Publications by authors named "David F Mcdermott"

Background: Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds to the intermediate-affinity interleukin-2 receptor, preferentially activating CD8 T cells and natural killer cells, with minimal expansion of regulatory T cells, thereby mitigating the risk of toxicities associated with high-affinity interleukin-2 receptor activation. Clinical outcomes with nemvaleukin are unknown. ARTISTRY-1 investigated the safety, recommended phase 2 dose (RP2D), and antitumor activity of nemvaleukin in patients with advanced solid tumors.

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  • Immunotherapy, like the combination of nivolumab and ipilimumab (NIVO+IPI), can lead to prolonged disease control and treatment-free survival (TFS) for cancer patients, even after stopping treatment, which is not accounted for by standard survival measures.
  • A study analyzed data from 1,096 advanced renal cell carcinoma patients to estimate TFS, comparing those treated with NIVO+IPI against sunitinib (SUN), focusing on both survival time and treatment-related adverse events (TRAEs).
  • Results showed that 48% of patients on NIVO+IPI were alive after 5 years, with a significant difference in mean TFS compared to SUN, particularly in favorable-risk patients, highlighting the importance of considering
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Autologous therapeutic tumor-infiltrating lymphocyte (TIL) therapy is a promising strategy to enhance antitumor immunity. Optimization of ex vivo TIL expansion could expand current immunotherapy options. Previous attempts to generate TIL in renal cell carcinoma (RCC) have been technically challenging.

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  • The study investigated the effectiveness of nivolumab, an immunotherapy drug, used before and after surgery in patients with high-risk renal cell carcinoma compared to traditional surgery alone.
  • It was a randomized phase 3 trial involving 819 patients across multiple sites in the US and Canada, who were assigned to either the nivolumab plus surgery group or surgery only group.
  • The primary outcome measured was recurrence-free survival, with safety being assessed for all patients who started treatment, and the trial has been officially closed to new participants.
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  • Patients with biochemically recurrent (BCR) prostate cancer prioritize metastasis-free survival over simply having time without treatment.
  • This indicates that minimizing the risk of cancer spreading is a key concern for them.
  • Understanding this preference can help healthcare providers tailor treatment plans that align with patient values.*
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Purpose: Both clear cell and papillary renal cell carcinomas (RCCs) overexpress kidney injury molecule-1 (KIM-1). We investigated whether plasma KIM-1 (pKIM-1) may be a useful risk stratification tool among patients with suspicious renal masses.

Methods: Prenephrectomy pKIM-1 was measured in two independent cohorts of patients with renal masses.

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  • The study examines the Lung Immune Prognostic Index (LIPI) to see if it can predict survival in patients with metastatic renal cell carcinoma (mRCC).
  • LIPI categorizes patients into groups based on specific blood markers, and results show that those with a better LIPI score have significantly longer overall and progression-free survival.
  • The findings indicate that LIPI can be a useful prognostic tool for mRCC patients regardless of the type of treatment they receive, whether it’s immune checkpoint inhibitors or antiangiogenic therapy.
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Background: Adjuvant pembrolizumab therapy after surgery for renal-cell carcinoma was approved on the basis of a significant improvement in disease-free survival in the KEYNOTE-564 trial. Whether the results regarding overall survival from the third prespecified interim analysis of the trial would also favor pembrolizumab was uncertain.

Methods: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 1:1 ratio) participants with clear-cell renal-cell carcinoma who had an increased risk of recurrence after surgery to receive pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks for up to 17 cycles (approximately 1 year) or until recurrence, the occurrence of unacceptable toxic effects, or withdrawal of consent.

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Background: As part of a partitioned survival analysis, treatment-free survival (TFS) can characterize the overall survival time patients spend between the cessation of immunotherapy and the start of subsequent therapy; both with and without toxicity. Significant TFS was reported for the nivolumab/ipilimumab arms of the CheckMate 067 and 214 trials for patients with advanced melanoma or renal cell carcinoma (aRCC), respectively, where immunotherapy was often halted for toxicity rather than a predefined treatment endpoint. We therefore sought to assess TFS in the HCRN GU16-260 trial, which was designed to reduce toxicity and cap immunotherapy duration.

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  • The study aimed to assess treatment-free survival (TFS) in patients with advanced renal cell carcinoma (aRCC) undergoing immune-oncology (IO) and VEGF tyrosine kinase inhibitor (TKI) combination therapies compared to TKI alone.
  • The analysis pooled data from three randomized trials involving over 2,300 patients, evaluating outcomes like overall survival (OS), TFS with and without toxicity across a 30-month period.
  • Results indicated that both treatment groups experienced similar TFS durations, with slightly different rates of being free from severe toxicity, suggesting the treatment protocols influenced the observed outcomes.
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Background: Tivozanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) with efficacy in advanced renal cell carcinoma (RCC). Long-term exploratory analyses from the TIVO-3 trial in relapsed/refractory (R/R) RCC including patients (26%) with prior immuno-oncology (IO) therapy are reported.

Methods: Patients with R/R advanced RCC that progressed with 2 or 3 prior systemic therapies (≥1 VEGFR TKI) were randomized to tivozanib 1.

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Purpose: Programmed cell death protein 1 (PD-1) expression on CD8+TIM-3-LAG-3- tumor-infiltrating cells predicts positive response to PD-1 blockade in metastatic clear-cell renal cell carcinoma (mccRCC). Because inhibition of PD-1 signaling in regulatory T cells (Treg) augments their immunosuppressive function, we hypothesized that PD-1 expression on tumor-infiltrating Tregs would predict resistance to PD-1 inhibitors.

Experimental Design: PD-1+ Tregs were phenotyped using multiparametric immunofluorescence in ccRCC tissues from the CheckMate-025 trial (nivolumab: n = 91; everolimus: n = 90).

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Background: Accumulation of the HIF-2α transcription factor is an oncogenic event implicated in the tumorigenesis of clear cell renal cell carcinoma (ccRCC). In the phase I LITESPARK-001 study, the first-in-class HIF-2α inhibitor belzutifan demonstrated antitumor activity and an acceptable safety profile for pretreated patients with advanced ccRCC. Updated data with additional follow-up of > 40 months are presented.

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  • The OPTIMIzE registry study examined the effectiveness of immuno-oncology therapies in advanced melanoma by comparing outcomes of patients treated with anti-PD-1 monotherapy and a combination of nivolumab and ipilimumab.
  • Patients receiving the combination therapy had a non-significantly lower risk of death and a higher disease control rate compared to those on monotherapy but experienced more severe side effects.
  • Overall, the findings suggest that immuno-oncology treatments can be beneficial for patients with advanced melanoma, balancing effectiveness with potential adverse effects.
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  • HHLA2 is an immune checkpoint associated with kidney cancer and other tumors, and understanding its expression regulation is key for developing targeted therapies.
  • HHLA2 expression is found in primary kidney tumors but decreases in vitro, while it can be induced in vivo under specific tumor microenvironment conditions.
  • Only certain cytokines like IL-10 and BMP4 can modestly enhance HHLA2 expression in immune cells, indicating complex regulation involving tumor and immune cell interactions.
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Introduction: Sarcomatoid renal cancer (sRCC) patients have poor outcomes. EA1808 evaluated sunitinib and gemcitabine (SG) and sunitinib alone (S) in sRCC in a randomized cooperative group phase II trial (NCT01164228).

Patients And Methods: Pts were aggregated 1:1 to SG (45 pts) or S (40 pts) using a 2-stage design.

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Renal cell carcinoma (RCC) of variant histology comprises approximately 20% of kidney cancer diagnoses, yet the optimal therapy for these patients and the factors that impact immunotherapy response remain largely unknown. To better understand the determinants of immunotherapy response in this population, we characterized blood- and tissue-based immune markers for patients with variant histology RCC, or any RCC histology with sarcomatoid differentiation, enrolled in a phase II clinical trial of atezolizumab and bevacizumab. Baseline circulating (plasma) inflammatory cytokines were highly correlated with one another, forming an "inflammatory module" that was increased in International Metastatic RCC Database Consortium poor-risk patients and was associated with worse progression-free survival (PFS; P = 0.

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Background: Few treatment options are available for patients with advanced renal cell carcinoma who have received previous anti-PD-1-based or anti-PD-L1-based immunotherapy. Combining belzutifan, an HIF-2α inhibitor, with cabozantinib, a multitargeted tyrosine-kinase inhibitor of VEGFR, c-MET, and AXL, might provide more antitumoural effects than either agent alone. We aimed to investigate the antitumour activity and safety of belzutifan plus cabozantinib in patients with advanced clear cell renal cell carcinoma that was previously treated with immunotherapy.

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Background: To determine the efficacy and toxicity of nivolumab monotherapy in treatment-naïve patients with non-clear cell renal cell carcinoma (nccRCC) and the efficacy of nivolumab/ipilimumab salvage therapy in patients with tumors unresponsive to initial nivolumab monotherapy.

Methods: Eligible patients with treatment-naïve nccRCC received nivolumab until progressive disease (PD), toxicity, or completion of 96 weeks of treatment (Part A). Patients with PD prior to, or stable disease (SD) at 48 weeks (prolonged SD) were potentially eligible to receive salvage nivolumab/ipilimumab (Part B).

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  • High-dose interleukin-2 (HD IL-2) and pembrolizumab are FDA-approved treatments for metastatic melanoma, and this study aims to evaluate their combined safety.
  • In a Phase Ib trial, 10 patients received differing doses of IL-2 alongside pembrolizumab to determine the maximum tolerated dose (MTD).
  • Results showed that adverse events increased with higher IL-2 doses, but no serious toxicities were found, and one patient experienced a partial response, suggesting the combination is manageable and warrants further exploration.
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Purpose: Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued.

Patients And Methods: Patients with advanced melanoma (N = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation.

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  • Immune checkpoint inhibitors (ICIs) like atezolizumab are effective cancer treatments, but many patients still face therapeutic resistance.
  • High levels of interleukin 6 (IL-6) correlate with a poor response to atezolizumab in advanced cancers, indicating a potential target for overcoming resistance.
  • Combining PD-L1 blockade with IL-6 receptor inhibition shows promising results in preclinical studies by enhancing the effectiveness of anti-tumor immune responses, suggesting IL-6 signaling inhibitors could improve ICI therapies in cancer patients.
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Background: In phase III TIVO-3 trial, tivozanib improved progression-free survival (PFS) compared to sorafenib for patients with metastatic renal cell carcinoma (mRCC). However, the effectiveness of this drug after exposure to other selective VEGFR agents has not yet been defined. Herein, we characterize the clinical efficacy of tivozanib in patients with mRCC previously treated with axitinib.

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