Xaluritamig (AMG 509) is a six-transmembrane epithelial antigen of the prostate 1 (STEAP1)–targeted T-cell engager designed to facilitate lysis of STEAP1-expressing cancer cells, such as those in advanced prostate cancer. This first-in-human study reports monotherapy dose exploration for patients with metastatic castration-resistant prostate cancer (mCRPC), primarily taxane pretreated. Ninety-seven patients received ≥1 intravenous dose ranging from 0.001 to 2.0 mg weekly or every 2 weeks. MTD was identified as 1.5 mg i.v. weekly via a 3-step dose. The most common treatment-related adverse events were cytokine release syndrome (CRS; 72%), fatigue (45%), and myalgia (34%). CRS occurred primarily during cycle 1 and improved with premedication and step dosing. Prostate-specific antigen (PSA) and RECIST responses across cohorts were encouraging [49% PSA50; 24% objective response rate (ORR)], with greater frequency at target doses ≥0.75 mg (59% PSA50; 41% ORR). Xaluritamig is a novel immunotherapy for prostate cancer that has shown encouraging results supporting further development.Significance: Xaluritamig demonstrated encouraging responses (PSA and RECIST) compared with historical established treatments for patients with late-line mCRPC. This study provides proof of concept for T-cell engagers as a potential treatment for prostate cancer, validates STEAP1 as a target, and supports further clinical investigation of xaluritamig in prostate cancer.See related commentary by Hage Chehade et al., p. 20.See related article by Nolan-Stevaux et al., p. 90.This article is featured in Selected Articles from This Issue, p. 5

Considering the high morbidity and mortality of Coronavirus disease 2019 (COVID-19) in patients with malignancy, they are regarded as a priority for COVID-19 vaccination. However, general vaccine uptake rates among cancer patients are known to be lower than in their healthy counterparts. Thus, we aimed to investigate the attitude and acceptance rates for the COVID-19 vaccine in cancer patients and identify predictive factors for vaccination that could be modified to increase vaccine uptake rates, via a paper-based survey (58 items over six domains). A total of 1001 cancer patients participated in this nationwide, multicenter survey between February and April 2021. We observed that 61.8% of respondents were willing to receive the COVID-19 vaccine. Positive predictive factors found to be independently associated with vaccination were male gender, older age, obesity, previous influenza vaccination history, absence of cancer recurrence, time since cancer diagnosis over 5 years, and higher EuroQol Visual Analogue Scale scores. Along with the well-known factors that are positively correlated with vaccination, here, we report that patients’ disease status and current health status were also associated with their acceptance of the COVID-19 vaccination. Moreover, 91.2% of cancer patients were willing to be vaccinated if their attending physicians recommend it, indicating that almost 30% could change their decision upon physicians’ recommendation. Unlike other factors, which are unmodifiable, physicians’ recommendation is the single modifiable factor that could change patients’ behavior. In conclusion, we firstly report that Korean cancer patients’ acceptance rate of the COVID-19 vaccination was 61.8% and associated with disease status and current health status. Physicians should play a major role in aiding cancer patients’ decision-making concerning COVID-19 vaccines.

Background: Immune checkpoint inhibitors (ICIs) have shown significant improvements in patients with advanced non–small cell lung cancer (NSCLC). One of the major issues with ICIs is determining the optimal treatment duration.Methods: This multicenter, retrospective study analyzed clinical outcomes in patients with NSCLC who completed 2 years of ICI therapy or were treated for more than 6 months and then discontinued ICIs without disease progression at 11 medical centers in Korea between August 2017 and December 2020.Results: Ninety‐six patients who completed 2 years of ICIs were reviewed. The median durations of treatment and follow‐up were 24.0 and 33.9 months, respectively. The objective response rate (ORR) was 85.4%. The median progression‐free survival (PFS) and overall survival (OS) periods were not reached. After completion, the PFS and OS rates were 81.1% and 96.4%, respectively, at 12 months. Forty‐three patients were identified who discontinued ICIs without disease progression: 26 (60.5%) for adverse events and 17 (39.5%) for other causes. The median durations of treatment and follow‐up were 10.5 and 21.2 months, respectively. The ORR was 90.7%. The median PFS and OS periods were not reached. After discontinuation, the PFS and OS rates were 71.0% and 90.0%, respectively, at 12 months.Conclusions: A significantly high proportion of patients who completed 2 years of ICI therapy continued to experience long‐term PFS. Even if ICIs are discontinued after 6 months in patients without disease progression, they may achieve a durable response and facilitate long‐term survival.Lay Summary: The optimal treatment duration for immune checkpoint inhibitors (ICIs) remains to be determined. This study reports the long‐term outcomes of patients with non–small cell lung cancer who completed 2 years of ICI therapy or achieved a durable response after the discontinuation of ICIs without disease progression in real‐world practice. A significantly high proportion of patients who completed 2 years of ICIs continued to experience long‐term progression‐free survival. In addition, even if ICIs are discontinued after 6 months in patients without disease progression, they may achieve a durable response and facilitate long‐term survival.

Objective: While immune checkpoint inhibitors are increasingly used for various cancers, unpredictable immune‐related adverse events (irAEs) such as autoimmune encephalitis is life‐threatening. Here, we report an association between human leukocyte antigen (HLA) and atezolizumab‐induced encephalitis.Methods: From an institutional prospective cohort for encephalitis, we identified patients with autoimmune encephalitis after the use of atezolizumab, a PD‐L1 (programmed death‐ligand 1) inhibitor, from August 2016 to September 2019 and analyzed their HLA genotypes.Results: A total of 290 patients received atezolizumab, and seven patients developed autoimmune encephalitis, and five of whom were enrolled for the analysis. The patients presented altered mentality, seizures, or myelitis. Three patients had the HLA‐B*27:05 genotype in common (60%), which is significantly frequent given its low frequency in the general population (2.5%). After Bonferroni correction, HLA‐B*27:05 was significantly associated with autoimmune encephalitis by atezolizumab (corrected P < 0.001, odds ratio 59, 95% CI = 9.0 ~ 386.9).Interpretation: Here we found that three in five patients with autoimmune encephalitis associated with atezolizumab had the rare HLA‐B*27:05 genotype. Further systematic analyses in larger cohorts are necessary to investigate the value of HLA screening to prevent the life‐threatening adverse events.

Purpose: Histologic transformation from EGFR-mutant non–small cell lung cancer (NSCLC) to small-cell lung cancer (SCLC) is a key mechanism of resistance to EGFR tyrosine kinase inhibitors (TKI). However, transcriptomic changes between NSCLC and transformed SCLC (t-SCLC) remain unexplored. Experimental Design: We conducted whole-transcriptome analysis of 59 regions of interest through the spatial profiling of formalin-fixed, paraffin-embedded tissues obtained from 10 patients (lung adenocarcinoma, 22; combined SCLC/NSCLC, 7; and t-SCLC, 30 regions of interests). Transcriptomic profiles and differentially expressed genes were compared between pre- and post-transformed tumors. Results: Following EGFR-TKI treatment, 93.7% (15/16) of t-SCLC components evolved into neuroendocrine-high subtypes (SCLC-A or SCLC-N). The transition to t-SCLC occurred regardless of EGFR-TKI treatment and EGFR mutational status, with a notable decrease in EGFR expression (P < 0.001) at both mRNA and protein levels. Pathway analysis revealed that gene overexpression was related to epigenetic alterations in t-SCLC. Interestingly, histone deacetylase inhibitors restored EGFR expression in SNU-2962A cells and their organoid model. The synergistic effects of third-generation EGFR-TKI osimertinib and the histone deacetylase inhibitor fimepinostat were validated in both in vitro and in vivo models. Conclusions: Our study demonstrated that most t-SCLC cases showed neuronal subtypes with low EGFR expression. Differentially expressed gene analysis and t-SCLC preclinical models identified an epigenetic modifier as a promising treatment strategy for t-SCLC.

Objective: The purpose of this study was to evaluate the prognostic impact of body composition parameters based on computed tomography (CT) in patients with non-small cell lung cancer (NSCLC) who received ICI treatment. Methods: This retrospective study analyzed the data from advanced NSCLC patients treated with ICI therapy between 2013 and 2019. We included patients with NSCLC who underwent baseline CT scans. The exclusion criteria included patients who received three or more lines of chemotherapy, those with insufficient clinical information, or those without treatment response evaluation. Results: A total of 136 patients were enrolled. Among the volumetric body composition parameters, patients in the highest quartiles (Q2–4) of the visceral fat index (VFI) exhibited a higher response rate to ICI therapy than those in the lowest quartile (Q1) of VFI (Q1 vs. Q2–4: 18.2% vs. 43.1%, p = 0.012). Patients with a VFI in Q2–4 had significantly prolonged progression-free survival (PFS) and overall survival (OS) (PFS, Q1 vs. Q2–4: 3.0 months vs. 6.4 months, p = 0.043; OS, Q1 vs. Q2–4: 5.6 months vs. 16.3 months, p = 0.004). Kaplan–Meier analysis based on the VFI and visceral fat Hounsfield unit (HU) revealed that patients with VFI in Q1 and HU in Q2–4 had the worst prognosis. Conclusions: Visceral fat volume is significantly associated with treatment outcomes in ICI-treated patients with NSCLC. Moreover, fat quality may impact the treatment outcomes. This finding underscores the potential significance of both fat compartments and fat quality as prognostic indicators. Critical relevance statement: Visceral fat volume is significantly associated with treatment outcomes in ICI-treated patients with non-small cell lung cancer. Moreover, fat quality may impact the treatment outcomes. This finding underscores the potential significance of both fat compartments and fat quality as prognostic indicators. Graphical Key points: • We found that visceral fat volume positively correlated with treatment response and survival in patients with non-small cell lung cancer receiving immune checkpoint inhibitors. • Additionally, a trend toward a negative correlation between visceral fat attenuation and survival was observed. • The findings highlight the prognostic utility of fat compartments and fat quality.