Pathology Review Research Articles

Analysis of different color unmixing methods for cMET-PDL1-EGFR multiplex assay.

e21080 Background: Multiplex brightfield imaging offers the advantage of simultaneously analyzing multiple biomarkers on a single slide, as opposed to single biomarker labeling on multiple consecutive slides. To accurately analyze multiple biomarkers localized to the same cellular compartment, a set of common lung panel markers were selected as a model, cMET-PDL1-EGFR. One of the most crucial preliminary stages for analyzing this assay is identifying the unique chromogens on individual cells. This is a challenging problem due to the co-localization of membranes from all the three biomarkers. It requires advanced color unmixing for creating equivalent singleplex images (referred as synthetic singleplexes) from each triplex image for each biomarker. Methods: We explored different unsupervised methods for unmixing cMET-PDL1-EGFR images. Initially we explored an unsupervised method based on Lee et al. [1], which formulated the color unmixing problem as a non-negative matrix factorization (NMF) method and proposed a system capable of performing the color decomposition in a fully automated manner, where no reference stain color selection is required. Next, we developed cycle-Generative Adversarial (cycle-GAN) [2] models, for each of the three stains – TAMRA (purple), QM-Dabsyl (yellow) and Green. The models were trained on 6 cases of lung having different intensities of the stains. Results: The NMF and cycle-GAN method was validated on 5400 lung images. On analysis of the results and on review with pathologists, we observed that NMF was able to produce reasonable results on synthetic PDL1 and EGFR, but the synthetic Green images did not replicate the adjacent Green images properly. On the other hand, cycle-GAN was able to generate similar synthetic images for all three stains as demonstrated by the similarity metrics in Table 1. Pathologist review of the cycle-GAN results determined that the difference in percentage scores between pairs of adjacent and synthetic singleplex images would be within the range 2%-5% only. Conclusions: In this project, we performed detailed analysis of two unsupervised methods for color unmixing on triplex images. On comparison of the methods based on image similarity measures and pathologist review, we conclude that the cycle-GAN method is competent in generating synthetic images.

Identification of the Optimal Candidates for Nodal Staging with Extended Pelvic Lymph Node Dissection Among Prostate Cancer Patients Who Underwent Preoperative Prostate-specific Membrane Antigen Positron Emission Tomography. External Validation of the Memorial Sloan Kettering Cancer Center and Briganti Nomograms and Development of a Novel Tool

BackgroundAlthough the therapeutic role of extended pelvic lymph node dissection (ePLND) in patients with prostate cancer (PCa) is still under debate, this procedure is recommended for staging purposes in selected cases. Nomograms for predicting lymph node invasion (LNI) do not account for prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging, which is characterized by a high negative predictive value for nodal metastases. ObjectiveTo externally validate models predicting LNI in patients with miN0M0 PCa at PSMA PET and to develop a novel tool in this setting. Design, setting, and participantsOverall, 458 patients with miN0M0 disease undergoing radical prostatectomy (RP) and ePLND at 12 centers between 2017 and 2022 were identified. Outcome measurements and statistical analysesAvailable tools were externally validated using calibration plots, the area under the receiver operating characteristic curve (AUC), and decision curve analyses to assess calibration, discrimination, and the net benefit. A novel coefficient-based model was developed, internally validated, and compared with available tools. Results and limitationsOverall, 53 patients (12%) had LNI. The AUC was 69% for the Briganti 2012, 64% for the Briganti 2017, 73% for the Briganti 2019, and 66% for the Memorial Sloan Kettering Cancer Center nomogram. Multiparametric magnetic resonance imaging stage, biopsy grade group 5, the diameter of the index lesion, and the percentage of positive cores at systematic biopsy were independent predictors of LNI (all p ≤ 0.04). Internal cross-validation confirmed a coefficient-based model with AUC of 78%, better calibration, and a higher net benefit in comparison to the other nomograms assessed. Use of a 5% cutoff would have spared 47% ePLND procedures (vs 13% for the Briganti 2019 nomogram) at the cost of missing only 2.1% LNI cases . The lack of central review of imaging and pathology represents the main limitation. ConclusionsTools for predicting LNI are associated with suboptimal performance for men with miN0M0 PCa. We propose a novel model for predicting LNI that outperforms available tools in this population. Patient summaryTools currently used to predict lymph node invasion (LNI) in prostate cancer are not optimal for men with negative node findings on PET (positron emission tomography) scans, leading to a high number of unnecessary extended pelvic lymph node dissection (ePLND) procedures. A novel tool should be used in clinical practice to identify candidates for ePLND to reduce the risk of unnecessary procedures without missing LNI cases.

Treatment of focal anaplastic Wilms tumor (FAWT): A report from the Children’s Oncology Group (COG) AREN0321 and AREN03B2 studies.

10005 Background: FAWT represents tumors with circumscribed small areas of anaplastic nuclear changes confined to the kidney within an otherwise favorable histology WT. In National Wilms Tumor Study-5, patients with stage I FAWT treated with vincristine and dactinomycin (VA) without flank radiation had 4-year event-free survival (EFS) and overall survival (OS) of 67.5% and 88.9%, respectively. Patients with stage II-IV FAWT were treated with VA plus doxorubicin and radiation (DD4A). Of the 20 patients with stage II-III FAWT, 4 had a relapse and 3 died. The 4-year EFS and OS for stage IV FAWT/upfront nephrectomy were 61.4% and 71.6%, respectively. The COG AREN0321 study evaluated whether intensifying therapy for stage I and IV FAWT would improve survival of these patients. Methods: Tumor histology and stage were confirmed for all patients by real-time central pathology, surgery, and radiology review on protocol AREN03B2, the COG renal tumor classification, biology, and banking study. Patients then enrolled on AREN0321 with stage I-III FAWT received DD4A and those with stage IV FAWT received vincristine, doxorubicin, cyclophosphamide, carboplatin and etoposide with radiation (UH-1). We analyzed outcomes of patients with FAWT treated on AREN0321 and those enrolled only on AREN03B2 who received the same chemotherapy regimens. Results: A total of 46 patients (25 AREN0321 and 21 AREN03B2) were included in the analyses. Of the 25 AREN0321 patients, 17 (68%) had upfront nephrectomy and all 25 received radiation. Of the 5 AREN0321 patients with stage IV FAWT, 4 had metastasis to lung and 1 to lung and liver. Of the 21 AREN03B2 patients, 19 (90%) had upfront nephrectomy and 17 (81%) reported receiving radiation. The 2 AREN03B2 stage IV patients had lung only metastases. The 4-year EFS and OS are displayed in the table below. No events occurred in stage I-II AREN0321 patients nor in any AREN03B2 patients. Of 10 patients with stage III FAWT on AREN0321, 3 had a relapse. None of the 7 stage IV FAWT patients who received UH-1 had a relapse, but one patient died due to toxicity. Conclusions: Patients with stage I and II FAWT had outstanding survival when treated with DD4A and radiation. Intensification of therapy may be warranted for stage III FAWT and appears to have improved patient survival for stage IV FAWT but with increased risk of toxicity. Strategies to alleviate toxicity of UH-1 therapy have been incorporated into the ongoing COG trial for high-risk patients. Clinical trial information: NCT00335556 . [Table: see text]

Trabectedin (T) versus adriamycin plus dacarbazine (A-DA) in advanced solitary fibrous tumor (SFT): Results from a phase II randomised clinical study (STRADA).

11571 Background: T and A-DA showed antitumor activity in a PDX model of dedifferentiated-SFT (D-SFT) and a few cases of activity in advanced SFT pts have been reported. The efficacy of these agents in advanced typical- (T-)/ malignant- (M-)SFT is unclear. A phase 2 randomised (R) study was conducted within the Italian Sarcoma Group (ISG) to investigate the activity of T and A-DA in advanced T-, M- and D-SFT (Clin-Gov: NCT03023124). Methods: An Italian, multicentre, investigator-initiated prospective open-label, R, non-comparative, phase 2 trial was started in July 2017 involving 6 ISG sites, to evaluate the activity of front-line T (1,5-1,3 mg/sqm at investigator’s discretion, day 1 every 3 wks; arm A) vs A-DA (A 75 mg/sqm day 1 + DA 400 mg/sqm days 1,2 every 3 wks; arm B) in > 18 years-old pts with advanced SFT (T-SFT, M-SFT, D-SFT) until progression or limiting toxicity; in arm B, a maximum number of 6 cycles was foreseen, given the constrain of the maximum tolerated dose of A. Eligible pts had to show RECIST progression in the 6 mos prior to study entry. Centralized pathologic and radiologic review was performed. Pts were randomly assigned to Arm A or Arm B (1:1 ratio), with cross over in case of progression (PD) or unacceptable toxicity prior to the completion of the 6 cycles (arm B in case of randomization to arm A and vice versa). An interim analysis was pre-planned after reaching 10 evaluable pts in each arm, and at least 1 response in arm A was required to continue the study. Primary end-point was the overall response rate (ORR) by RECIST; secondary end-points ORR by Choi, progression-free survival (PFS), overall survival (OS). Results: Enrolment for the interim analysis was completed in September 2022. 30 pts were screened and 23 were enrolled (7 screening failure): T-SFT = 7, M-SFT = 14, D-SFT = 2. All pts were naïve; 3 pts are ongoing, 20 completed their treatment (12 = PD, 8 = other). All pts were evaluable for RECIST. No responses by RECIST were seen in each arm (ORR 0%), while stable disease (SD) and PD were 9 (45%) and 1 (5%) in arm A and 8 (40%) and 2 (10%) in arm B, respectively. At a 15.9-mo (I.Q. range 11.3-29.0) m-FU, m-PFS by RECIST was 9.2 (2.7-not assessable) mos in arm A and 8.0 (1.1-not assessable) mos in Arm B, with 29.6% progression-free pts at 1 year in arm A and 18.7% in arm B. Median OS was 34.3 (9.3-not assessable) mos in arm A, 31.5 (4.2-31.5) mos in arm B. Conclusions: No responses were seen neither to T nor to A-DA across all SFT subtypes; therefore, the study was closed to enrolment for T-SFT and M-SFT after the interim analysis. Noteworthy, both T and A-DA stabilised the disease in about 40% of previously progressive pts, and nearly 30% of pts treated with T were free from progression at 1 year. On the other hand, no conclusion can be drawn yet on the activity of T / A-DA in this SFT subtype, since D-SFT cases who entered the study were only 2 and the enrolment of D-SFT is still ongoing. Clinical trial information: NCT03023124 .

GOLIDOCITINIB IN TREATING REFRACTORY OR RELAPSED PERIPHERAL T‐CELL LYMPHOMA: PRIMARY ANALYSIS OF THE MULTINATIONAL PIVOTAL STUDY RESULTS (JACKPOT8)

Introduction: Currently there is no consensus on the treatment of relapsed/refractory (r/r) PTCL, and patient prognosis was poor. Golidocitinib is an orally available, JAK1-selective inhibitor currently being evaluated in a multinational, pivotal study in r/r PTCL (JACKPOT8 Part B, NCT04105010). Here we reported the primary analysis of efficacy and safety results of this study. Methods: PTCL patients who had relapsed from or had been refractory/intolerant to ≥1 (but ≤3) prior systemic therapy(ies) were enrolled to receive golidocitinib at 150 mg once daily until disease progression or pre-defined discontinuation criteria were met. The primary endpoint was CT-based objective response rate (ORR) assessed by an independent review committee (IRC) according to Lugano 2014 classification. The efficacy analysis set included patients whose pathological diagnosis of PTCL had been retrospectively confirmed by a central laboratory and who had at least one measurable lesions at baseline. The safety analysis set included all dosed patients. Results: As of 30 November 2022, a total of 104 patients with r/r PTCL were enrolled and dosed with golidocitinib. Baseline characteristics: median age was 58 yrs; 64.4% were male; 20.2% had baseline bone marrow involvement. Major subtypes included NOS (46.2%), AITL (15.4%) and ALCL (9.6%). The median prior lines of therapies were two. All of the patients had been treated with chemotherapies, and 48.1% had been treated with histone deacetylase inhibitors. By the data cut-off (DCO) date, a total of 80 patients had both IRC assessment and central pathology review results available, and thus were included in the efficacy analysis. Among them, 35 patients achieved tumor response (ORR = 43.8%), including 20 patients (25.0%) achieved complete responses. Tumor response was observed in various subtypes, including AITL (56.3%), NOS (45.7%), ALCL (11.1%) and others (44.4%). In patients who relapsed from HDAC inhibitor treatment, 54.8% achieved tumor response. With a median follow-up of 5.5 months for responders, the median duration of response (DoR) has not been reached. Golidocitinib was tolerated in patients with r/r PTCL. By the DCO date, the longest duration on treatment was 15.7 months (still responding). The most common ≥ grade 3 treatment-related adverse events (TRAEs) were hematological in nature, including neutrophil count decreased (26.0%), white blood cell count decreased (25.0%), platelet count decreased (16.3%) and lymphocyte count decreased (16.3%). TRAEs leading to dose interruption, reduction, and discontinuation were 37.5%, 5.8%, and 7.7%, respectively. The majority of TRAEs were reversible or clinically manageable. Conclusions: Golidocitinib demonstrated its potential as a novel targeted therapy for the treatment of r/r PTCL. The updated data will be presented at the conference. Encore Abstract—previously submitted to ASCO 2023 Keywords: aggressive T-cell non-Hodgkin lymphoma, molecular targeted therapies Conflicts of interests pertinent to the abstract W. Yu Employment or leadership position: Employed by Dizal Pharmaceutical

Influence of follow-up time on outcome of children and adolescents with atypical Spitz tumor/Spitz melanoma (AST/SM): Results from the MACMEL registry.

e21558 Background: Pediatric melanoma is a rare and challenging diagnosis, requiring an integrated clinicopathologic and genomic approach to optimize diagnosis and clinical care. The Molecular Analysis of Childhood Melanocytic Tumors (MACMEL) registry (Pappo A Cancer. 2021 Oct 15;127(20):3825-3831) was developed to better characterize pediatric melanocytic lesions by including clinical information, central pathology review, and genomic analysis. The AST/SM subtype of melanocytic lesions often affects younger patients, have a high incidence of nodal involvement, and are genomically characterized by copy number aberrations and kinase fusions. Methods: A review of the MACMEL registry data for patients with AST/SM enrolled from May 2016 to December 2022. Patient data included demographics (age, sex, ethnicity), anatomic location of lesion, sentinel node involvement, AJCC staging, genomic and germline findings, therapy, and disease outcomes. Results: We identified 60 patients with AST (n=17) and SM (n=43). 28 patients had stage III disease and 16 had stage IIIC disease. There were 38 females, and 22 males. The most common primary sites were the extremities and the most common gene rearrangements included MAP3K8 (n= 10) and ALK (n= 12). Other genomic alterations identified included kinase fusions NTRK, ROS1, BRAF, FLOT2-ARAF, RAC1, BRIP1, SDHAF2, ATM, GPNMB-ERBB2, and CDKN2B. None of the 55 patients that underwent TERT promoter analysis had a mutation. Adjuvant treatment was given to 8 patients (interferon 3, pembrolizumab 4, larotrectinib 1). The median follow-up time for the cohort is 3.1 years, with 57 patients alive with no evidence of disease. 1 patient had a local relapse treated with wide local excision and is currently alive with no evidence of disease. 3 patients were lost to follow up. Event free survival (EFS) for the cohort is 98% and overall survival (OS) is 100%. Conclusions: Patients with AST/SM comprise the largest subtype of melanocytic lesions enrolled on the MACMEL registry and have an excellent clinical outcome. This supports our previous observations that patients with AST/SM who lack TERT promoter mutations may be able to be managed conservatively and that an integrated diagnostic approach incorporating genomic information is vital for optimal diagnosis and clinical management. [Table: see text]

NEO-CESQ study: Neoadjuvant plus adjuvant treatment with cemiplimab in surgically resectable, high risk stage III/IV (M0) cutaneous squamous cell carcinoma.

9576 Background: In the last years, the treatment of locally advanced and/or metastatic cutaneous squamous cell carcinoma (CSCC) has been revolutionized by the introduction of cemiplimab, an anti-PD-1 antibody, which showed a 50% overall response rate and long term benefit (1). Recently, a phase II trial of neoadjuvant cemiplimab in resectable CSCC patients (2), showed a major pathological response (MPR) rate of 63.3%. In the current multicenter, phase II trial we evaluated the efficacy of neoadjuvant plus adjuvant immune checkpoint inhibitor in patients with surgically resectable, high-risk stage III/IV (M0) CSCC. Methods: Patients with surgically resectable high-risk stage III/IV (M0) CSCC received cemiplimab at a dosage of 350 mg every 3 weeks for two cycles prior surgery and for one year after surgery. The study primary endpoint was MPR [pathological complete response (pCR) or near pCR ( < 10% remaining viable tumour cells in the surgical pathology sample)] per independent central pathology review. Key secondary endpoints included recurrence-free survival (RFS), overall survival (OS), safety and the analysis of predictive biomarkers. Results: From May 2021 to October 2022 twenty-three patients were enrolled in 6 centers. pCR was observed in 9 (39%) patients and near pCR in 2 (8%) patients, while pathological partial response (10-50% remaining viable tumour cells) and no pathologic response was observed in 1 patient and 11 patients, respectively. At data lock of 31st January 2023, only one patient was discontinued due to clinical progression. Furthermore, it was observed n = 60 (57%) any adverse events (AE) and n = 29 (30%) treatment-related AE. No any G3/G4 AE were observed. Conclusions: Neoadjuvant cemiplimab induced a pathological response in 52% of stage III/IV (M0) CSCC patients with a MPR in 48%. The study is still ongoing to evaluate the impact of combined neoadjvuant and adjuvant immunotherapy on RFS and biomarkers analysis. Clinical trial information: NCT04632433 .

Orelabrutinib, a new‐generation bruton tyrosine kinase inhibitor, demonstrates safety and efficacy in relapsed/refractory marginal zone lymphoma

Introduction: Marginal zone lymphoma (MZL) is an indolent type of non-Hodgkin lymphoma that develops through pathological B cell receptor signaling. Orelabrutinib, a new-generation oral small molecule Bruton’s tyrosine kinase (BTK) inhibitor, was evaluated in relapsed/refractory (r/r) MZL patients. Methods: Previously treated r/r MZL patients received orelabrutinib 150 mg once daily in a phase 2, multicenter, single-arm study conducted in China. The primary endpoint was overall response rate (ORR) assessed by an Independent Review Committee (IRC) based on the Lugano 2014 classification. Other efficacy, safety, and pharmacokinetic parameters were evaluated as secondary outcome measures. Results: Between April 2019 and November 2021, 111 Chinese patients with a median age of 60 y/o (range 23–77) were enrolled. Among those, 83 patients who received at least 1 prior therapy with an anti-CD20 antibody-containing regimen were confirmed with MZL by the central pathological review, who were mainly with extranodal MZL of mucosa-associated lymphoid tissue (MALT, 45.8%) and nodal MZL (36.1%). The majority had late-stage diseases, the stage IV accounting for 75.9%. After a median follow-up of 22.3 months, the IRC-assessed ORR was 57.8% (95% CI, 46.5% to 68.6%). Ten patients achieved a complete response (CR, 12%), and 38 achieved a partial response (PR, 45.8%). The IRC-assessed median duration of response (DoR) and median progression-free survival (PFS) was 34.3 months and 36.0 months, respectively, with a 12-month PFS rate of 84.3% (95% CI, 73.9% to 90.8%). The rate of overall survival (OS) was 91.5% (95% CI, 82.9% to 95.8%) at 12 months. Treatment was well tolerated with most treatment-related adverse events (TRAE) being grade 1 or 2. In all the 111 patients, common all-grade TRAEs included anemia (27.9%), neutrophil count decrease (23.4%), white blood cell count decrease (18.0%), platelet count decrease (17.1%), rash (14.4%), and upper respiratory tract infection (10.8%). Thirty-four patients (30.6%) experienced grade 3 or higher TRAEs. Serious TRAEs occurred in 18 patients (16.2%), of which pneumonia (5.4%) was the most common. Seven patients (6.3%) discontinued orelabrutinib due to TRAEs. Conclusions: Orelabrutinib demonstrated high response rates with durable disease remission and was well tolerated in Chinese patients with r/r MZL. This trial is registered at ClinicalTrials.gov as NCT03797456. Keyword: Indolent non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

Golidocitinib in treating refractory or relapsed peripheral T-cell lymphoma: Primary analysis of the multinational pivotal study results (JACKPOT8).

7503 Background: Currently there is no consensus on the treatment of relapsed/refractory (r/r) PTCL, and patient prognosis was poor. Golidocitinib is an orally available, JAK1-selective inhibitor currently being evaluated in a multinational, pivotal study in r/r PTCL (JACKPOT8 Part B, NCT04105010). Here we reported the primary analysis of efficacy and safety results of this study. Methods: PTCL patients who had relapsed from or had been refractory/intolerant to ≥ 1 (but ≤ 3) prior systemic therapy(ies) were enrolled to receive golidocitinib at 150 mg once daily until disease progression or pre-defined discontinuation criteria were met. The primary endpoint was CT-based objective response rate (ORR) assessed by an independent review committee (IRC) according to Lugano 2014 classification. The efficacy analysis set included patients whose pathological diagnosis of PTCL had been retrospectively confirmed by a central laboratory and who had at least one measurable lesions at baseline. The safety analysis set included all dosed patients. Results: As of November 30, 2022, a total of 104 patients with r/r PTCL were enrolled and dosed with golidocitinib. Baseline characteristics: median age was 58 years old; 64.4% were male; 20.2% had baseline bone marrow involvement. Major subtypes included NOS (46.2%), AITL (15.4%) and ALCL (9.6%). The median prior lines of therapies were two. All of the patients had been treated with chemotherapies, and 48.1% had also been treated with histone deacetylase inhibitors. By the data cut-off (DCO) date, a total of 80 patients had both IRC assessment and central pathology review results available, and thus were included in the efficacy analysis. Among them, 35 patients achieved tumor response (ORR = 43.8%), including 20 patients (25.0%) achieved complete responses. Tumor response was observed in various subtypes, including AITL (56.3%), NOS (45.7%), ALCL (11.1%) and others (44.4%). In patients who relapsed from HDAC inhibitor treatment, 54.8% achieved tumor response. With a median follow-up of 5.5 months for responders, the median duration of response (DoR) has not been reached. Golidocitinib was tolerated in patients with r/r PTCL. By the DCO date, the longest duration on treatment was 15.7 months (still responding). The most common ≥ grade 3 treatment-related adverse events (TRAEs) were hematological in nature, including neutrophil count decreased (26.0%), white blood cell count decreased (25.0%), platelet count decreased (16.3%) and lymphocyte count decreased (16.3%). TRAEs leading to dose interruption, reduction, and discontinuation were 37.5%, 5.8%, and 7.7%, respectively. The majority of TRAEs were reversible or clinically manageable. Conclusions: Golidocitinib demonstrated its potential as a novel targeted therapy for the treatment of r/r PTCL. The updated data will be presented at the conference. Clinical trial information: NCT04105010 .

Immunotherapy for localized dMMR/MSI tumors: First interim analysis of the IMHOTEP trial.

2591 Background: Immune checkpoint inhibitors (ICI) have demonstrated their efficacy in advanced dMMR/MSI (deficient mismatch repair/microsatellite instability) tumors and increasing data are also accumulating in localized resectable stages with about 60% of pathological complete response rate. The goal of the IMHOTEP trial is to assess the safety and efficacy of peri-operative pembrolizumab in localized dMMR/MSI tumors independently of their anatomical origin. Methods: IMHOTEP is a prospective, multicenter, phase II study aimed to include 120 patients (pts) with localized resectable dMMR/MSI tumors, eligible for curative surgery. Pembrolizumab 400 mg flat dose is administered as a perioperative treatment with 1 or 2 doses every 6 weeks before surgery and thereafter every 6 weeks for one year. Primary objective is to evaluate the pathological complete response (pCR) rate defined as ypT0N0 stage. Secondary objectives are to assess major pathological response, centralized pathological review, safety, clinical response rate, recurrence-free survival and overall survival. Here, we present the interim analysis of safety and pathologic response data for the first 70 treated pts. Results: Median age was 67.5 years (26-89), 54.3% were males, and 42.0% were ECOG-PS 0. Surgery was performed in 54/70 pts including 27/35 colorectal (CRC), 16/21 oesogastric (OGC), 4/5 endometrial (EC) and 7/9 other (6 small intestine, 1 bile duct) (OC) cancers. 16 pts (22.9%) were not operated, mainly due to patient’s decision following complete clinical response (n=7). Only one patient was not submitted to surgery because of disease progression. Focusing on the 54 operated pts, 31 and 23 pts received 1 and 2 neoadjuvant pembrolizumab doses respectively. The pCR rate was 38.9% (40.7%, 25.0%, 0.0% and 85.7% in CRC, OGC, EC and OC respectively). Grade 3-4 immune-related adverse events were observed in 4 (5.7%) patients including transaminases increase (n=1), arthritis (n=1), acute kidney injury (n=1) and pneumonitis (n=1). Conclusions: In this IMHOTEP interim analysis, we observed a limited complete pathologic response rate to short-course neoadjuvant pembrolizumab. If we add patients in clinical complete response who chose not to be operated to those with pCR, our results compare with those previously reported. But we can also hypothesize that preoperative treatment duration should be prolonged to obtain more pCR. Overall, tolerance of pembrolizumab was acceptable without new safety signal. Centralized pathological review, major pathological response evaluation and clinical response rate analysis are ongoing. IMHOTEP trial has been registered (first post: March 12th, 2021). Clinical trial information: NCT04795661 .

Integration of trastuzumab (T), with or without pertuzumab (P), into perioperative chemotherapy (CT) of HER-2 positive gastric (GC) and esophagogastric junction cancer (EGJC): First results of the EORTC 1203 INNOVATION study, in collaboration with the Korean Cancer Study Group, and the Dutch Upper GI Cancer group.

4057 Background: 10-20% of GC are HER-2 positive. The role of perioperative anti-HER2-directed treatment is yet undefined. Methods: This randomized, open-label phase II-trial investigates the benefit of combining T alone or with P and perioperative CT for GC and EGJC. Between 2015 and 2021,172 of a planned 215 patients (pts) with centrally confirmed, positive HER-2 status and resectable GC or EGJC (UICC TNM stages Ib-III) were included. Recruitment was prematurely terminated due to slow accrual. Pts were randomized in a 1:2:2 ratio to: Arm A (CT alone) (35 pts); Arm B (CT+ T [8mg/kg, followed by 6mg every 3 weeks]) (67 pts); Arm C (CT + T+ P [840mg every 3 weeks]) (70 pts). CT was initially cisplatin (80 mg/m2 d1) and capecitabine (2 x 1000 mg/m2/d d1) for 3 cycles before and after surgery. After publication of the FLOT-4 study, the protocol was amended. CT changed to four cycles FLOT (Al-Batran Lancet 2019) with FOLFOX or CAPOX as alternative for pts ineligible for FLOT. In the experimental arms, T and P were continued beyond CT at the same dose for a total of 17 cycles. Major pathological response rate (mpRR) determined by central pathology review was the primary endpoint. The study was designed to have 80% power to detect an increase in mpRR from 25% with CT to 45% with CT+T+P or CT+T with a one-sided alpha of 10%. CT+T+P was first tested versus CT and if positive, CT+T would be tested versus CT. Results: Out of 172 pts randomized, 161 fulfilled all important eligibility criteria and started their allocated treatment (per protocol population). 62.1% of pts had EGJC and 72.0% an intestinal subtype. Main CT regimens were cisplatin+capecitabine (42.2%) and FLOT (46.6%). In Arm A:B:C, 90.9%, 92.2% and 81.3% completed neoadjuvant treatment. Major reason for treatment discontinuation was toxicity (70%). Surgery was performed in 84.8%, 98.4%, 92.2% pts in Arm A:B:C. R0 resection rates were 83.9%, 90.3% and 85.9%. At present, results of central pathology review of mpRR are available for 126 out of 150 operated pts (84.0%). Pts not operated (n=11) were considered as failures for mpRR. MpRR was 23.3%, 37.0%, 26.4% in Arm A:B:C. The increase of 3.1% (80% CI: [-9.5%, 15.7%], one-sided p=0.378) in Arm C vs. A was not statistically significant. The increase in Arm B vs. A was 13.7% (80% CI: [0.7%,26.7%], one-sided p=0.099). MpRR was 33.3%, 53.3% and 37.9% in Arm A:B:C after amending the protocol while, in contrast, it was 8.3%, 16.7% and 12.5% before. Conclusions: The primary endpoint analysis did not meet the pre-specified criteria of efficacy for the combination of CT+T+P. However, CT+T showed interesting response rates, especially with FLOT as CT backbone. Follow-up data including survival is necessary to define the clinical value of this regimen. Clinical trial information: NCT02205047 .

Study EV-103: Neoadjuvant treatment with enfortumab vedotin monotherapy in cisplatin-ineligible patients (pts) with muscle invasive bladder cancer (MIBC): Updated results for Cohort H.

4595 Background: Cisplatin-ineligible pts with MIBC have no established neoadjuvant treatment options known to prolong survival before undergoing radical cystectomy and pelvic lymph node dissection (RC+PLND), Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in urothelial cancer. In a phase 3 study, EV showed improved overall survival vs standard chemotherapy and a tolerable safety profile in pts with advanced urothelial cancer previously treated with a platinum agent and a PD-1/L1 inhibitor (Powles NEJM 2021). In Cohort H of the EV-103 phase 1b/2 study, preliminary results, including pathological complete response (pCR) and pathological downstaging (pDS) rates, showed antitumor activity in cisplatin-ineligible pts with MIBC who received neoadjuvant EV treatment (Petrylak ASCO GU 2022). Here we report updated results, including event-free survival (EFS) and subsequent cancer-related therapy. Methods: Cohort H of the EV-103 phase 1b/2 study (NCT03288545) enrolled cisplatin-ineligible pts with MIBC (T2-T4aN0M0) and ECOG PS ≤2 who were eligible for RC+PLND. Pts received neoadjuvant EV (1.25 mg/kg) on Days 1 and 8 every 21 days for 3 cycles before undergoing RC+PLND. The primary endpoint was pCR rate (ypT0 and N0) by central pathology review. Key secondary endpoints included pDS rate (ypT0, ypTis, ypTa, ypT1, and N0), EFS based on investigator assessment, and safety. Results: 22 pts (median age 74.5 yr, range 56-81) were enrolled and treated; 17 pts (77.3%) remain on study. Pts had stage cT2 (68.2%), cT3 (27.3%), or cT4 (4.5%) disease. 68.2% of pts had transitional cell carcinoma only; 31.8% had a mixed histology. 86.4% of pts completed all 3 cycles of EV treatment; the median duration of EV treatment was 2.1 months (range 0.7-2.3). The pCR rate was 36.4% (95% CI, 17.2, 59.3) and the pDS rate was 50.0% (95% CI, 28.2, 71.8). Median EFS has not been reached. The EFS rate at 12 months was 76.4% (95% CI, 52.2, 89.4). All pts underwent surgery with no delays due to EV-related TEAEs. The most common EV-related TEAEs were fatigue (45.5%), dysgeusia (36.4%), and alopecia (31.8%); 18.2% of pts had grade ≥3 EV-related TEAEs. 68.2% of pts had surgery-related TEAEs and 31.8% pts had grade ≥3 surgery-related TEAEs. The most common surgery-related TEAEs were procedural pain (18.2%), anaemia (13.6%), and constipation (13.6%). 3 pts died due to AEs unrelated to EV treatment; in 2 pts the AEs occurred >30 days after RC+PLND. 36.4% of pts received subsequent cancer-related therapy. Conclusions: Neoadjuvant EV monotherapy treatment showed promising results for antitumor activity and EFS with a manageable safety profile in cisplatin-ineligible pts with MIBC. These results support ongoing phase 2 and 3 programs in MIBC evaluating EV alone or combined with pembrolizumab (EV-103 Cohort L, KN-905, KN-B15). Clinical trial information: NCT03288545 .

Biological medicines for diffuse intrinsic pontine glioma (DIPG) eradication (BIOMEDE): Final results of an international randomized phase II platform trial comparing 3 targeted therapies in combination with radiotherapy from ITCC, SIOPE-Brain and ANZCHOG.

10003 Background: DIPG is the most aggressive brain cancer in children and adolescents with a median survival of 9 months. Surgery is not possible due to the invasive nature of the disease in a critical area of the brain; only radiotherapy has shown a transient palliative effect on disease progression and no adjuvant therapy has proven to increase disease control. Methods: We launched a large randomized biomarker-driven platform trial to compare three targeted therapies (erlotinib, everolimus and dasatinib) in combination with 54 Gy radiotherapy, in newly diagnosed patients with DIPG (NCT02233049). A central pathological review was performed prior to study entry to confirm the diagnosis of DIPG with H3K27me3 loss (with or without H3K27M mutation) and assess biomarkers. The randomization was designed so that a drug could not be allocated if the corresponding biomarker was absent in the tumor (EGFR overexpression for erlotinib, mTOR activation for everolimus, no specific biomarker for dasatinib). Tumors underwent whole genome sequencing and RNAseq to evaluate prognostic and theranostic biomarkers. Primary endpoint was overall survival. Results: Among the 279 DIPG patients screened for the randomized trial between October 2014 and September 2019, 233 were enrolled in 45 centers in 7 countries; among the 46 screen failures, the diagnosis of DIPG could not be confirmed in 23 patients. No biopsy- or treatment-related death was reported. Serious adverse events > = 3 unrelated to disease progression were reported in 40% of patients, 34%, 36% and 46%, in the erlotinib, everolimus and dasatinib arms, respectively (p = 0.32). With a median follow-up of 5.3 years, median overall survival (OS) from the date of randomization was 9.0 (95% confidence interval, 7.4-14.4), 11.3 (10.3-13.4) and 9.4 (7.7-10.7) months for erlotinib, everolimus and dasatinib, respectively (p = 0.45). OS were not statistically different from those of a historical biopsy-proven cohort. The molecular profiling with copy number aberrations (CNA) had a strong impact on survival (log-rank test, p = 0.0001) as shown by the preliminary analysis of the first hundred patients identifying a group of tumors with very poor prognosis with a HR for death of 1.96 (1.07-3.64) characterized by TP53 mutations (p = 3.05e-11) associated with more CNA (p < 0.0001). Conclusions: This trial demonstrated the feasibility and safety of a large randomized trial for DIPG based on biomarker information from a stereotactic biopsy at diagnosis in an international multicenter setting and generated new tumor biological insights to further develop innovative therapies. Clinical trial information: NCT02233049 .

Large versus limited molecular profiling panel screening program in patients with metastatic sarcoma: An exploratory subgroup analysis from the ProfiLER 02 trial.

11545 Background: Profiler 02 (NCT03163732) is a multicentre, randomized molecular screening clinical trial aiming to evaluate the feasibility and the benefit of a large NGS (Next-generation sequencing) panel (FoundationOne Medicine NGS panel or FOne, 324 cancer-related genes) compared to a limited one (Control panel or CTRL, 87 cancer-related genes) in terms of clinical, quality of life and health economic outcomes. We present here the results of the patients with advanced/metastatic sarcoma included in the Profiler 02 trial. Methods: Patients (pts) were enrolled during their first-line of standard therapy for an advanced sarcoma. All sarcomas diagnosIs were performed within the RRePS network (French pathology network of reference for sarcomas) and a central pathological review confirmed if quality and quantity of material were acceptable for molecular analysis. Patients were randomized within the two study arms (FOne versus CTRL) and DNA was analysed using both panels. The primary objective of the study was to compare the proportion of patients for whom a genomically driven recommended therapy (RT) could be initiated based on the FOne versus CTRL panels. A dedicated Molecular Tumour Board (MTB) reviewed tumour genomics data of both panels independently to propose a RT. Results: From January 2018 to July 2019, 39 pts with sarcoma (20F, 19M), with a median age of 54 years [21-81], were randomized between FOne Arm (17 pts) and CTRL Arm (22 pts). Pathological subtypes per arm are presented in the the table. Overall, 19 pts (49%) had at least one genomically driven RT, 11 according to both panels and 8 according to FOne panel exclusively (McNemar’s test, p=0.01). Main RT were CDK4/6 inhibitors ( n=5), PI3K/AKT/mTOR inhibitors ( n=4), and immunotherapy ( n=4). After the MBT, a RT was initiated for seven patients, four according to FOne panel only and three according to both panels. Importantly, a complete response was observed for a metastatic MPNST (Malignant Peripheral Nerve Sheath Tumor) with a high tumour mutational burden (TMB) detected by the FOne panel (37 mutations per megabase) and treated with durvalumab (anti-PDL1) + tremelimumab (anti-CTLA4). Conclusions: Although from an exploratory subgroup analysis, these results suggest that a large molecular profiling panel including TMB (FOne panel) might increase the number of RT and the number of sarcoma patients treated. Studies of precision medicine in rare cancers such as sarcomas are feasible,this approach could benefit to patients. Clinical trial information: NCT03163732 . [Table: see text]

Distinct molecular features and potential therapeutic strategies for spinal cord gliomas.

2056 Background: Spinal cord gliomas (SCG) are rare primary CNS tumors with varied prognosis. Standard treatment remains poorly defined, as no clear survival advantage exists with extensive resection, radiation, or chemotherapy. Mounting evidence suggests that tumors from different regions of the CNS harbor unique molecular signatures. In a retrospective study, we comprehensively characterized molecular alterations to identify potential therapeutic strategies in the largest cohort of SCG reported to date. Methods: We performed centralized pathology review and analyzed SCG with next-generation sequencing of DNA (592 gene NextSeq or WES, Novaseq), RNA (WTS, NovaSeq) and pyrosequencing (MGMT promoter methylation, MGMTme). We estimated tumor microenvironment cell infiltration by quanTIseq & Epithelial-Mesenchymal Transition (EMT) by RNAseq. We used X2/Fisher’s-exact/Mann-Whitney U tests for comparison & determined significance (p < 0.05), adjusting for multiple comparison by the Benjamini-Hochberg method (q < 0.05). Results: We analyzed 39 surgically accessible SCG (19 high grade, 17 low grade, 3 NOS); ependymomas were excluded. The most common alterations were mutations in H3F3A (31%), TP53 (25%), ATRX (21%), NF1 (18%) & BRAF fusion (19%). H3F3A mutations occurred exclusively in high grade SCG (63%, q < 0.05) while BRAF fusions occurred exclusively in low grade SCG (60%, p < 0.05). TP53 mutations were more prevalent in high grade SCG (50% vs. 8%, p < 0.05). Compared to intracranial gliomas (n = 6732), SCG harbor significantly more frequent H3F3A (31% vs. 1.6%), KRAS mutations (10% vs. 0.7%) & BRAF fusions (19% vs. 0.7%) but less frequent TERT (4.3% vs. 66%) & PTEN (0 vs. 27%) mutations or EGFR amplification (0 vs. 28%) (all q < 0.05). SCG rarely harbor the canonical intracranial alterations IDH1 (2.6% vs. 17%), EGFRvIII (0 vs. 17%) or MGMTme (19% vs. 47%) (p < 0.05). SCG have greater penetration of immune infiltrates of DCs (median cell fraction/MCF: 13% vs. 9%), T regs (positive percent: 47% vs. 26%) & B cells (MCF: 9% vs. 7%), with less penetration of monocytes (MCF: 0 vs. 2%) (q < 0.05). EMT score associates with high grade glioma in intracranial disease (q < 0.05) but does not recapitulate in SCG (p > 0.05). Conclusions: Clinical management of SCG is currently drawn from experience with intracranial gliomas. Our results identify unique molecular features of SCG suggesting an underlying biology distinct from intracranial gliomas. In SCG, H3F3A mutations are exclusive to high grade while BRAF fusions are exclusive to low grade; SCG rarely harbor canonical intracranial alterations such as IDH1, EGFR or MGMTme; and SCG have greater penetration of DCs with less penetration of monocytes. We provide a biological explanation for limited effectiveness of current therapies in SCG with potential implications for chemotherapy, targeted and immunotherapy. Our work underscores the need for investigations dedicated uniquely to SCG.

Prognostic factors for relapse in patients with clinical stage I testicular seminoma: A nationwide, population-based cohort study.

5041 Background: Approximately 20% of patients with clinical stage I testicular seminoma will relapse after orchiectomy. No robust prognostic factors for relapse exist which challenges risk assessment and counselling for patients. Previous studies have been hampered by selection bias and variable pathology reporting that limit interpretation and generalization of results. We therefore assessed prognostic factors for relapse in a large unselected nationwide population-based setting with centralized pathology review. Methods: Patients with clinical stage I seminoma diagnosed in Denmark between 2013 and 2018 were identified in the prospective Danish Testicular Cancer database. By linkage to the Danish National Pathology Registry, microscopic slides from the orchiectomy specimens were retrieved and reviewed blinded to the clinical outcome. Clinical data were obtained from medical records with follow-up until July 2022. The association between prespecified clinical and histopathological prognostic factors and relapse were assessed by use of Cox regression analysis. Potential prognostic factors included age, pre-orchiectomy values of β-human chorionic gonadotropin (β-hCG) and lactate dehydrogenase (LDH), tumor size, tumor multifocality, tumor necrosis, lymphovascular invasion, pagetoid rete involvement, and invasion of rete testis, hilar soft tissue, epididymis, spermatic cord, tunica albuginea, and tunica vaginalis. Results: In total, 924 patients were included. During a median follow-up of 6.3 years, 148 (16%) patients relapsed. Invasion of the testicular hilum (rete testis and hilar soft tissue), lymphovascular invasion, and elevated pre-orchiectomy levels of β-hCG and LDH were independent predictors of relapse. The estimated 5-year risk of relapse ranged from 6% in patients with no risk factors, to 64% in patients with all four risk factors with tumor extension into the hilar soft tissue of the testicular hilum. After internal model validation, the model had an overall concordance statistic of 0.70. Conclusions: The provided prognostic factors allow a long-awaited opportunity to make more informed treatment decisions about post-orchiectomy management in patients with clinical stage I seminoma. These should replace current risk factors in guidelines and be used in future studies investigating risk-adapted follow-up and treatment strategies. [Table: see text]

Perioperative toripalimab + platinum-doublet chemotherapy vs chemotherapy in resectable stage II/III non-small cell lung cancer (NSCLC): Interim event-free survival (EFS) analysis of the phase III NEOTORCH study.

8501 Background: Adjuvant and neoadjuvant immunotherapy have been approved by US FDA to treat early-stage NSCLC. However, the optimal neoadjuvant and adjuvant treatment, including duration of treatment, are unknown. We present the interim results of a randomized, double-blind, placebo-controlled, Phase III trial to evaluate the efficacy and safety of perioperative toripalimab plus chemotherapy followed by toripalimab maintenance vs chemotherapy in resectable stage III NSCLC. Methods: Patients with stage II/III resectable NSCLC, without EGFR/ALK alterations for non-squamous NSCLC, were randomized 1:1 to receive 240 mg toripalimab or placebo combined with chemotherapy Q3W for 3 cycles before surgery and one cycle after surgery, followed by toripalimab or placebo monotherapy Q3W for 13 cycles. Stratification variables for randomization included disease stage, histopathologic subtype, PD-L1 expression and surgical procedure. Primary endpoints were EFS by investigator and major pathological response (MPR) rate by a blinded independent pathologic review (BIPR) in the stage III and the ITT populations. Secondary endpoints included overall survival (OS), pathologic complete response (pCR) rate, EFS by independent review committee (IRC), and safety. A planned interim analysis was performed on the primary endpoint of EFS in the stage III subjects. Results: A total of 404 stage III NSCLC patients were randomized to toripalimab (n=202) or placebo (n=202). By the data cutoff date (November 30, 2022), the median follow-up was 18.3 months. Baseline characteristics were well balanced between the two arms. EFS was significantly improved in the toripalimab arm, HR=0.40, 95% CI (0.277-0.565), P<0.0001, and crossed the pre-specified efficacy boundary. The median EFS was not reached in the toripalimab arm and 15.1 months in the placebo arm. A consistent effect on EFS, favoring toripalimab, was observed in all subgroups. The MPR and pCR rates per BIPR were also higher in the toripalimab arm, 48.5% vs 8.4% and 24.8% vs 1.0%, respectively. The OS results showed a trend favoring toripalimab. The incidence of Grade ≥3 adverse events (AEs) (63.4% vs 54.0%), fatal AEs related to toripalimab/placebo (0.5% vs 0%) and AEs leading to discontinuation of toripalimab/placebo (9.4% vs 7.4%) were comparable between the two arms. However, the incidence of immune-related AEs (42.1% vs 22.8%) was more frequent in the toripalimab arm. Conclusions: The addition of toripalimab to perioperative chemotherapy showed statistically significant improvements in EFS for stage III NSCLC patients with a manageable safety profile. Patients will be followed for overall survival. Clinical trial information: NCT04158440 .

Clinical implications of molecular alterations in intraductal carcinoma of the prostate.

5024 Background: Intraductal carcinoma of the prostate (IDC-P) is a recent addition to the 2016 WHO classification system and little is known about the nature of its true incidence and biology. Clinically, it has been observed to be associated with higher grade group tumors and a more aggressive disease course with a high risk of local recurrence and distant metastasis. However, the molecular underpinnings which define IDC-P are not well elucidated. Initial case series with molecular profiling have suggested an enrichment of alterations in DNA damage/repair (DDR), PI3K, WNT and MAPK pathways. We now present comprehensive molecular profiling data from the largest cohort of IDC-P reported to date in order to better characterize this relatively new histologic entity. Methods: Eligible patients included those with radical prostatectomy tumor tissue labeled as IDC-P on testing requisition with available tissue-based DNA and RNA sequencing utilizing a commercially available CLIA-certified assay (Caris Life Sciences). Prostatic tumor specimens were analyzed using NextGen DNA sequencing (NextSeq, 592 genes and NovaSeq, WES). Digitized H&E slides underwent central pathological review by a board certified pathologist (SW) specializing in genitourinary malignancies to confirm presence of intraductal histology according to the 2022 WHO classification. Results: 31 of 44 submitted cases were confirmed to be IDC-P on central review. Median age of patients was 64 yrs (range 44-79). The majority of cases (26/31 - 84%) were Grade Group 5 and all were Grade Group 3 or higher. Overall the most frequently detected alterations were in TP53 (39%), TMPRSS2 fusion (39%), FOXA1 (16%), CDK12 (10%), PIK3CA (10%), SPOP (10%), ATM (7%), AKT1 (7%) and RB1 (5%). The most commonly altered pathways were in cell cycle regulators (50%), DDR ( BRCA1/2, ATM, CDK12) (23%), and PI3K/AKT/MTOR (23%) and WNT (10%). The FOXA1 mutation rate in this cohort was higher compared to the localized prostate cancer cohort from the TCGA (16% - 5/31 vs 6% - 82/1325). In the IDC-P cohort, there were no tumors which demonstrated mismatch-repair deficiency (dMMR) or microsatellite instability and none of the profiled tumors had a high tumor mutational burden (≥10 mutations/megabase). Conclusions: This data suggests that IDC-P harbors targetable molecular alterations in DDR genes ( BRCA1/2 and CDK12) with approved targeted agents (e.g. PARP inhibitors). These findings should underscore the importance of germline and somatic mutation testing when IDC-P is identified. We also found enrichment of oncogenic FOXA1 mutations in IDC-P which are associated with prostate cancer progression, castrate-resistance and an unfavorable prognosis. Further efforts are ongoing to expand this cohort of IDC-P cases and compare them with a matched cohort of pure adenocarcinoma cases and will include analysis of key RNA expression signatures.

NeoCOAST-2: A phase 2 study of neoadjuvant durvalumab plus novel immunotherapies (IO) and chemotherapy (CT) or MEDI5752 (volrustomig) plus CT, followed by surgery and adjuvant durvalumab plus novel IO or volrustomig alone in patients with resectable non-small-cell lung cancer (NSCLC).

TPS8604 Background: Neoadjuvant platinum-based CT plus IO prolongs event-free survival (EFS) and increases pathological complete response (pCR) rate in patients with resectable NSCLC vs CT alone (Forde et al. N Engl J Med 2022). IO+IO+CT combinations have the potential to further improve pCR and survival outcomes. The phase 2 NeoCOAST-2 study (NCT05061550) is evaluating multiple neoadjuvant IO+IO+CT combinations in patients with resectable, early stage NSCLC. Novel IO molecules being evaluated include the anti-CD73 monoclonal antibody (mAb), oleclumab; the anti-NKG2A mAb, monalizumab; and the PD-1/CTLA-4 bispecific mAb, volrustomig. The latter recently demonstrated durable responses vs a PD-1 inhibitor plus CT as first-line treatment for patients with metastatic NSCLC (ESMO 2022; LBA56). Here we describe the NeoCOAST-2 study design. Methods: This randomized, open-label, multicenter study will enrol approximately 210 patients with previously untreated, histologically/cytologically confirmed, resectable Stage IIA–IIIB (AJCC 8th edition) NSCLC. Patients will be stratified by PD-L1 expression ( < 1% vs ≥1%) and receive treatment with durvalumab + oleclumab + CT, durvalumab + monalizumab + CT, or volrustomig + CT every 3 weeks for 4 cycles prior to surgery, followed by adjuvant durvalumab + oleclumab, durvalumab + monalizumab, or volrustomig for up to 1 year or until disease progression per RECIST v1.1. Surgery should occur within 40 days after the last dose of neoadjuvant therapy and adjuvant therapy should commence within 10 weeks after surgery. The primary endpoints are pCR rate (per blinded independent pathologist review) and safety and tolerability. Secondary endpoints include investigator-assessed EFS, disease-free survival and overall survival, feasibility to surgery, major pathological response rate, objective response rate following neoadjuvant therapy, pharmacokinetics, immunogenicity, and changes in circulating tumor DNA. The study is currently recruiting patients across the US, Europe, Canada, and Asia. Clinical trial information: NCT05061550 .

Extensor Carpi Ulnaris Instability: A Comprehensive Review of Pathology and Operative Techniques.

The extensor carpi ulnaris (ECU) is primarily responsible for extension and ulnar deviation at the wrist. Secondary to repetitive loading of, or acute trauma to the flexed, supinated and ulnarly deviated wrist, the ECU tendon can be a common source of ulnar-sided wrist pain. Common pathology includes ECU tendinopathy, tenosynovitis, tendon instability, and tendon rupture. Extensor carpi ulnaris pathology commonly occurs in athletes and patients with inflammatory arthritis. Given the multitude of available methods to treat ECU tendon pathology, the aim of our study was to outline operative management of ECU tendon pathology, with emphasis on reviewing techniques for addressing ECU instability. We acknowledge a continuing debate between anatomical and nonanatomical techniques for ECU subsheath reconstruction. However, use of a portion of the extensor retinaculum for nonanatomical reconstruction is commonly used and demonstrates successful outcomes. Future comparative studies on ECU fixation are required to increase data on patient outcomes, to further define and standardize these techniques.