitted work; and a patent pending for Neoantigens in Cancer (PCT/US2020/031357). Dr Gajate reported personal fees from BMS, Merck, Roche, Pfizer, Astellas, Janssen, and MSD outside the submitted work. Dr Morales-Barrera reported serving in an advisory role for MSD, Pfizer, Merck, Janssen, and Astellas, as well as receiving honoraria or travel expenses from Roche, Sanofi Aventis, Astellas, Janssen, MSD, Bayer, Merck, and Pfizer. Dr de Braud reported personal fees from Pierre Fabre, Mattioli 1885, MSD, IQVIA, BMS, Indena, Incyte, Taiho, Menarini, Novartis, Roche, Sanofi, AccMed, Itanet, ESO, Dephaforum, Nadirex, Events, Fare Comunicazione, Motore Sanità, Effetti, Ambrosetti, Dynamicom Education, and AstraZeneca outside the submitted work. Dr Grünwald reported personal fees from Bristol Myers Squibb, Merck Serono, MSD, AstraZeneca, and Astellas during the conduct of the study; personal fees from AstraZeneca, Gilead, Pfizer, Novartis/AAA, Janssen-Cilag, Amgen, Ipsen, Eisai, Debiopharm, Apogepha, PCI Biotech, Synthekine, and Oncorena outside the submitted work. Dr Rosenberg reported personal fees from Bayer during the conduct of the study; personal fees from Janssen, AstraZeneca, Chugai, Merck, Seagen, Pfizer, Astellas, Genentech/Roche, EMD-Serono, Boehringer Ingelheim, Lilly/Loxo Oncology, Tyra Biosciences, QED Therapeutics, Gilead, Hengrui, Century Therapeutics, and Aktis Consultant outside the submitted work. No other disclosures were reported., (Copyright 2024 Sweis RF et al. JAMA Oncology.)

Background and Objective: Checkpoint inhibitor therapy (CPI) has demonstrated survival benefits in urothelial carcinoma (UC); however, not all patients benefit from CPI due to resistance. Combining sitravatinib, a multitargeted receptor tyrosine kinase inhibitor of TYRO3, AXL, and MERTK (TAM) receptors and VEGFR2, with CPI may improve antitumor responses. Our objective was to assess the efficacy and safety of sitravatinib plus nivolumab in patients with advanced/metastatic UC., Methods: The 516-003 trial (NCT03606174) is an open-label, multicohort phase 2 study evaluating sitravatinib plus nivolumab in patients with advanced/metastatic UC enrolled in eight cohorts depending on prior treatment with CPI, platinum-based chemotherapy (PBC), or antibody-drug conjugate (ADC). Overall, 244 patients were enrolled and treated with sitravatinib plus nivolumab (median follow-up 14.1-38.2 mo). Sitravatinib (free-base capsules 120 mg once daily [QD] or malate capsule 100 mg QD) plus nivolumab (240 mg every 2 wk/480 mg every 4 wk intravenously)., Key Findings and Limitations: The primary endpoint was objective response rate (ORR; RECIST v1.1). The secondary endpoints included progression-free survival (PFS) and safety. The Predictive probability design and confidence interval methods were used. Among patients previously treated with PBC, ORR, and median PFS were 32.1% and 3.9 mo in CPI-naïve patients (n = 53), 14.9% and 3.9 mo in CPI-refractory patients (n = 67), and 5.4% and 3.7 mo in CPI- and ADC-refractory patients (n = 56), respectively. Across all cohorts, grade 3 treatment-related adverse events (TRAEs) occurred in 51.2% patients and grade 4 in 3.3%, with one treatment-related death (cardiac failure). Immune-related adverse events occurred in 50.4% patients. TRAEs led to sitravatinib/nivolumab discontinuation in 6.1% patients., Conclusions and Clinical Implications: Sitravatinib plus nivolumab demonstrated a manageable safety profile but did not result in clinically meaningful ORRs in patients with advanced/metastatic UC in the eight cohorts studied., Patient Summary: In this study, the combination of two anticancer drugs, sitravatinib and nivolumab, resulted in manageable side effects but no meaningful responses in patients with bladder cancer., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: The majority of patients with metastatic prostate cancer who receive androgen-deprivation therapy and androgen receptor (AR) signaling inhibitors (ARSI) progress. Activation of the glucocorticoid receptor (GR) is associated with ARSI resistance. This single-arm phase I trial assessed safety and pharmacokinetic (PK) feasibility of a combined AR antagonist (enzalutamide) and selective GR modulator (relacorilant) in patients with metastatic castration-resistant prostate cancer (mCRPC)., Patients and Methods: This was a phase I trial (NCT03674814) of relacorilant and enzalutamide in patients with refractory mCRPC enrolled using a 6+3 design. The enzalutamide dose was kept constant at 120 mg/d with escalating doses of relacorilant based on safety and PK measures in cohorts of ≥6 patients. The primary objective was safety and establishment of pharmacologically active doses. Secondary objectives were related to antitumor activity., Results: Thirty-five patients with mCRPC were enrolled. Twenty-three were accrued across three dose cohorts in the dose-escalation phase, and 12 enrolled at the recommended phase II dose. The combination was generally well tolerated, safe, and achieved desirable enzalutamide PK. RP2D of 120 + 150 mg/d, respectively, was established. Median time on study was 2.2 months with four patients remaining on study for longer than 11 months. Four of 12 evaluable patients had a prostate-specific antigen (PSA) partial response., Conclusions: This is the first prospective trial combining an AR antagonist and a nonsteroidal selective GR modulator. The combination was safe and well tolerated with PSA response and prolonged disease control observed in a limited subset of patients. Further prospective trials are justified to evaluate efficacy and identify predictive biomarkers of response., (©2024 American Association for Cancer Research.)

Background: Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients., Methods: We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0-1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov (NCT02501096) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants., Findings: Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3-28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8-89·3) of 22 treatment-naive patients, seven (41·2%, 18·4-67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7-65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 [21%] of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia)., Interpretation: Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC., Funding: Eisai and Merck Sharp & Dohme., Competing Interests: Declaration of interests C-HL received support for this Article from Eisai and Merck; grants or contracts to their institution from Eisai and Merck; consulting fees from Eisai and Merck; for attending meetings and travel from Eisai; and fees for participation in a scientific advisory committee for Merck; consulting fees from Amgen, Bristol Myers Squibb, Exelixis, Pfizer, and EMD Serono; honoraria from AiCME, Intellisphere, and Research to Practice; research funds to the institute from Bristol Myers Squibb, Calithera, Eisai, Eli Lilly, Exelixis, Merck, and Pfizer. AYS participated on an advisory board for Eisai, Exelixis, Pfizer, and Roche; and received research funding from Bristol Myers Squibb, Eisai, and EMD Serono. DR received support for this Article from Eisai. AR received grants or contracts to their institution from Eisai and Merck; consulting fees to their institution from Eli Lilly; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bayer, Cardinal Health, Eli Lilly, and Sanofi; and research funding to their institution from Clovis Oncology, Eli Lilly, Pfizer/Astellas, and Seattle Genetics/Astellas. MHT received clinical research funding for the present work to their institution from Eisai; and honoraria for participation in advisory boards and speakers' bureaus from Eisai. JJH received grants or contracts from Merck; consulting fees from BostonGene and Eisai; support for attending meetings or travel, or both from Elsevier; and stock or stock options from BostonGene. AP received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Ipsen, and Pfizer; and support for attending meetings or travel, or both, from Bristol Myers Squibb and Pfizer. RGS received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Janssen, and Roche; support for attending meetings or travel, or both, from MSD-Merck and Pfizer; and participation on a data safety monitoring board or advisory board from Bristol Myers Squibb. ALC received consulting fees from Amgen; and payment for expert testimony from the Department of Justice. NJV received support for this Article, including provision of study patients, payments to institution, medical writing, and manuscript writing charges from Eisai and Merck; consulting fees from Eisai and Merck; and payment for legal testimony from Merck. MAB received grants or contracts to their institution from Advanced Accelerator Applications, a Novartis Company, AstraZeneca, Bayer, Bristol Myers Squibb, Genentech/Roche, Genome & Company, Incyte, Nektar, Peloton Therapeutics, Pfizer, Seattle Genetics, Tricon Pharmaceuticals, and Xencor; honoraria for participation in a data safety monitoring board or advisory board for AstraZeneca, Bayer, Bristol Myers Squibb, Calithera Biosciences, Eisai, Exelixis, Genomic Health, Janssen, Nektar, Pfizer, and Sanofi. ØKT received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from Astellas and Bristol Myers Squibb; and fees for participation on a data safety monitoring board or advisory board for Bayer. RFS received grants or contracts to their institution from AbbVie, Aduro, Bayer, Bristol Myers Squibb, CytomX, Eisai, Eli Lilly, Genentech/Roche, Immunocore, Merck, Mirati, Moderna, Novartis, and QED therapeutics; consulting fees from Aduro, Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, Janssen, Mirati, Pfizer, Puma, and Seattle Genetics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astellas, Bristol Myers Squibb, Eisai, Exelixis, Pfizer, and Seattle Genetics; support for attending meetings or travel, or both, from AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Mirati; and patents pending, PCT/US2020/031357 on neoantigens in cancer. DH received support for this Article to their institution from Eisai; consulting fees from Astellas, AstraZeneca, Bayer, Eisai, Ipsen, Janssen-Cilag, and Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Advanced Accelerator Applications, a Novartis Company, Astellas, Bayer, Bristol Myers Squibb, Ipsen, Janssen-Cilag, Novartis, and Sanofi; and participation on an advisory board for Astellas, AstraZeneca, Bayer, Eisai, Ipsen, Janssen-Cilag, and Roche; SJ has stock or stock options in Merck. EVS and RFP are employed by, and have stock or stock options in, Merck. JW and PK are employed by Eisai. CEO and ADS are employed by Eisai Europe. RJM received support for the present Article from Eisai and Merck; grants or contracts from Bristol Myers Squibb, Genentech, Novartis, Pfizer, and Roche; consulting fees from AstraZeneca, Aveo Pharmaceuticals, EMD Serono, Exelixis, Genentech, Incyte, Eli Lilly, Novartis, Pfizer, and Roche; and support for attending meetings or travel, or both, from Bristol Myers Squibb. CDS, DRS, SGR, MG, DR, and JC declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)