作者: Loboda, Andrey ; Knelson, Erik H. ; Hess, Dagmar ; Powell, Steven F. ; Jamal, Rahima ; Siu, Lillian L. ; Joerger, Markus ; Mach, Nicolas ; Chen, Yao ; Shumway, Stuart ; Stathis, Anastasios

AbstractTherapeutic blockade of PD-1:PD-L1/L2 interactions is effective in many cancers, particularly those with pre-existing inflammation and T cell infiltration. We identified a correlation between high interleukin 4 induced 1 (IL4I1) gene expression within the tumor micorenvironment (TME) of tumors and response to the PD-1 inhibitor pembrolizumab (pembro). IL4I1 protein is secreted by myeloid and tumor cells into the extracellular TME where it generates hydrogen peroxide upon deamination of amino acid substrates, primarily L-phenylalanine to phenylpyruvate. At IL4I1 concentrations similar to those measured in human tumors, hydrogen peroxide generated by IL4I1 is cytotoxic to T cells in vitro and suppresses T cell responses in mixed lymphocyte reactions. These data collectively support an immunosuppressive role of IL4I1 in the TME. Small molecule inhibitory ligands of IL4I1 have not been previously described. Chemical optimization led to the discovery of MK-6598, which has an IC50 of 16 nM against recombinant IL4I1 in a biochemical assay and exhibits a robust PK/PD relationship based on tumor phenylpyruvate concentrations in mouse models. Mixed lymphocyte reactions and ex vivo organoids were used to validate the target and mechanism of action of MK-6598 in preclinical models. The phase 1 MK-6598-001 dose escalation study (NCT05594043) was designed to assess the safety, tolerability, PK, and antitumor activity of MK-6598 administered orally at four doses from 50-500 mg once daily as monotherapy (arm 1) or in combination with pembro 200 mg administered intravenously every 3 weeks in participants (pts) with previously treated advanced solid tumors. 20 pts received MK-6598 alone in arm 1, and 19 received MK-6598 plus pembro in arm 2. Median age was 62 y. Of the 20 tumor types represented, ovarian and colorectal were the most common (n=6 each). There were no dose limiting toxicities (DLTs) in the monotherapy arm and 3 DLTs observed in the pembro combination arm (grade 3 maculopapular rash, grade 3 Stevens-Johnson syndrome [recovered], and delay in dosing due to grade 1 fever). MK-6598 plasma concentrations increased with dose and were above the predicted IC70 for all pts and the predicted IC90 for >80% of pts. Tumor biopsies were performed at baseline and predose at cycle 2 day 1 (C2D1) to quantitatively assess IL4I1 protein and phenylpyruvate by mass spectrometry. Evidence of IL4I1 inhibition was illustrated by reductions in tumor phenylpyruvate at C2D1 in >90% of pts, with reductions >50% observed in >60% of pts. The only response was in a pt with mismatch repair-deficient endometrial cancer that progressed on prior pembro achieved a partial response after crossing over from MK-6598 monotherapy to MK-6598 plus pembro. These data suggest that despite its ability to inhibit IL4I1 protein, MK-6598 has limited antitumor activity as monotherapy or in combination with pembro in pts with previously treated advanced solid tumors.Citation Format:Dagmar Hess, Nicolas Mach, Rahima Jamal, Anastasios Stathis, Steven F. Powell, Markus Joerger, Andrey Loboda, Yao Chen, Stuart Shumway, Erik H. Knelson, Lillian L. Siu. Discovery and preliminary clinical findings of MK-6598, a potent and selective inhibitor of the immune checkpoint IL4I1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT074.

2024-06-01·Journal of Clinical Oncology

Evaluating perceived barriers to optimal care in head and neck cancer: A mixed-methods study.

作者: Powell, Steven Francis ; Plotkin, Elana ; Kim, Joseph ; Dibble, Jacqueline ; Haynes-Lewis, Hilda ; Rush, Angie ; Hutkin-Slade, Linda ; Demirhan, Kimberly ; Watts, Tammara L ; Maxwell, Jessica H. ; Beadle, Beth Michelle

6079 Background: Head and neck cancer (HNC) is a complex disease that requires multidisciplinary care and poses significant challenges for patients and healthcare providers. Despite the availability of evidence-based guidelines, achieving optimal HNC care faces many barriers. This mixed-methods study explores the perceived barriers by patients and clinicians to optimal HNC care. Methods: The Association of Cancer Care Centers (ACCC) collaborated with the Head and Neck Cancer Alliance and the American Society for Radiation Oncology (ASTRO), along with an expert steering committee of multidisciplinary roles representing diverse cancer care centers, to evaluate the current landscape of HNC care delivery. Using an explanatory sequential design, ACCC conducted patient (n= 247) and provider (n=206) surveys and four focus groups which included patients with HNC and clinicians to capture barriers to optimal HNC care. Results: Barriers were classified as patient-related, provider-related, and system-related factors. Survey highlights include: 32% of patients received multimodal treatment including surgery, radiation, and medications; 50% of clinicians were at centers that utilized multidisciplinary clinics for HNC; 60% of patients “strongly agreed” they were satisfied with their care; 48% of patients felt members of their treatment team communicated and coordinated care “very well”; and 56% of patients “strongly agreed” clinicians explained their diagnosis comprehensibly. Clinicians and patients differed in their perspectives on how care was delivered in a few areas: 52% of clinicians vs. 40% of patients agreed that side effects of treatment were explained in ways that patients could understand; 29% of clinicians vs. 21% of patients felt that emotional concerns and mental health needs were addressed. Clinicians identified key areas that needed improvement to provide more effective care: financial resources (62%), dedicated navigation (45%), and coordination across members of the care team (45%). Qualitative analysis of focus group responses identified travel logistics to care centers, inadequate health insurance coverage, and lack of dental insurance delaying care as major systems-related barriers to optimal HNC care. Conclusions: This study revealed insights into the delivery of optimal care in HNC in the US, including being a high-volume center, having dedicated HNC nurse navigators, and multidisciplinary meetings for care coordination. Multifactorial barriers to optimal HNC care were also identified and will be used to inform future educational programming and the development of interventions to improve care.

2024-06-01·Journal of Clinical Oncology

NRG-LU002: Randomized phase II/III trial of maintenance systemic therapy versus local consolidative therapy (LCT) plus maintenance systemic therapy for limited metastatic non-small cell lung cancer (NSCLC).

作者: Gerber, David E ; Simone, Charles B. ; Wu, Jackie ; Stephans, Kevin L. ; Iyengar, Puneeth ; Sampson, Pamela ; Hu, Chen ; Weldon, Michael ; Robinson, Clifford Grant ; Nowak, Ryan Kenneth ; Timmerman, Robert D. ; Lyness, Jessica ; Bradley, Jeffrey D. ; Gomez, Daniel Richard ; Swisher, Stephen ; Rashdan, Sawsan ; Higgins, Kristin Ann ; Faller, Bryan A. ; Donington, Jessica ; Waqar, Saiama Naheed

8506 Background: First line therapy options for advanced NSCLC without actionable molecular alterations include immunotherapy (IO) -/+ chemotherapy or chemotherapy alone. NRG-LU002 was a randomized phase II/III study assessing the benefits of local consolidative therapy (LCT) when added to systemic therapy as maintenance in management of oligometastatic NSCLC. Methods: Eligible patients had metastatic NSCLC with 3 or fewer extracranial metastatic sites (excluding primary) exhibiting at least stable disease after 4 cycles of 1st line systemic therapy. Patients were randomized 1:2 to maintenance systemic therapy or LCT (radiation and/or surgery) followed by maintenance systemic therapy until progression, death, or intolerable toxicity. Stratification factors included histology and IO use. In the randomized phase II (RPhII) portion of the study, the primary endpoint was progression-free survival (PFS) with a planned decision analysis after 216 patients were enrolled and 138 PFS events observed. Secondary endpoints included overall survival (OS), quality of life, and toxicity. The RPhII portion was designed to provide at least 95% power to detect a PFS hazard ratio (HR) of 0.60 at 1-sided significance level of 0.15, and the phase III portion warranted only if the estimated HR was less than 0.83. Results: NRG-LU002 accrual was initiated in 4/2017 and suspended in 11/2021 when the RPhII portion sample size was met. Following the planned interim analysis, the study was closed in 12/2023. Overall, 215 patients (81 -LCT arm, 134 +LCT arm) were enrolled from 68 sites with a median age of 65 years (40-86), 77% white, 95% PS 0/1, 78% non-squamous histology, and 90% having received IO-based systemic therapy. Median follow-up among all/surviving patients were 21.9/29.4 months, respectively. With 138 PFS events from both arms, estimated 1-yr and 2-yr PFS rates were 48% (95% CI: 35.9, 59.0) and 36% (95% CI: 24.8, 47.2) in the maintenance systemic therapy arm and 52% (95% CI: 42.5, 59.8) and 40% (95% CI: 31.5, 48.6) in the LCT + maintenance systemic therapy arm, respectively (2-sided log-rank test p-value = 0.66). Corresponding HR was 0.93 (95% CI: 0.66, 1.31). Of 185 patients treated with IO-containing regimens, the PFS HR was 0.90 (95% CI: 0.61, 1.32). OS HR between two arms was 1.05 (0.70, 1.56) among all patients and 1.05 (0.68, 1.63) among IO-treated patients. For adverse events reported as definitely, probably or possibly related to treatment, there were more LCT + maintenance systemic therapy patients with overall grade 2 or higher toxicities (73% vs 84%) and grade 3 or higher pneumonitis (1% vs 10%). Conclusions: LCT added to IO-based 1st line systemic therapy was associated with a PFS HR of 0.90. Reducing toxicity and increasing biologically-driven patient selection may optimize this therapeutic ratio. Clinical trial information: NCT03137771 .

100 项与 Sanford Cancer Center 相关的药物交易

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