Simple Summary Metastatic urothelial carcinoma is sensitive to immunomodulation. Immune checkpoint inhibitors (ICIs) have been FDA approved for use as single agents to treat locally advanced or metastatic urothelial carcinoma (mUC) since 2016. Immunotherapy has a lower incidence of side effects and longer durability of response compared to chemotherapy. Most recently, both the first-line combinations of pembrolizumab plus enfortumab vedotin and of nivolumab plus gemcitabine plus cisplatin showed significant overall survival benefit over prior standard-of-care chemotherapy and will be the fifth and sixth new drug regimens approved for mUC in the past four years. Treatment options for mUC are expected to continue to rapidly evolve. Here, we summarize clinical trials of immunotherapy that have led to the current standard of care for mUC, then review clinical trials testing novel immunotherapeutic approaches. A comprehensive understanding of current clinical trials will enable anticipation of upcoming developments and future research directions for mUC. Abstract Urothelial cancer is an immune-responsive cancer, but only a subset of patients benefits from immune checkpoint inhibition. Currently, single-agent immune checkpoint inhibitors (ICIs) and the combination of pembrolizumab with the antibody–drug conjugate enfortumab vedotin are approved to treat patients with metastatic UC (mUC). Approval of first-line nivolumab in combination with gemcitabine and cisplatin is expected imminently. Many treatment approaches are being investigated to better harness the immune system to fight mUC. In this review, we summarize the landmark clinical trials of ICIs that led to their incorporation into the current standard of care for mUC. We further discuss recent and ongoing clinical trials in mUC, which are investigating ICIs in combination with other agents, including chemotherapy, antibody–drug conjugates, tyrosine kinase inhibitors, and novel antibodies. Lastly, we review novel approaches utilizing bispecific antibodies, cellular therapies, and vaccines. The landscape of immunotherapy for mUC is rapidly evolving and will hopefully lead to better outcomes for patients.

A Comprehensive Review of Immunotherapy Clinical Trials for Metastatic Urothelial Carcinoma: Immune Checkpoint Inhibitors Alone or in Combination, Novel Antibodies, Cellular Therapies, and Vaccines

Background PF-06952229 is a selective small-molecule inhibitor of transforming growth factor-β (TGF-β) receptor 1. We evaluated its antitumor activity in preclinical studies and its safety, tolerability, pharmacokinetics, and pharmacodynamics in a phase I study (NCT03685591). Patients and methods In vitro and in vivo preclinical studies were conducted. Patients (aged ≥18 years) received PF-06952229 monotherapy [20-500 mg, oral b.i.d., 7 days on/7 days off, 28-day cycles, Part 1A (P1A)] for advanced/metastatic solid tumors and combination therapy [250/375 mg with enzalutamide, Part 1B (P1B)] for metastatic castration-resistant prostate cancer (mCRPC). Primary endpoints were dose-limiting toxicity (DLT), adverse events (AEs), and laboratory abnormalities. Efficacy, pharmacokinetic parameters, and biomarker modulation were assessed. Results PF-06952229 showed activity in preclinical murine tumor models including pSMAD2 modulation in tumors. The study (NCT03685591) enrolled 49 patients (P1A, n = 42; P1B, n = 7). DLTs were reported in 3/35 (8.6%) P1A patients receiving PF-06952229 375 mg (anemia, intracranial tumor hemorrhage, and anemia and hypertension, all grade 3, n = 1 each). The most frequent grade 3 treatment-related AEs (TRAEs) were alanine aminotransferase increased and anemia (9.5% each). There were no grade 4-5 TRAEs. Plasma PF-06952229 exposures were dose proportional between 80 and 375 mg. Pharmacodynamic studies confirmed target modulation of pSMAD2/3 (peripheral monocytes). One P1A patient with prostate cancer receiving PF-06952229 375 mg monotherapy achieved confirmed partial response (31-month duration of response). A total of 8 patients (P1A, n = 6; P1B, n = 2) achieved stable disease. Conclusions Antitumor activity of PF-06952229 was observed in preclinical studies. PF-06952229 was generally well tolerated with manageable toxicity; a small group of patients achieved durable responses and/or disease stabilization.

PF-06952229, a selective TGF-β-R1 inhibitor: preclinical development and a first-in-human, phase I, dose-escalation study in advanced solid tumors

Targeted therapies are the mainstay of systemic therapies for patients with advanced, unresectable, or metastatic hepatocellular carcinoma. Several therapeutic targets, such as c-Met, TGF-β, and FGFR, have been evaluated in the past, though results from these clinical studies failed to show clinical benefit. However, these remain important targets for the future with novel targeted agents and strategies. The Wnt/β-catenin signaling pathway, c-Myc oncogene, GPC3, PPT1 are exciting novel targets, among others, currently undergoing evaluation. Through this review, we aim to provide an overview of previously evaluated and potentially novel therapeutic targets and explore their continued relevance in ongoing and future studies for HCC. 

Targeted therapies in hepatocellular carcinoma: past, present, and future

Introduction Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a significant cause of cancer-related morbidity and mortality. Limited treatment options for advanced stages emphasize the need for effective therapies. 

Promising PD-1 antagonists for liver cancer: an evaluation of phase II and III results

<h3>Background</h3> Glycoprotein-A repetitions predominant (GARP) is expressed on regulatory T-cells and modulates release of active transforming growth factor β1 (TGFβ1), an immunosuppressive cytokine. ABBV-151 is a first-in-class monoclonal antibody (mAb) that binds to the GARP-TGFβ1 complex, blocking the release of active TGFβ1. Preclinical data demonstrate that blocking GARP-TGFβ1 and programmed cell death protein-1 (PD-1) improves antitumor efficacy compared with anti–PD-1 alone. Combining ABBV-151 with the anti–PD-1 mAb budigalimab may enable increased antitumor efficacy by reducing the immunosuppressive effects of TGFβ1. Herein, we report preliminary safety, efficacy, and pharmacokinetic (PK) results from a first-in-human, phase 1 study (NCT03821935) assessing ABBV-151 ± budigalimab in adult patients (≥18 years) with locally advanced/metastatic solid tumors. Results from the all-comer dose escalation (ESC) phase and two cohorts from the dose expansion (EXP) phase are available: anti-PD-1/PD-ligand (L)1 naïve hepatocellular carcinoma (HCC) and anti-PD-1/PD-L1 relapsed/refractory urothelial cancer (UC). <h3>Methods</h3> ESC patients must be refractory/intolerant to existing effective therapies; EXP cohorts have tumor-specific eligibility requirements. The primary ESC endpoint is the recommended phase II dose of ABBV-151 ± budigalimab. The primary EXP endpoint is preliminary efficacy of ABBV-151 + budigalimab, assessed by objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. <h3>Results</h3> As of June 2022, 157 patients have been enrolled, 57 in ESC (23 ABBV-151 monotherapy; 34 combination therapy) and 100 in EXP (including 36 UC; 12 HCC). As of January 2022, safety data were available for 129 patients. Any-grade adverse events (AEs) were reported in 119/129 (92%) patients. Most commonly: fatigue (28%), pruritus (27%), and nausea (22%). Grade 3-4 AEs occurred in 66/129 (51%) patients, with drug-related grade 3-4 AEs in 18/129 (14%) patients. ABBV-151 showed dose proportional PK. No antitumor responses were reported for the ABBV-151 monotherapy ESC cohorts. In the combination ESC cohorts, there were 4 confirmed responses, 1 unconfirmed response, and 4 patients had stable disease (SD) ≥6 months. In the anti-PD-1/PD-L1 relapsed/refractory UC EXP cohort, there were 5 confirmed responses, 1 unconfirmed response, and 5 patients had a best response of SD. In the anti-PD-1/PD-L1 naïve HCC EXP cohort, there were 5 confirmed responses, including one response per immune RECIST, and 3 patients had a best response of SD. <h3>Conclusions</h3> ABBV-151 ± budigalimab showed a manageable safety profile in patients with advanced solid tumors. Preliminary efficacy results demonstrate durable antitumor activity with ABBV-151 + budigalimab, including in anti-PD-1 relapsed/refractory UC and in anti-PD-1 naïve HCC. <h3>Acknowledgements</h3> AbbVie and the authors thank all the trial investigators and the patients who participated in this clinical trial. Medical writing support was provided by Rebecca L. Crepeau, PhD, from Aptitude Health, Atlanta, GA, USA and funded by AbbVie. <h3>Trial Registration</h3> NCT03821935 <h3>Ethics Approval</h3> The study was approved by the Advarra Ethics Board, under the license number IRB00000971. 

https://jitc.bmj.com/content/jitc/10/Suppl_2/A801.full.pdf

770 Safety, efficacy, and pharmacokinetic results from a phase I first-in-human study of ABBV-151 with or without anti-PD1 mAb (budigalimab) in patients with locally advanced or metastatic solid tumors

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770 Safety, efficacy, and pharmacokinetic results from a phase I first-in-human study of ABBV-151 with or without anti-PD1 mAb (budigalimab) in patients with locally advanced or metastatic solid tumors