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SummaryPurpose and Methods Trop-2 is a glycoprotein over-expressed in many solid tumors but at low levels in normal human tissue, providing a potential therapeutic target. We conducted a phase 1 dose-finding study of PF-06664178, an antibody-drug conjugate that targets Trop-2 for the selective delivery of the cytotoxic payload Aur0101. The primary objective was to determine the maximum tolerated dose and recommended phase 2 dose. Secondary objectives included further characterization of the safety profile, pharmacokinetics and antitumor activity. Eligible patients were enrolled and received multiple escalating doses of PF-06664178 in an open-label and unblinded manner based on a modified continual reassessment method. Results Thirty-one patients with advanced or metastatic solid tumors were treated with escalating doses of PF-06664178 given intravenously every 21 days. Doses explored ranged from 0.15 mg/kg to 4.8 mg/kg. Seven patients experienced at least one dose limiting toxicity (DLT), either neutropenia or rash. Doses of 3.60 mg/kg, 4.2 mg/kg and 4.8 mg/kg were considered intolerable due to DLTs in skin rash, mucosa and neutropenia. Best overall response was stable disease in 11 patients (37.9%). None of the patients had a partial or complete response. Systemic exposure of PF-06664178 increased in a dose-related manner. Serum concentrations of free Aur0101 were substantially lower than those of PF-06664178 and total antibody. No correlation of Trop-2 expression and objective response was observed, although Trop-2 overexpression was not required for study entry. The intermediate dose of 2.4 mg/kg appeared to be the highest tolerated dose, but this was not fully explored as the study was terminated early due to excess toxicity. Conclusion PF-06664178 showed toxicity at high dose levels with modest antitumor activity. Neutropenia, skin rash and mucosal inflammation were dose limiting toxicities. Findings from this study may potentially aid in future antibody drug conjugate design and trials.

Background: Stromal hyaluronic acid (HA) poses a physical barrier and protects tumor cells from immune surveillance. Stroma targeting with pegylated human recombinant PH20 hyaluronidase (PEGPH20) demonstrated improved infiltration of cytotoxic T-lymphocytes and delivery of chemotherapy and PD1/PD-L1 antibodies in tumor models. This multicenter phase II study of PEGPH20 plus pembrolizumab evaluated the efficacy, safety and immune and stromal biomarkers in patients with HA-high refractory metastatic pancreatic ductal adenocarcinoma (mPDA). Patients and Methods: Patients were treated with PEGPH20 3 µg/kg IV weekly and pembrolizumab 200 mg IV in 3-week cycles. Tumor and blood samples were collected at baseline and on-study for biomarker analyses. Results: Between May and November 2019, 38 patients were screened and 8 treated, with median age 68 years (range 60–73) and median two (range 1–4) prior therapies. The study was closed to accrual early by pharmaceutical sponsor. Treatment was well tolerated, with expected grade 1/2 musculoskeletal toxicities. Best response was stable disease in 2 of 7 evaluable patients (29%). Median overall and progression-free survival were 7.2 months (95% CI 1.2–11.8) and 1.5 months (95% CI 0.9–4.4), respectively. Prolonged survival (range 10.2–27.6 months) occurred in patients treated with subsequent chemotherapy. Higher baseline tumor T cell receptor (TCR) clonality correlated with longer survival. Conclusions: Pembrolizumab with PEGPH20 was safe but did not have significant efficacy in refractory HA-high metastatic PDA.

Abstract Biliary tract cancers (BTCs) are a heterogeneous group of tumors arising from cells in the bile ducts and gallbladder. The 5-year overall survival rate for all BTC stages combined is ~20%, and treatment options for patients with unresectable disease are limited, leaving an unmet clinical need. In recent years, significant efforts have been made to refine and implement targeted therapeutic approaches for patients with BTC. The adoption of early and comprehensive molecular profiling is crucial to identifying patients who may be candidates for effective targeted therapies. Characterization of the molecular landscape of BTCs led to the identification of murine double minute 2 homolog gene (MDM2) amplification across all BTC subtypes. The MDM2 protein is a critical negative regulator of p53 stabilization and activity that is an emerging actionable biomarker in BTCs. There are multiple therapeutic approaches that aim to target MDM2 activity, thereby restoring the intrinsic tumor suppressor function of p53 and halting oncogenesis. However, these have been limited by our evolving understanding of the role of MDM2 in BTC pathogenesis. Here, we offer a review of the current understanding of the role of MDM2 in BTC biology and its therapeutic implications.

Abstract Purpose of reviewThe systemic treatment of advanced hepatocellular carcinoma (HCC) has significantly evolved. Immune checkpoint inhibitors (ICIs) have demonstrated clinical efficacy and more favorable toxicity profiles compared to multikinase inhibitors. Combination therapy with ICIs may provide greater anti-tumor activity compared to ICI monotherapy. This review will discuss the current treatment landscape of advanced HCC, with a focus on recently completed and ongoing trials of ICI combinations, as well as future directions. Recent findingsAtezolizumab/bevacizumab has been approved as first-line therapy in patients with advanced HCC based on its superiority over sorafenib in the pivotal IMbrave150 trial. Similarly, durvalumab/tremelimumab demonstrated an improvement in overall survival compared to sorafenib in the HIMALAYA trial. Other combinations of ICIs with targeted agents and dual immune checkpoint blockade are currently being investigated in large randomized Phase 3 trials for the first-line treatment of HCC.SummaryResults of several ICI combination trials have been reported or are anticipated in the next few years and may potentially expand the therapy options in this patient population. Further areas of exploration include the use of ICIs in earlier stages of disease, other immunotherapy approaches such as adoptive T cell therapy, and the identification of predictive biomarkers. These ongoing efforts will likely further improve patient outcomes in the future.

Purpose of ReviewCholangiocarcinoma is an aggressive cancer with a poor prognosis and limited treatment. Gene sequencing studies have identified genetic alterations in fibroblast growth factor receptor (FGFR) in a significant proportion of cholangiocarcinoma (CCA) patients. This review will discuss the FGFR signaling pathway’s role in CCA and highlight the development of therapeutic strategies targeting this pathway.Recent FindingsThe development of highly potent and selective FGFR inhibitors has led to the approval of pemigatinib for FGFR2 fusion or rearranged CCA. Other selective FGFR inhibitors are currently under clinical investigation and show promising activity. Despite encouraging results, the emergence of resistance is inevitable. Studies using circulating tumor DNA and on-treatment tissue biopsies have elucidated underlying mechanisms of intrinsic and acquired resistance. There is a critical need to not only develop more effective compounds, but also innovative sequencing strategies and combinations to overcome resistance to selective FGFR inhibition. Therapeutic development of precision medicine for FGFR-altered CCA is a dynamic process of involving a comprehensive understanding of tumor biology, rational clinical trial design, and therapeutic optimization.SummaryAlterations in FGFR represent a valid therapeutic target in CCA and selective FGFR inhibitors are treatment options for this patient population.

Fibroblast growth factor receptors (FGFR) are emerging as an important therapeutic target for patients with advanced, refractory cancers. Most selective FGFR inhibitors under investigation show reversible binding, and their activity is limited by acquired drug resistance. This review summarizes the preclinical and clinical development of futibatinib, an irreversible FGFR1-4 inhibitor. Futibatinib stands out among FGFR inhibitors because of its covalent binding mechanism and low susceptibility to acquired resistance. Preclinical data indicated robust activity of futibatinib against acquired resistance mutations in the FGFR kinase domain. In early-phase studies, futibatinib showed activity in cholangiocarcinoma, and gastric, urothelial, breast, central nervous system, and head and neck cancers harboring various FGFR aberrations. Exploratory analyses indicated clinical benefit with futibatinib after prior FGFR inhibitor use. In a pivotal phase II trial, futibatinib demonstrated durable objective responses (42% objective response rate) and tolerability in previously treated patients with advanced intrahepatic cholangiocarcinoma harboring FGFR2 fusions or rearrangements. A manageable safety profile was observed across studies, and patient quality of life was maintained with futibatinib treatment in patients with cholangiocarcinoma. Hyperphosphatemia, the most common adverse event with futibatinib, was well managed and did not lead to treatment discontinuation. These data show clinically meaningful benefit with futibatinib in FGFR2-rearrangement-positive cholangiocarcinoma and provide support for further investigation of futibatinib across other indications. Future directions for this agent include elucidating mechanisms of resistance and exploration of combination therapy approaches. Fibroblast growth factor receptors (FGFR) are emerging as an important therapeutic target for patients with advanced, refractory cancers. This review summarizes the preclinical and clinical development of futibatinib, an irreversible FGFR1-4 inhibitor.

The most recent generation to enter the workplace, generation Z, has been stereotyped as being less engaged in the workplace, despite being highly success oriented (Barna, 2018). This discrepancy might be explained by the theory of generations and generation units (Mannheim, 1952), which states that subgroups exist within each generational cohort. The purpose of this study is to identify intra-generational differences among generation Z employees in order to identify the subjective workplace perceptions and proclivities. In order to do so, we deployed Q methodology, which allowed us to identify subgroups within the generational cohort. Results indicated three distinct subgroups within generation Z: Social Investors, Chill Worker Bees, and Go Getters. Social Investors valued a work-life balance, Chill Worker Bees desired a comfortable workplace environment, and Go Getters prioritized advancing their career. All three groups reported prioritizing companies with high moral and ethical standards. These results present HR practitioners, employers, and managers with a new perspective on the distinct generation units within generation Z, including intra- and intergenerational overlap.

Background: The epidermal growth factor receptor (EGFR) is overactive in many tumors. This phase I trial evaluated the safety and preliminary efficacy of afatinib plus capecitabine in refractory pancreatic ductal adenocarcinoma (PDA), biliary tract cancers (BTC), and other solid tumors. Patients and Methods: The phase Ia study had a 3 + 3 design with capecitabine 1000 mg/m2 twice daily on days 1–14 and afatinib 20 mg, 30 mg, or 40 mg daily in 21-day cycles. In phase Ib, 15 patients, each with PDA and BTC, were treated at maximum tolerated dose (MTD). Results: A total of 41 patients were enrolled. No dose-limiting toxicities were observed, and the MTD was 40 mg afatinib plus capecitabine. Among 36 response-evaluable patients, one had a partial response (3%), and eight (22%) had stable disease. Median progression-free survival (PFS) was 1.9 months (95% CI 1.0, 2.0) for PDA and 1.9 months (95% CI 1.6, 3.4) for BTC. Median overall survival (OS) was 3.2 months (95% CI 2.0, 5.8) for PDA, and 4.6 months (95% CI 1.9, 6.1) for BTC. Median OS was 5.8 months (95% CI 2.0, 9.6) for KRASWT PDA, and 5.0 months (95% CI 1.6, 6.1) for KRASWT BTC, vs. 3.9 months (95% CI 1.9, 5.8) for KRASMUT PDA and 3.1 months (95% CI 1.0, 22.8) for KRASMUT BTC, respectively. Conclusions: Afatinib plus capecitabine is tolerable but does not have clinically meaningful efficacy in refractory PDA/BTC. Future studies should test novel anti-EGFR/HER2 therapies in KRASWT cancers further selected with a comprehensive molecular profile.