Dragnev, Konstantin H.

Abstract Background Reference sets are needed to evaluate performance of multi-cancer detection (MCD) assays. The National Cancer Institute funded the Alliance reference set study to assess MCDs for use in future trials. Methods Individuals with cancer and controls were recruited; blood specimens were collected prior to cancer treatment. A performance evaluation study was designed utilizing reference set samples. Companies (n = 6) were selected to participate based on review of performance data and ability to utilize the blood collection tube. Companies received samples from cancer types their assay was designed to detect (“targeted”), plus additional “non-targeted” and control samples. Companies reported positive/negative calls, risk scores, and tissue-of-origin (TOO) predictions. Sensitivity was computed for early (I-II) and late (III-IV) stage cases, based on positive/negative calls (SEPN) and at fixed 98% specificity (SE98). Specificity and TOO accuracy were computed. Results Five hundred and forty nine cases (encompassing 13 cancer types) and 413 controls from the reference set were included in the study. Companies assessed samples from median 6 (range 5-9) targeted cancer types and median 8 (range: 7-11) overall cancer types. Median (range) specificity was 92.3% (76.5%-98.5%). Median (range) SEPN was 32% (25%-42%) for early stage and 73% (48%-89%) for late stage; while median (range) SE98 was 19% (8%-35%) for early stage and 66% (13%-79%) for late stage. Median sensitivity for non-targeted types was 40% (early stage) and 52% (late stage). Median (range) TOO accuracy (primary predicted site) was 75% (64%-78%). Conclusions Sensitivity and specificity varied widely across assays with early-stage sensitivity substantially lower than late-stage sensitivity. Clinical Trial Registration Number ClinicalTrials.gov identifier NCT05334069.

Background Our study was designed to determine the safety, efficacy, and immunological effects of perioperative pembrolizumab in early-stage NSCLC. Methods This is a single-arm phase II study of perioperative pembrolizumab in patients with untreated, clinical stage IB to IIIA NSCLC. Patients received two doses of 200 mg pembrolizumab, surgery, standard adjuvant chemotherapy, followed by four doses adjuvant pembrolizumab. The primary objective of this study was to determine surgical feasibility rate, and secondary objectives are pathological response rate, treatment adverse events, efficacy data, and exploratory analysis of biomarkers. Results 30 patients initiated perioperative pembrolizumab, and 25 completed tumor resection. At median follow-up of 59 months after surgical resection, seven patients had disease progression, while six had died representing. A 5-year progression-free survival (PFS) from time of surgery was 72.0% (56.4%–91.9%) and overall survival (OS) from time of surgery was 75.8% (60.7%–94.7%). Major pathological response (MPR) was found in seven tumors (28%) including two complete responses (4%). Across all treated patients, four receiving neoadjuvant and four receiving adjuvant pembrolizumab experienced treatment-related adverse events of grade 3 or higher with no grade 5 events. Plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels increased across our patient cohort over time from baseline until postsurgery and remained elevated at the end of treatment. There was a significant difference between mean plasma PCSK9 levels for patients with MPR versus all other patients on study when checked postoperatively. Conclusions Perioperative pembrolizumab was safe and effective with promising MPR rate, PFS, and OS.