Karen L. Reckamp

Background: Cancer-associated cachexia is a multifactorial metabolic syndrome characterized by progressive skeletal muscle and/or adipose tissue loss and affects approximately 40% of patients with non-small cell lung cancer (NSCLC). However, reliable circulating biomarkers for early detection and risk stratification remain undefined. Based on prior observations linking elevated circulating mitochondrial DNA (mtDNA) to cachexia, we hypothesized that mtDNA and inflammatory protein levels in plasma could predict cachexia onset and trajectories. Methods: We evaluated 27 patients with stage IV NSCLC enrolled in the SeroNet-CORALE cohort with plasma samples collected between 2020 and 2023. Forty biomarkers were quantified at two timepoints (T1 and T2) using a multiplexed MesoScale Discovery platform. Associations between log2-transformed biomarker levels and cachexia status were assessed using Firth’s penalized logistic regression. Results: Among 27 patients (65% female; mean age 65 ± 10 years; 89% adenocarcinoma histology), cachectic patients exhibited lower body mass index at both time points (T1: 21.0 ± 2.0 vs. 27.0 ± 7.0; T2: 21.8 ± 4.9 vs. 25.2 ± 4.9). At T1, cachexia was strongly associated with elevated GDF15 (OR 4.29; 95% CI 1.04–29.74; p = 0.044) and IL-15 (OR 43.83; 95% CI 2.39–>999; p = 0.007), whereas IL-4 had a protective association (OR 0.09; 95% CI 0.00–0.66; p = 0.013). At T2, cachexia was associated with higher mtDNA levels (OR 2.13; 95% CI 1.07–7.69; p = 0.022) and lower levels of IL-15, IL12/IL23p40, and MDC. Conclusions: Distinct inflammatory and mitochondrial biomarkers tracked cachexia evolution in advanced NSCLC, with early GDF-15/IL-15 elevations and later increases in circulating mtDNA. Larger longitudinal studies are warranted to validate these findings and define their clinical relevance.

PURPOSE: A cancer service line (CSL) in academic medical centers provides a patient-centered approach aimed at enhancing the patient experience and clinical outcomes, managing financial operations, increasing access to clinical research, and reducing health disparities. In 2023, the Association of American Cancer Institutes (AACI) Physician Clinical Leadership Initiative (PCLI) Steering Committee conducted a survey to evaluate the current state of CSLs with respect to governance, leadership, organizational, and financial structure and function. METHODS: The survey was electronically sent to cancer center directors and administrative directors at 107 of AACI's 108-member cancer centers, achieving a response rate of 70%. Survey participation was voluntary, and no compensation was provided. RESULTS: Fifty-eight (77%) of the 75 survey respondents (which included 40 National Cancer Institute–designated cancer centers) had a defined CSL with only 35 (60%) using a formal charter. All CSL leadership teams included physician leaders, and 44 (76%) centers included their cancer center director within this leadership. More than 28 key services were identified as parts of the CSL structures. Most respondents reported that strategic planning (88%), quality and safety (83%), and regional alignment (78%) were key responsibilities. Twenty-six (45%) centers reported a policy defining a funds flow from the health system to the cancer center. Performance assessment for the CSLs included metrics related to growth and finance, access and services, quality and outcomes, and academics. CONCLUSION: These results demonstrate the diverse nature of CSLs across academic medical systems within the United States. Furthermore, given the complexity faced by academic cancer centers in establishing and expanding their CSLs, AACI remains committed to working closely with its members to identify best practices focused on innovative and value-based cancer care.

PURPOSE: Neuregulin-1 ( NRG1 ) fusions are rare but actionable oncogenic drivers in solid tumors. Seribantumab is a fully human anti-HER3 IgG2 monoclonal antibody. In this report, we present the antitumor activity and safety data of seribantumab from the CRESTONE study (ClinicalTrials.gov identifier: NCT04383210 ). PATIENTS AND METHODS: This was a prospective phase II clinical study in which patients with advanced solid tumors harboring an NRG1 fusion received seribantumab at a dose of 3,000 mg intravenously once weekly. The primary end point was objective response rate (ORR) by RECIST v1.1. Secondary end points included safety, duration of response, progression-free survival (PFS), overall survival (OS), and disease control rate (DCR). The study was terminated before full enrollment because of sponsor decision, unrelated to safety or efficacy. RESULTS: A total of 54 patients with nine different tumor types featuring 19 different NRG1 fusion partners were enrolled. For the 29 patients included in the primary efficacy analysis, the investigator-assessed ORR was 34.5% (95% CI, 17.9 to 54.3), with a DCR of 79% (95% CI, 60 to 92). The median PFS was 5.4 (95% CI, 3.9 to 10.8) months; the median OS was 20.3 (95% CI, 10.2 to not reached) months. In patients with non–small cell lung cancer, eight of 22 achieved response (ORR, 36.4%). Adverse events (AEs) were mostly grade 1 or 2. The most common treatment-related AEs were diarrhea (39%), fatigue (32%), and nausea (22%). CONCLUSION: These results support the antitumor activity and safety of seribantumab in patients with advanced solid tumors harboring NRG1 fusions.

Purpose: ctDNA is a powerful diagnostic companion to tissue profiling. Tumor fraction (TF) is a global assessment of an individual’s ctDNA burden. We evaluated the impact of plasma TF on mutation detection and clinical outcomes in patients with previously treated, advanced non–small cell lung cancer on the Lung Master Protocol (Lung-MAP). Experimental Design: Paired tumor tissue and plasma were collected prospectively from patients on the Lung-MAP study. Plasma was collected within 30 days of a new biopsy with no intervening therapies. Tissue and ctDNA genomic profiling and ctDNA TF levels were assessed by Foundation Medicine. TF was primarily calculated from tumor aneuploidy, defaulting to fragmentomics and maximum somatic allele frequencies when aneuploidy was not detectable. The effect of TF on tissue–plasma mutation concordance, overall survival, and its relation to variant allele frequencies was assessed using linear regression, Lin's coefficient, and Cox modeling/log-rank testing. Results: A total of 194 patients were eligible for analysis. TF ≥1% was significantly associated with improved positive percent agreement between ctDNA and tissue across multiple alteration types with the exception of copy-number gains. For short variants, positive percent agreement improved from 51% when TF <1% to 95% when TF ≥1%. TF showed a significant robust correlation with variant allele frequency for KRAS, STK11, and TP53—the three most common mutations. TF <1% was significantly associated with improved patient overall survival compared with TF ≥1% or TF ≥10%. Conclusions: TF provides an accurate, clinically useful assessment of ctDNA plasma levels from patients with refractory, advanced non–small cell lung cancer. TF levels ≥1% are associated with significantly worse overall survival but improved mutation detection in liquid biopsies.

Epidermal growth factor receptor (EGFR) mutations represent targetable alterations in non-small cell lung cancer (NSCLC). The treatment landscape in the frontline setting for patients with advanced EGFR-mutated NSCLC is evolving with increasing treatment options. EGFR tyrosine kinase inhibitors (TKIs) have significantly improved outcomes, but resistance inevitably develops, necessitating alternative strategies. Patritumab deruxtecan is a novel antibody-drug conjugate targeted human epidermal growth factor receptor-3 (HER3), delivering a topoisomerase-I inhibitor payload to HER3-expressing cancer cells. Phase I and II studies have demonstrated efficacy in patients with EGFR-mutant NSCLC with disease progression after prior therapies, including third-generation EGFR TKIs and platinum-based chemotherapy. The phase-II trial reported an objective response rate of 39% and a median progression-free survival of 5.5 months. Patritumab deruxtecan is associated with notable toxicities, including grade 3 and higher hematologic adverse events, gastrointestinal toxicity, and interstitial lung disease (ILD). ILD occurred in 5.3% of patients in the Phase-II study. Early detection and management are crucial to minimizing the risk of complications. Patients with advanced EGFR-mutant NSCLC who have received TKI therapy and chemotherapy have limited treatment options. Patritumab deruxtecan demonstrates clinical activity in this population with manageable side effects, addressing an unmet need for patients.