James Abbruzzese

<jats:p> TPS2671 </jats:p><jats:p> Background: MERTK is a receptor tyrosine kinase from the tumor-associated macrophage kinase (TAMK) family that regulates key aspects of immune homeostasis and responses to infection. MERTK inhibition may lower the threshold for immune activation thereby promoting anti-tumor activity. Agents with some degree of MERTK inhibitory activity have been investigated in the clinic, but are limited by poor potency in patients (pts) and significant off-targets effects. PF-07265807 (ARRY-067) is a selective small-molecule inhibitor of the TAMKs MERTK and AXL. In preclinical models, PF-07265807 monotherapy shows antitumor activity that results in long-term cures and resistance to tumor re-challenge when combined with anti-programmed cell death protein 1/programmed death-ligand 1 (anti-PD-1/PD-L1) antibodies. This first-in-human study will evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity of PF-07265807 in pts with selected advanced or metastatic solid tumors. This study will also explore the potential utility of PF-07265807 in combination with anti-PD-1/PD-L1 antibodies. Methods: This is a phase 1, open-label, multi-center, dose-escalation study (NCT04458259) to evaluate the safety, PK and tolerability of PF-07265807. Eligible participants will be adult pts with selected advanced or metastatic solid tumors who are intolerant or resistant to standard therapy. Other key eligibility criteria: measurable disease by RECIST 1.1 or non-measurable disease; Eastern Cooperative Oncology Group performance status 0–2; adequate bone marrow, renal and liver function; and resolved acute effects of any prior therapy. Successive cohorts of pts will receive escalating doses of PF-07265807 starting from 25 mg QD. Each cycle will be 21 days in duration (14 days on/7 days off). Study drug treatment will continue until disease progression or unacceptable toxicity, whichever occurs first. For dose escalation, a Bayesian logistic regression model will be used to model the relationship of dose-limiting toxicities (DLTs) to PF-07265807 dose. This model, along with escalation with overdose control, will guide the dose escalation of PF-07265807 after the completion of the DLT observation period (first two cycles of treatment, i.e. 42 days) of each cohort, until determination of the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D). After the MTD/RP2D is identified, the safety and efficacy of combined PF-07265807 and anti-PD1/PD-L1 treatment will be explored. Primary endpoints: incidence of DLTs, treatment-emergent adverse events and laboratory abnormalities. Secondary endpoints: PK parameters of PF-07265807, objective response rate and duration of response. The study began enrolling pts in September 2020 and is still recruiting. Clinical trial information: NCT04458259. </jats:p>

Carcinoma of unknown primary (CUP) is a diverse group of heterogeneous cancers presenting without a primary site and accounts for about 2% to 4% of all cancers. The past two decades have seen significant change in our approach to CUP patients. Therapy strategies have moved away from the empiric combination cytotoxic therapies and the “one treatment fits all” approach. The primary focus has been on improved methods to identify the putative primary tumor and to direct therapy at that tumor type. Albeit not uniform, there is consensus that the evaluation needs to be focused, with imaging and invasive tests based on symptomatology and pathologic evaluation. Although it has limitations including variable tissue antigenicity and interpretation, immunohistochemistry remains a powerful tool in the judicious pathologic assessment of metastatic tumor tissue. Over the last several years, cancer classifying tissue of origin profiling libraries has generated enormous data, analyses of which have led to additional insights. Using next generation sequencing, there is a push toward personalizing cancer care through the use of genomic tools to identify driver and actionable mutations in individual tumors. For this approach to be successful in CUP, it will require continued understanding of unique molecular insights for select CUP subsets, as well as leveraging novel drugs that are effective against specific mutations in known cancers.