Circulating Tumor DNA as a Predictive Biomarker for Clinical Outcomes With Margetuximab and Pembrolizumab in Pretreated HER2-Positive Gastric/ Gastroesophageal Adenocarcinoma.

PURPOSE: To assess the ability of circulating tumor DNA (ctDNA)-based testing to identify patients with HER2 (encoded by ERBB2)-positive gastric/gastroesophageal adenocarcinoma (GEA) who progressed on or after trastuzumab-containing treatments were treated with combination therapy of anti-HER2 and anti-PD-1 agents. METHODS: ctDNA analysis was performed retrospectively using plasma samples collected at study entry from 86 patients participating in the phase 1/2 CP-MGAH22-05 study (NCT02689284). RESULTS: Objective response rate (ORR) was significantly higher in evaluable ERBB2 amplification-positive vs - negative patients based on ctDNA analysis at study entry (37% vs 6%, respectively; P = .00094). ORR was 23% across all patients who were evaluable for response. ERBB2 amplification was detected at study entry in 57% of patients (all HER2 positive at diagnosis), and detection was higher (88%) when HER2 status was determined by immunohistochemistry fewer than 6 months before study entry. ctDNA was detected in 98% (84/86) of patients tested at study entry. Codetected ERBB2-activating mutations were not associated with response. CONCLUSIONS: Current ERBB2 status may be more effective than archival status at predicting clinical benefit from margetuximab plus pembrolizumab therapy. ctDNA testing for ERBB2 status prior to treatment will spare patients from repeat tissue biopsies, which may be reserved for reflex testing when ctDNA is not detected.

Clinical best practices in optimal monitoring, early diagnosis, and effective management of antibody-drug conjugate-induced interstitial lung disease or pneumonitis: a multidisciplinary team approach in Singapore.

INTRODUCTION: Interstitial lung disease (ILD) or pneumonitis remains an important adverse event identified with treatment with antibody-drug conjugates (ADCs). Drug-induced ILD (DILD) accounts for 3%-5% of common ILD cases and is a significant problem in clinical practice. Hence, with the anticipation of the widespread use of ADCs, it will be important for guidelines and recommendations to be established to direct and standardize the management of DILD by a multidisciplinary team (MDT). AREAS COVERED: A thorough literature search was conducted using PubMed to identify relevant articles related to ADCs published between 1 January 2010 and 31 November 2022. Based on the review of the literature combined with expert opinions, this review article offers an overview of incidences of ILDs associated with the use of newer anticancer therapies, specifically ADCs, and discusses local-regional best practices in optimal monitoring, early diagnosis, and management of DILD involving an MDT. EXPERT OPINION: Multidisciplinary input and consensus are crucial in the accurate diagnosis of DILD. The core group of essential attendees in the MDT are oncologists, pulmonologists, thoracic radiologists, and pathologists. This allows for the integration of expertise from different specialists to achieve a 'best fit' diagnosis and management.

Overcoming the impact of the COVID-19 pandemic on oncology early phase trials and drug development in Asia-Experiences and perspectives of the Asian Oncology Early Phase 1 Consortium.

AIM: The significance and prioritization of early phase oncology trial continuation during a global pandemic is unknown. This study reported the outcomes, multiple challenges, and broad recommendations associated with the impact of the novel coronavirus disease 2019 (COVID-19) on oncology early phase 1 trials-and on drug development in Asia-based on the experiences and perspectives of Asian oncology phase 1 centers. METHODS: Between March and April 2020 during the initial period of outbreak, the impact of COVID-19 across oncology phase 1 sites in five Asian countries-China (Hong Kong), Japan, South Korea, Taiwan, and Singapore-was retrospectively analyzed. RESULTS: There was no trial termination or treatment discontinuation in all five countries. Although the most common impact was new patient enrollment being placed on hold, which was based on pharmaceutical sponsors' decision-making, the situation varied per site. Most sites had no restrictions in place that would limit their ability to fully comply with the requirements of conducting the early phase studies. The number of protocol deviations during the pandemic was largely dependent on domestic transportation status during the outbreak rather than the ability of the clinical trial centers. CONCLUSION: Determining the risk to benefits ratio of patients with cancer who are enrolled in early phase 1 clinical trials under the unusual circumstances of a global pandemic is important. Specific guidance or guidelines on the conduct of early phase 1 clinical trials during public health emergencies that are based on the recent lessons learned is urgently required.

Chemoradiation-induced changes in systemic inflammatory markers and their prognostic significance in oesophageal squamous cell carcinoma.

OBJECTIVE: Chemoradiation (CRT) may induce a change in systemic inflammatory state which could affect clinical outcomes in oesophageal cancer. We aimed to evaluate the changes and prognostic significance of systemic inflammatory markers following definitive CRT in oesophageal squamous cell carcinoma. METHODS: A total of 53 patients treated with concurrent CRT were included in this retrospective analysis. We compared neutrophils, lymphocytes, platelets, neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) before and after CRT using Wilcoxon signed-rank test. Overall survival (OS) and progression-free survival (PFS) were calculated. Univariable and multivariable survival analysis were performed using Cox regression analysis. Clinical univariable survival prognostic factors with p < 0.1 were included in a multivariable cox regression analysis for backward stepwise model selection. RESULTS: Both NLR (median ∆+2.8 [IQR -0.11, 8.62], p < 001) and PLR (median ∆+227 [81.3-523.5], p < 0.001) increased significantly after CRT. Higher levels of pre-CRT, post-CRT and change (∆) in NLR and PLR were associated with inferior OS and PFS. Post-CRT NLR (HR 1.04, 95% CI 1.02-1.07, p < 0.001), post-CRT platelets (HR 1.03, 95% CI 1.01-1.05, p = 0.005), cT-stage (HR 3.83, 95% CI 1.39-10.60, p = 0.01) and RT dose (HR 0.41, 95% CI 0.21-0.81, p = 0.01) were independent prognostic factors for OS in multivariable analysis. Change in NLR (HR 1.04, 95% CI 1.01-1.06, p = 0.001), post-CRT platelets (HR 1.03, 95% CI 1.01-1.05, p = 0.002), cT-stage (HR 3.98, 95% CI 1.55-10.25, p = 0.004) and RT dose (HR 0.41, 95% CI 0.21-0.80, p = 0.009) were independent prognostic factors for PFS. CONCLUSION: Both NLR and PLR increased following definitive CRT. Post-CRT NLR and ∆NLR were associated with adverse survival in oesophageal SCC. ADVANCES IN KNOWLEDGE: We showed that CRT increased PLR and NLR, possibly reflecting a systemic inflammatory state which were associated with poor clinical outcomes in oesophageal SCC.