bluuebunny/crossref_metadata_2025 huggingface dataset:
IBI110 (anti-LAG-3 mAb) as a single agent or in combination with sintilimab (anti-PD-1 mAb) in patients with advanced solid tumors: Updated results from the phase Ia/Ib dose-escalation study.
Authors: Xu Nong , Mao Chenyu , Qian Jiong , Zheng Yulong , Jiang Haiping , Gao Yuan , Xiao Cheng , Xiong Anwen , Li Wei , He Yayi , Ren Shengxiang , Wang Lei , Yu Jia , Zhu Jun , Liu Ying , Zhou Caicun
Published: June 2022

2650

Background: Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor protein that functions to control T cell response, activation and growth. Dual inhibition of PD-1 and LAG-3 may improve anti-tumor effect synergistically. A phase Ia/Ib dose-escalation study evaluated IBI110 ± sintilimab in patient with advanced solid tumors; initial efficacy and safety data were previously presented (C Zhou et al. ASCO 2021; NCT04085185). Here, we reported the updated results. Methods: Eligible patients were ECOG PS 0-1 and had locally advanced, recurrent or metastatic solid tumors for whom standard therapy had failed. Patients received escalating doses of IBI110 (0.01/0.1/0.3/1/3/10/20mg/kg) IV Q3W in phase Ia and escalating doses of IBI110 (0.3/0.7/1.5/3/5/8/10 mg/kg) in combination with sintilimab 200 mg IV Q3W in phase Ib. Crossover from monotherapy to combination therapy was allowed at progression. The primary objectives were safety, tolerability, and anti-tumor activity of IBI110 alone or IBI110+sintilimab (per RECIST v1.1). Results: Phase Ia: 28 patients (median age of 60.5 years [range 35-72], ECOG PS of 0 [n = 14] and 1 [n = 14]) were enrolled. Dose escalation was completed and no dose-limiting toxicity (DLT) was observed in all dose cohorts. The safety profile was generally consistent with the initial. By investigator-assessment, best response was 1 confirmed partial response (PR) and 6 stable diseases (SD) with monotherapy. After crossing to combination therapy at progression, 8 patients who failed prior anti-PD-(L)1 mAb therapy achieved SD. Phase Ib: Overall, 45 patients (median age: 60.0 yr [range 33-74]; ECOG PS: 0 [n = 14], 1 [n = 31]) were enrolled in all dose levels. Dose escalation was completed and no DLT was observed. The most common treatment-related adverse events (TRAEs) were aspartate aminotransferase increased (28.9%), anaemia (24.4%), and alanine aminotransferase increased (22.2%). TRAEs ≥ grade 3 occurred in 10 (22.2%) patients. Immune-related AE (irAE) incidence was 31.1%, and the most common irAE was hypothyroidism (15.6%). In 43 patients who had undergone at least 1 post-baseline tumor assessment, the investigator-assessed best response included 6 PRs (1 endometrial cancer, 4 NSCLC, and 1 SCLC patients) and 23 SDs. Three patients showed a progression-free survival > 1 year and continued treatment. Conclusions: IBI110 alone or plus sintilimab demonstrated acceptable safety profile and promising antitumor activity in patients with advanced solid tumors. Clinical trial information: NCT04085185.
Immune-related adverse events and immunotherapy efficacy in patients with cancer: A retrospective study.
Authors: Prather Lyndsey L , Ali Atif , Wang Hannah , Du Wendy , Chen Nan , Sheth Aakash , Sandulache Vlad , Sabichi Anita Lyn , Kemnade Jan Ole , Wang Daniel Ying
Published: June 2022

2654

Background: Immune checkpoint inhibitors are revolutionizing cancer care and providing new treatment options with promising outcomes for many cancers. However, immune-related adverse events (irAEs) are not infrequent and can be severe. An intriguing relationship between the presence of irAEs and treatment efficacy has been described but lacks thorough characterization. We aimed to further elucidate a relationship between immune checkpoint inhibitor (ICI) irAEs and efficacy. Methods: We identified cancer patients treated with ICI from 2015-2021 across two institutions: Michael E DeBakey Veterans Affairs Medical Center (MEDVAMC) and Baylor St. Luke’s Medical Center (BSLMC). Clinical data including cancer type, irAEs type and grade, ICI response, progression free survival (PFS) and overall survival (OS) was collected. Using the Kaplan Meier method, survival curves were generated and comparisons were made amongst groups using the log-rank test. Fisher’s exact test was used to compare progression of disease between groups. To determine if variables were associated with survival, multivariable Cox regression analysis was used. Results: Of the 456 patients treated with ICI, irAEs were seen in 165 (36%) patients. Of these, 81 (49%) patients had grade 1 toxicities, most commonly arthritis, diarrhea, and dermatitis. 47 (28%) patients had grade 2 toxicities (colitis, hypothyroidism, adrenal insufficiency). 34 (21%) patients had grade 3 toxicities (pneumonitis, pancreatitis, hepatitis). 3 patients had grade 4 toxicities (pneumonitis, DRESS syndrome, and hepatorenal syndrome). 1 patient expired and 24 (15%) patients discontinued ICI due to irAEs. 55 (33%) of patients with irAEs were treated with steroids. For patients assessed for efficacy, objective response rate (ORR) to ICI was higher in patients with irAEs [47% (12% CR) vs 33% (11% CR)]. In fact, the presence of any irAEs was significantly likely to predict response to ICI (OR 1.90, 95% CI 1.25 - 2.86, p = 0.0026). In a subset of patients evaluable for survival (n = 375), patients with any irAEs had a significantly improved median PFS compared to those without irAEs (9.0 vs. 4.8 months, p = 0.0018). Multivariable analysis demonstrated that the development of any irAEs was related to a significantly improved OS (HR 0.63, 95% CI 0.43-0.89, p = 0.01). Conclusions: The development of irAEs in cancer patients treated with immunotherapy may predict better treatment efficacy and overall survival. Further prospective studies are needed to confirm these associations and mechanism of action.
Increased incidence of immune-mediated myocarditis in advanced skin malignancies treated with immune checkpoint inhibitors in the COVID-19 era.
Authors: Gradone Allison , Ma Vincent T , Fecher Leslie Anne , Yentz Sarah Elizabeth , Vasbinder Alexi , Hayek Salim S. , Lao Christopher D.
Published: June 2022

2664

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced stage skin malignancies. Immunotherapy related adverse events (irAE) are toxicities associated with ICI therapy. Myocarditis is a rare life-threatening irAE. We attempt to characterize cases of myocarditis related to ICI therapy that have occurred since the start of the COVID-19 pandemic. Methods: We performed a single-center, retrospective cohort analysis of patients with advanced stage skin cancers who were treated with ICIs and identified cases of ICI-mediated myocarditis. ICI-mediated myocarditis was defined as evidence of myocardial injury in the setting of irAEs and exclusion of cardiovascular causes. Clinicopathologic variables and clinical outcomes were assessed in these patients. Results:A review of 361 patients that received ICI from 9/2014 – 10/2019 found 0 cases of ICI-mediated myocarditis. From 11/2019 – 12/2021, an additional 425 patients were identified of whom 11 (2.6%) developed ICI-mediated myocarditis. 10 patients had melanoma and 1 patient had Merkel cell carcinoma. 10/11 patients were male. 9/11 were treated with anti-PD-1 monotherapy and 2/11 were treated with ipilimumab with nivolumab. All patients had elevated high sensitivity troponin (median 361 pg/mL on presentation, reference range 0-19 pg/mL). 11/11 patients presented with elevated CPK (median 1734 IU/L, reference range 38-240 IU/L) and 8/11 presented with elevated AST:ALT ratio (median 1.58:1) on routine screening which prompted further investigation. 1 patient tested positive for COVID-19 13 days after initial biochemical concern for myocarditis, and 5 patients had received COVID-19 vaccines between 2.5-11 months prior to myocarditis onset. All patients were treated with high dose steroids, and 4 were treated with abatacept. 2 patients died within 30 days after diagnosis of myocarditis and 2 patients later died from malignancy progression. 2 patients developed progressive disease and 1 was successfully rechallenged with ICI with no myocarditis recurrence. 2 patients remain on active surveillance, 2 continue on a steroid taper, and 1 was lost to follow up. All patients with at least 5 months of follow up from myocarditis onset (n = 5) had persistently elevated HS-troponin despite normalization of CPK levels. Conclusions: In this single center study, we noted an increase in the frequency of ICI-mediated myocarditis in patients with advanced skin cancers during the pandemic era (2.6% vs 0% pre-pandemic) which is higher than reported in the literature (0.04-1.14%). The impact of COVID-19 during this time is suspicious and warrants further investigation. Therefore, we suggest heightened awareness in the COVID-19 era that elevated CPK levels and AST:ALT ratios merits further diagnostic investigation of ICI-mediated myocarditis.
TLD-1, a novel liposomal doxorubicin, in patients (pts) with advanced solid tumors: Dose escalation and expansion part of a multicenter open-label phase I trial (SAKK 65/16).
Authors: Hess Dagmar , Colombo Ilaria , Haefliger Simon , Rabaglio Manuela , Bastian Sara , Schwitter Michael , Eckhardt Katrin , Garzon Jesus Glaus , Hayoz Stefanie , Kopp Christoph , Holer Lisa , Mc Laughlin Anna , Kloft Charlotte , Sessa Cristiana , Stathis Anastasios , Halbherr Stefan , Baumgartner Christian , Joerger Markus
Published: June 2022

3027

Background: TLD-1 is a novel liposomal doxorubicin that compared favorably to conventional liposomal formulations of doxorubicin in preclinical in vivo mouse breast cancer models. This phase I first-in-human trial is aiming to determine the recommended phase II dose (RP2D), toxicity profile, pharmacokinetics and preliminary activity. Methods: Patients with a maximum of 3 prior lines of systemic chemotherapy and preferably anthracycline-sensitive disease were eligible. TLD-1 was administered on day 1 iv over 60-90 minutes (depending on individual dose) q 21 days, for up to 6 or 9 cycles (according to prior anthracycline-exposure) with premedication of 8mg dexamethasone. Dose escalation with dose levels (DL) 1-7 of 10, 16, 23, 30, 35, 40 and 45mg/m2 started with an accelerated titration design, treating one pt at each DL up to DL6 (40mg/m2) followed by a modified continual reassessment method at DL7 due to observed toxicity. Results: 30 pts (F:M = 24:6) have been treated, one each at DLs 1-6, 15 pts at DL7 and an additional 9 pts at DL6. Most frequent tumor types included breast (n = 13), ovarian (n = 6), cervical cancer (n = 2) and cholangiocarcinoma (n = 2). Median age was 67.5 years (range:38-83), 13 pts were exposed to prior anthracyclines. The median number of cycles was 4 (range:1-9). No dose-limiting toxicities (DLT) occurred during cycle 1. At DLs 1 to 5, no treatment-related G3 AEs (TRAE) were observed. At DL6, there was one case of mucositis G3, one of palmar-plantar-erythrodysesthesia (PPE) G3 and one of anemia and neutropenia G3 each. One patient with pre-existing valvular cardiopathy developed symptoms of heart-failure G3 after 8 cycles. Echocardiography showed severe mitral regurgitation with normal LV-EF. In addition one case of urinary-tract infection G3 was seen. Dose-modifications or -delays due to AEs occurred in 7/50 cycles. At DL7, one case of mucositis G3, 3 events of PPE G3 and one case of fatigue G3 were reported. In addition, one case of infection with shingles occurred. Dose-modifications or -delays due to AEs occurred in 12/61 cycles. Shingles and heart failure were reported as SAEs. All toxicities listed above were categorized as TRAE. 29/30 pts were evaluable for response. Three breast cancer pts had a partial response, 2 at DL7 and 1 at DL6, 14 pts had stable disease. Conclusions: No DLT was observed up to DL7. RP2D was defined at 40mg/m2 due to cumulative PPE G3 at DL7. The trial is ongoing with a comparative PK-part evaluating the two iv liposomal formulations of doxorubicin TLD-1 and Caelyx. Clinical trial information: NCT03387917.
An ultra-sensitive assay using cell-free DNA fragmentomics for multi-cancer early detection.
Authors: Shao Yang , Bao Hua , Wang Zheng , Ma Xiaoji , Guo Wei , Zhang Xiangyu , Wang Xinyu , Chen Yikuan , Mo Shaobo , Liang Naixin , Ma Qianli , Li Yaqi , Zhang Long , Tan Fengwei , Xue Qi , Liu Fangqi , Cai Sanjun , Gao Shugeng , Peng Junjie , Zhou Jian
Published: June 2022

3037

Background: Although most cancer can benefit from early detection by more effective treatments and better prognosis, current screening programs are only limited to tumor-specific tests for a subset of common cancers. To benefit a broader population and outweigh the risks of single-cancer tests, an effective and affordable multi-cancer test should be developed for sensitive early detection of multiple cancers and accurate prediction of cancer tissue of origin simultaneously. Methods: In this study, we enrolled 971 cancer patients of the most prevalent and lethal cancer types, including primary liver cancer (PLC, N= 381), colorectal adenocarcinoma (CRC, N= 298), and lung adenocarcinoma (LUAD, N= 292), as well as 243 healthy controls. The participants were randomly divided into a training cohort and a test cohort in a 1:1 ratio. Five fragmentomic features representing cfDNA fragmentation size, motif sequence, and copy number variation were extracted from processed whole-genome sequencing (WGS) data of the participants to build the base models. Each base model implemented five machine learning algorithms for model training, and the optimal base models were used to create the final multi-dimensional model through ensemble stacked machine learning. The integrated multi-cancer model is composed of the first-level binary cancer detection model and the second-level multi-classification cancer origin model. The training cohort was used to train the models with 10-fold cross-validation. The test cohort remained untouched during model construction and was solely used for performance evaluation. Results: Our cancer samples are highlighted by mostly early-stage diseases (early-stage PLC: 88.5%; CRC: 100.0%; LUAD: 100.0%). The cancer detection model reached an area under the curve (AUC) of 0.983 for differentiating cancer patients from healthy individuals in the test cohort. At 95.0% specificity, the sensitivity of detecting all cancer is 95.5%, and 100.0%, 94.6%, and 90.4% for PLC, CRC, and LUAD, respectively. Its sensitivity is consistently high for early-stage, small-size tumors. The cancer origin model demonstrated an overall 93.1% accuracy for predicting tissue of origin in the test cohort (97.4%, 94.3%, and 85.6% for PLC, CRC, and LUAD, respectively). Furthermore, the model's cancer detection and origin classification performance remained robust when reducing sequencing depth to 1× (cancer detection: ≥ 91.5% sensitivity at 95.0% specificity; cancer origin: ≥ 91.6% accuracy). Conclusions: We utilized multiple plasma cfDNA fragmentomic features to build an ensemble stacked machine learning model. The assay reached ultrasensitivity and accuracy for multi-cancer early detection, shedding light on leveraging cfDNA fragmentomics for early screening in clinical practice.
Characterization of genomic landscape using comprehensive circulating cell-free tumor DNA next generation sequencing in advanced thyroid carcinoma.
Authors: Tarasova Valentina , Tsai Jill , McIver Bryan , Hallanger-Johnson Julie E. , Veloski Colleen , Agosto Salgado Sarimar , Masannat Jude , Drusbosky Leylah , Chung Christine H.
Published: June 2022

3045

Background: Availability of targeted therapies in thyroid carcinoma (TC) has challenged the conventional treatment algorithms and established urgency for timely identification of targetable genetic abnormalities. Tissue-based next generation sequencing (NGS) is often limited by tumor insufficiency and slow turn-around time. Plasma-based circulating tumor DNA (ctDNA) NGS overcomes these barriers and has been widely adopted across advanced-stage solid tumors. To date, plasma-based NGS characterization of genomic alterations in TC has not been determined. Herein, we profile potential actionable mutations detected via ctDNA in patients with advanced TC subtypes. Methods: A retrospective analysis of Guardant Health, Inc database was performed using the commercially available Guardant360 plasma-NGS test on advanced metastatic TC samples collected between 2016 and 2021. Patients with papillary TC (PTC), follicular TC (FTC), poorly differentiated TC (PDTC), medullary TC (MTC), and anaplastic TC (ATC) were clustered into four groups (G1: ATC, G2: PTC, FTC, and PDTC, G3: MTC, and G4: unspecified TC). The landscape of genetic alterations, frequencies of alterations in clinically relevant genes, and tumor mutation burden (TMB) were analyzed. Results: Of the 1,108 patients included, 47.1% were male. The median age was 65 years old (range 13-98), and 0.18% (n = 5) patients were under 18 years old. Alteration frequencies of selected, clinically relevant genes are demonstrated in the table below. TMB analysis was performed on 315 samples, and the mean TMB was higher in G1 compared to G2, G3, and G4 (p = 0.0029, 0.0826, and 0.0112, respectively). Conclusions: Plasma-based comprehensive NGS by Guardant360 may be utilized in patients with advanced metastatic TC for detecting clinically relevant genetic alterations for the selection of available targeted therapies, immunotherapy, or determination of the clinical trial eligibility. Future validation of the clinical utility by analysis of paired tumor and plasma samples is warranted. [Table: see text]
A phase I/II study of first-in-human trial of JAB-21822 (KRAS G12C inhibitor) in advanced solid tumors.
Authors: Li Jian , Zhao Jun , Cao Baoshan , Fang Jian , Li Xiaoyan , Wang Mengzhao , Ba Yi , Li Xingya , Li Zhihua , LIU Zhe , Wang Yongsheng , Cheng Ying , Bai Chunmei , Shen Lin
Published: June 2022

3089

Background: KRAS G12C mutation occurs in approximately 4% of non-small cell lung cancer (NSCLC), 1-2% of colorectal cancer (CRC) and other solid tumors in China. JAB-21822 (Jacobio, Beijing, PRC) is a highly selective, covalent oral inhibitor of KRAS G12C. Methods: NCT05009329 is an ongoing first-in-human, open label phase I/II study of JAB-21822 in patients with advanced solid tumors. The primary objective is to evaluate the safety and tolerability of JAB-21822. Other objectives include preliminary efficacy, pharmacokinetics, and biomarkers. Here we report the results from the dose escalation phase of the trial. Results: As of January 28th, 2022, 53 patients with a median age of 62 years (39-79) were enrolled in 5 different dose levels: 200mg QD, 400mg QD, 800mg QD, 400mg BID and 400mg TID. Most patients (55%) had ≥ 2 prior lines of therapy. No dosing-limiting toxicities were observed. Two treatment-related adverse events (TRAEs) were G4 neutropenia (1 in 400mg BID and 1 in 400mg TID). The most common TRAEs (≥ 10%) included anemia (24.5%), total bilirubin increase (20.8%), direct bilirubin increase (15.1%), proteinuria (13.2%) and indirect bilirubin increase (11.3%). Only Grade 1 and 2 TRAEs were observed in the QD cohorts. A total of 33 patients (22 NSCLC, 9 CRC and 2 pancreatic cancer) had at least 1 post-baseline tumor assessment; in the 800mg QD cohort, overall response rate (ORR) and disease control rate (DCR) were 50% (5/10) and 100% (10/10), respectively, including 4 non-confirmed partial response (PR); in the 400mg QD cohort had an ORR and DCR of 80% (4/5) and 100% (5/5) respectively, including 2 non-confirmed PR. Patients with NSCLC (400mg QD and 800mg QD), the ORR and DCR were 70% (7/10) and 100% (10/10), respectively, including 5 non-confirmed PR. With respect to the pharmacokinetics analysis, JAB-21822 was rapidly absorbed with an average Tmax of 2 hr and reached higher plasma exposures (Cmax and AUC0-24h) after a single dose and multiple doses at C1D8. Conclusions: JAB-21822 was well tolerated with impressive preliminary efficacy in patients with heavily treated solid tumors harboring KRAS G12C mutation. The study is enrolling patients in the expansion phase. Multiple JAB-21822-based combination trials are also ongoing. Clinical trial information: NCT05009329.
Adaptive response analysis of colorectal cancer cells to low-dose oxaliplatin as a tool to deciphering mechanisms of synergistic drug interaction.
Authors: Tosi Diego , Robin Mathilde , Bini Marta , Marchive Candice , Djiane Alexandre , Heron-Milhavet Lisa , Bréhélin Laurent , Gongora Céline
Published: June 2022

3091

Background: Using an in vitro dose matrix approach, we previously showed in multiple colorectal cancer cell lines a striking cytotoxic synergism between oxaliplatin at very low concentrations and the ATR inhibitor VE-822. We confirmed this finding in vivo, and, surprisingly, in this setting the oxaliplatin-induced cell addiction to VE-822 persists over several days after oxaliplatin elimination. We tried to elucidate the molecular mechanism of the latter phenomenon. Methods: We evaluated by RNAseq the gene expression changes induced in vitro by low-dose oxaliplatin in the colorectal cancer cell line HCT-116 after 24 and 48 hours of treatment. In order to untangle the functional significance of the adaptive response to oxaliplatin, we performed on the RNAseq data an extensive gene set enrichment analysis (GSEA) using gene set from all Molecular Signature Database v7.4 collections with the exception of C7. For ontology-based gene set collections, we clusterized the enriched gene sets using the semantic similarity methodology in order to increase the readability of global functional response. Results: Extensive GSEA showed that after 24 hours of oxaliplatin treatment cancer cells upregulate several gene sets involved in aspecific responses to cellular stress or to various type of extracellular stimulations, including other organisms, oxygen-containing compounds, abiotic stimuli and hypoxia. In addition, several gene sets involved in proteolysis and autophagy are upregulated, suggesting a rewiring of cell machinery. After 48 hours of oxaliplatin treatment, we observed the activation of ribosome function, mitochondrial assembly and synthesis of aminoacids and ribonucleosides. Finally, a widespread negative enrichment of gene sets involved in DNA repair-related was detected both at 24 and at 48 hours, with a far greater negative enrichment at 48 hours, which suggest a commitment of cancer cell to a major limitation of DNA repairing capability lasting several days following a DNA damaging insult. Analysis of leading edge genes from the DNA repair gene sets showed a profound repression both at 24 and 48 hours of the transcripts of BRCA1, BRCA2, ATM, CHK1, WEE1, BARD1, BRIP1, NEHJ1, RAD51, XRCC2, CLSPN, GEN1, DNA2, EXO1, TOPBP1, POLE, RMI1. Interestingly, ATR mRNA was minimally repressed both at 24 and at 48 hours, which could explain the long-standing in vivo dependence of cancer cell to ATR after a brief oxaliplatin exposure. Conclusions: Extensive GSEA was able to elucidate the molecular mechanism underlying synergistic interaction between oxaliplatin and VE-822. The impact of profiling cancer cell adaptive responses by extensive GSEA should be further evaluated in the setting of rational development of drug combinations.
Theranostic pairing: ABY-025/251 targeting HER2 with 68Ga and 188Re—Minimized radioligands using Affibody peptide scaffold technology.
Authors: Liu Yongsheng , Sorensen Jens Benn , Brun Nikolai C. , Frejd Fredrik Y. , Tolmachev Vladimir
Published: June 2022

3093

Background: HER2 expressing tumors such as subsets of metastatic breast cancer and gastro-esophageal tumors can be targeted using specific antibodies or antibody-drug-conjugates (ADCs). However, some tumors remain refractory to treatment. External radiation therapy is unsuited to advanced metastatic disease. Targeted molecular radiation therapy has proven useful in other tumors such as neuroendocrine tumors or prostate cancer using 177Lu. 188Re is a beta emitting isotope that when chelated to the ABY-251 Affibody molecule has the potential to precisely target HER2 expressing tumors locally. The ABY-251 Affibody molecule is a very small, structured protein scaffold with a molecular weight of only 7 kDa targeting HER2 with high affinity (KD = 100pM). ABY-251 can be manufactured by chemical synthesis. A diagnostic analog molecule ABY-025 was also developed with chelation to 68Ga ideal for PET visualization. Methods: A pre-clinical study in mice was conducted to investigate tumor/tissue uptake, followed by a clinical diagnostic study for visualization in HER+ patients with metastatic breast cancer, to be followed by a theranostic study in humans. Results: Pre-clinical Study: A preclinical study in mice has previously demonstrated high contrast uptake in HER2 tumor tissue using the diagnostic analog ABY-025. Off target accumulation was seen in kidney tissue using the diagnostic ABY-025, which in the ABY-251 therapeutic molecule has been reduced by further engineering of the molecule. This molecule has now been proven to increase survival in mice bearing HER2+ tumors. Median survival in the treated animals was 68 days as compared to 29 and 27.5 days in animals treated with vehicle and non-labelled peptide respectively. Clinical diagnostic study ph1/2: ABY-025 was studied in HER2+ patients with metastatic breast cancer. In a study of 16 women with refractory metastatic breast cancer (>2 prior lines of therapy, 12 IHC positive and 4 IHC negative) 9 out of 10 patients showed high HER2 expression levels as measured with ABY-025 PET despite ongoing treatment with HER2 targeted therapy. Persistent high 68Ga-ABY-025 tumor uptake in patients despite treatment with standard HER2-targeted therapies is a sign of therapeutic drug resistance. These patients would be eligible for treatment with the therapeutic analog ABY-251 using 188Re generated beta radiation for tumor eradication. Clinical therapeutic study (planned): ABY-251 is in development to soon enter therapeutic clinical Ph1/2a trials in patients with refractory HER2+ tumors and positive tumor imaging using ABY-025 as a theranostic pair. Conclusions: A radiopharmaceutical theranostic approach diagnosing HER2+ patients with metastatic disease using 68Ga-ABY-025 for targetability and subsequent treatment using 188Re-ABY-251 seems feasible and is currently in clinical trials. Clinical trial information: NCT01858116.
A study of senaparib in combination with temozolomide for the treatment of patients with advanced solid tumors and extensive-stage small cell lung cancer.
Authors: Gao Bo , Lin Chia-Chi , Bai Li-Yuan , Chung Wei-Pang , Kao Wan-Chen , Zielinski Robert , Shim Byoung Yong , Hong Min Hee , Kim Sang-We , Liu Chien-Ying , Hsieh Chih-Yi , Cai Sui Xiong , Tian Ye Edward , Liu Lan , Niu Tiantian , Halcro Clare , Li Baoyue , Ma Ning , Zhang Congcong , Chen Xiangna
Published: June 2022

3102

Background: Senaparib (or IMP4297) is a PARP inhibitor with a novel chemical structure. Preliminary data demonstrate senaparib has significant anti-tumor activity with good tolerability in some patients with advanced solid tumors. DNA damage caused by temozolomide, a non-classic oral alkylating agent, can sensitize tumors to the effects of PARP inhibitors. In a xenograft model, synergistic antitumor effect was observed with the combination of senaparib and temozolomide, supporting this trial (NCT04434482). Methods: This is a phase Ⅰb/Ⅱ dose-escalation and dose-expansion study. Patients with advanced solid tumors were enrolled for dose escalation to evaluate the safety, tolerability using a modified “3+3” design. Low dose temozolomide (20 to 30 mg, once daily, days 1 to 21) in combination with continuous senaparib (40 to 80 mg, once daily, days 1 to 28) of each 28-day cycle was evaluated. Dose expansion will establish anti-tumor activity and safety of the combination in patients with extensive stage small cell lung cancer (ES-SCLC). Results: A total of 14 patients were enrolled for dose escalation as follows: Cohort 1 (1 patient; senaparib 40 mg plus temozolomide 20 mg), Cohort 2 (3 patients; senaparib 60 mg plus temozolomide 20 mg), Cohort 3 (7 patients; senaparib 80 mg plus temozolomide 20 mg), Cohort 4 (3 patients; senaparib 80 mg plus temozolomide 30 mg). One DLT (Grade 4 thrombocytopenia) was observed in Cohorts 3 and 4. The MTD and RP2D were determined as: senaparib 80 mg plus temozolomide 20 mg. Anaemia, neutropenia and thrombocytopenia were the only Grade ≥3 TEAEs occurring in > 1 patient. All AEs were manageable, and no treatment related deaths were reported. The ORR was observed in 3 of 12 (25.0%) evaluable patients, including 2 confirmed PR and 1 unconfirmed PR. The DCR was 83.3% (10 of 12 evaluable patients). Two patients remain on treatment for more than 1 year. Conclusions: Preliminary results suggest that low dose temozolomide (D1-21 of a 28-day cycle) in combination with continuous senaparib is generally well tolerated with encouraging anti-tumor activity. Recruitment for dose expansion for ES-ECLC patients has commenced (Sep 2021). Clinical trial information: NCT04434482.
Genomic landscape of SMARCA4-deficient lung tumors by clinical RNA sequencing.
Authors: Pham Brian , Ma Weijie , Call Greg , Ashok Arya , Mauer Elizabeth , Kamangar Elham , Li Tianhong
Published: June 2022

3118

Background: SMARCA4-deficient lung cancer is an undifferentiated lung cancer subtype associated with poor prognosis and morphological features that make them challenging to distinguish from sarcoma. These tumors are known to be resistant to standard of care surgery, radiation, and chemotherapy. Recent case reports suggest that these tumors might be resistant to immunotherapy. An assessment of the genomic and transcriptomic features of SMARCA4-deficient thoracic tumors may identify potential novel targets and treatment strategies for this new WHO lung cancer classification. Methods: We retrospectively analyzed de-identified NGS data from 8,484 thoracic formalin-fixed, paraffin-embedded tumor biopsies from lung cancer patients sequenced using the Tempus|xT solid tumor assay (DNA-seq of 595-648 genes at 500x coverage; whole-exome capture RNA-seq). Tumor-normal match sequencing was performed for all tumors, enabling the detection of incidental germline alterations across 46 genes. SMARCA4-deficiency was defined as tumors with a pathogenic or likely pathogenic SMARCA4 single nucleotide variant, insertion/deletion, or copy number alteration. Statistical significance was determined using Fisher's exact test and Wilcoxon rank-sum tests. Results: SMARCA4-deficiency was detected in 370 (4.4%) tumors, of which over 80% were stage III or IV. SMARCA4-deficient tumors included more male patients (63% vs 49%, p < 0.001) and younger age at diagnosis (median 64 vs 68 years, p < 0.001). There were more patients with high tumor mutational burden (TMB-H, ≥10 mutations per megabase) (34% vs 15%, p < 0.001), and fewer patients with positive PD-L1 immunohistochemical staining (44% vs 54%, p = 0.009) compared to SMARCA4 wild-type tumors. Microsatellite instability status occurred at similar low frequencies across SMARCA4-deficient vs wild-type tumors (0.8% vs 0.5%, p = 0.5). SMARCA4-deficient tumors showed enrichment for somatic mutations in TP53 (71% vs 47%, q < 0.001), STK11 (22% vs 6.8%, q < 0.001), KEAP1 (15% vs 4.2%, q < 0.001), and CDKN2A (15% vs 5.9%, q < 0.001) compared to wild-type. Tumor normal-match sequencing identified incidental germline mutations in MUTYH (2.2%), ATM (1.1%), ATP7B (0.5%), and MSH6 (0.5%) for SMARCA4-deficient tumors. RNA-sequencing analysis confirmed reduced transcriptional expression of SMARCA4 (p < 0.001), CD274 (PD-L1; p < 0.001), TNFRSF18 (p < 0.001), and TNFRSF4 (p = 0.035) in deficient tumors vs wild-type. Furthermore, SMARCA4-deficient tumors revealed reduced infiltration of CD4+ T cells (19% vs 22%, p < 0.001). Conclusions: This study reveals the unique genomic and transcriptional characteristics of SMARCA4-deficient lung tumors. Further studies are needed to assess the impact of immunotherapies and targeted therapies among this patient population.
Molecular characterization of cancers with ALK gene fusions in nonlung tumors.
Authors: Zhang Jin , Han Yushuai , Wang Weiran , Xu Mengxiang , Zhu Jianhua , Ma Tonghui
Published: June 2022

3121

Background: ALK gene rearrangement is known as “diamond mutation”. Targeted tyrosine kinase inhibitors have perfect therapeutic effects on ALK fusion lung cancer patients (pts), but the molecular characteristics of ALK fusions in other cancers have not been systematically elucidated. Methods: We retrospectively analyzed the NGS data of ALK fusion-positive Chinese tumor pts (n = 1068) to characterize ALK fusions in pan-cancer (excluding lung cancer) pts. Results: A total of 66 ALK fusion-positive pts with 13 types of cancer (excluding lung cancer) were screened, including 0.4% (24/5800) of brain tumor pts, 0.1% (11/7725) of gastrointestinal cancer pts, 0.4% (7/1741) of thyroid cancer pts, 0.5% (8/1732) of sarcoma pts, 0.2% (4/2031) of liver cancer pts, 0.6% (3/540) of melanoma pts, 9% (2/22) of inflammatory myofibroblastic tumor pts, 2.5% (2/79) of embryonal tumor pts, 0.4% (1/282) of lymphoma pts, 3.2% (1/31) of parotid carcinoma pts, 0.1% (1/985) of breast cancer pts, 0.4% (1/241) of prostatic cancer pts and 0.3% (1/320) of ovarian cancer pts. Herein, we reported 28 ALK fusion patterns, of which the most common partners were EML4 (n = 24) and STRN (n = 8), and mainly occurred in brain tumors (14/24, 58.8%) and thyroid cancers (6/8, 75%), respectively. In addition, there were 8 ALK fusion modes that were never reported before. Of the ALK fusion patterns described above, 92.4% (61/66) of fusions were located at the most canonical site of ALK (exon20), preserving the intact kinase domain. Meanwhile, rare fusion positions in the ALK gene were also found, such as PPP1CB-ALK(ex2:ex4), NUP107-ALK(ex20:ex3), COL14A1-ALK(ex8:ex4), BRAF-ALK(ex9:ex4), which preserve the extracellular and transmembrane domains, as well as RASD2-ALK(ex2:ex24), of which the breakpoint in ALK gene may disrupt the formation of kinase domain. Conclusions: We demonstrated the rarity of ALK gene fusions in nonlung cancers. Analyzing the ALK fusion characteristics of these cancer may help to clarify their pathogenesis and provide ideas for new drug treatment.[Table: see text]
Molecular reflex testing in non-small cell lung cancer: An optimal approach?
Authors: Hooper Kari , Witten Toni , Leader Benjamin , Fesko Yuri Anthony , Kruzel Mark
Published: June 2022

3127

Background: Molecular testing of non-squamous non-small cell lung cancer (NSCLC) tumors can guide appropriate treatment decisions and improve patient outcomes, but guideline complexity and frequent revision may negatively affect adherence. To assist oncologists in making timelier informed treatment decisions, we implemented a pathologist-directed molecular reflex pathway for non-squamous NSCLC at our clinical laboratory. Testing patterns and adherence to NCCN testing guidelines before and after implementation were reviewed. Methods: This retrospective cohort analysis included patients with diagnosed NSCLC who had molecular testing performed without a molecular reflex testing pathway in place (April 2016-March 2018, cohort A) and after the pathway was implemented (April 2018-March 2020, cohort B) at our clinical laboratory. TATs were calculated using dates of biopsy specimen submission and of molecular testing completion. Molecular testing methods (e.g., polymerase chain reaction, next-generation sequencing [NGS]), genetic alterations tested for and identified, PD-L1 by immunohistochemistry, and specimen quantity not sufficient (QNS) for testing were obtained from patients’ clinical laboratory reports. NSCLC diagnosis and cancer stage were obtained from electronic medical records, and adherence to NCCN guidelines (i.e., under-tested, over-tested genetic alterations) was evaluated according to specimen submission. Results: The mean TAT was 35.1 days for cohort A (n = 123) and 15.8 days for cohort B (n = 168), though the median in both was 14 with a range of 6 – 674 days in cohort A and 9 – 44 in cohort B (Table).Targetable genetic alterations were identified in 12.4% of patients in cohort A and 61.3% in cohort B; 46.3% in cohort A and 60.1% in cohort B had ≥1% positive PD-L1 staining. QNS results declined from 16.7% (n = 20) in cohort A to 12.5% (n = 21) in cohort B. Non-NCCN guideline testing was observed in 86.7% of patients in cohort A and 25.6% in cohort B, with those in cohort A being primarily under-tested (70%) and those in cohort B being over-tested. Only 13.3% of cohort A had alignment with NCCN guidelines for appropriate time of testing. Conclusions: Implementation of a pathology-driven molecular reflex pathway for non-squamous NSCLC was associated with increased identification of potentially targetable genetic alterations and improved adherence to NCCN NSCLC testing guidelines, along with reduction in QNS results. Though the TAT mean decreased after pathway implementation, the median did not change, offsetting the often increased lab TAT for NGS methodology vs. PCR and FISH alone. [Table: see text]
A digital imaging analysis (DIA) platform for identifying tertiary lymphoid structures (TLS) in lung adenocarcinoma (LUAD).
Authors: Kushnarev Vladimir , Belozerova Anna , Dymov Daniil , Popov Yuriy , Lukashevich Nadezhda , Valiev Ivan , Shamsutdinova Diana , Akaeva Aida , Galkin Ilia , Popyvanov Lev , Svekolkin Viktor , Nomie Krystle , Love Anna , Bagaev Alexander , Postovalova Ekaterina , Fowler Nathan
Published: June 2022

3142

Background: Previous studies of non-small cell lung cancer (NSCLC) have shown that TLS can be predictive of therapy response and a positive prognostic factor for survival. Currently, TLS identification is manually performed by pathologists with limited morphological criteria. Standardizing TLS detection with an automated DIA workflow could guide clinical trials in precision medicine by improving patient stratification. Here, we investigate the reproducibility and sensitivity of our DIA platform for evaluating TLS in LUAD using digital histopathology and machine learning. Methods: TLS were assessed by 3 pathologists on whole slide images (WSI) in a validation cohort of 22 LUAD samples using current TLS characterization criteria of dense lymphoid structures, the presence/absence of a germinal center, and high endothelial venules (HEVs). The intraclass correlation coefficient (ICC) was used to measure reproducibility between pathologists. The BostonGene DIA platform was used to train models for automated TLS detection. Quantitative measurements of area, lymphocyte number, and density of each TLS were obtained. A prospective cohort of 8 samples was used to compare pathologist and DIA identification of TLS. Normalized numbers of TLS in the tumor area were used for cohort stratification for overall survival (OS) analysis using the Kaplan-Meier method in an independent clinical cohort of 104 TCGA-LUAD patients. Results: A panel of 3 pathologists identified 326 unique TLS from 22 samples. Between-pathologist detection of TLS, independent of germinal center or HEV criteria, resulted in good reproducibility with an ICC of 0.77. Our DIA platform exhibited excellent reproducibility with an ICC of 0.94 when compared to validated prospective cohort annotation. In total, 155 and 189 TLS were identified by pathologists and our DIA platform, respectively. The DIA platform demonstrated a markedly improved sensitivity of 0.91 for TLS identification. Furthermore, OS analysis revealed that a TLS density greater than 0.94 TLS per mm2 of tumor assessed by DIA is a statistically significant independent biomarker of better OS in the LUAD cohort from TCGA. Conclusions: These results demonstrate the BostonGene DIA platform detects TLS in LUAD, with improved reproducibility and sensitivity over previous methods. Additionally, the DIA platform showed a TLS density greater than 0.94 TLS per mm2 of tumor is a positive prognostic marker for OS in LUAD. Standardized TLS DIA identification can be exploited in digital pathology applications for future clinical trials, informing clinicians of predictive and prognostic information during the decision-making process.
BRAF-targeted therapy for locally advanced ameloblastoma of the mandible: A potential neoadjuvant strategy.
Authors: Grynberg Shirly , Steinberg Yael , Asher Nethanel , Ben-betzalel Guy , Stoff Ronen , Markel Gal , Shapira-Frommer Ronnie , Schachter Jacob , Hirschhorn Ariel
Published: June 2022

3149

Background: Ameloblastoma is a rare benign but locally aggressive odontogenic neoplasm, with 2% of cases representing ameloblastic carcinoma or metastatic ameloblastoma. It affects young adults with high recurrence rates after surgery. The standard therapy is radical bone resection with subsequent functional, aesthetic & psychological impairments. Therefore, other therapeutic options, including neoadjuvant approach, should be considered. Sixty to 70% of mandible Ameloblastoma carry a BRAF mutation, usually V600E, and previous case reports have shown durable responses to treatment with BRAF inhibitors in these patients. We sought to explore the possibility of neoadjuvant BRAF or BRAF+MEK inhibition as neoadjuvant treatment in mandible Ameloblastoma. Here we present results of 12 patients with locally advanced disease who were treated with BRAF with or without MEK inhibitors. Methods: Patients who were unable to undergo jaw preservation surgery for locally advanced Ameloblastoma with a BRAF V600E mutation were treated with Dabrafenib or Dabrafenib-Tratmetinib in an EAP form. Patient records were analyzed for baseline parameters, treatment regimen, toxicity, response to therapy and the ability to convert to a mandible preservation surgery. Data were collected and analyzed in accordance with Sheba Medical Center IRB approval. Statistical analyses were done with STATA v.17. Results: Twelve patients were treated with Dabrafenib/ Dabrafenib-Tratmetinib between 2017-2021. Five patients received BRAF-MEK inhibitors and 7 BRAF inhibitor alone. Median age was 21. Ten patients(83%) showed excellent response to therapy and have successfully converted from planned radical bone resection to mandible preservation surgery. The other 2 patients are still on therapy and have also showed deep responses that enable conversion to mandible preservation. Median time to surgery was 10 months. With median follow up of 18 months, no cases of recurrence were documented. Rate of adverse events was as expected with only 1 case of G3-4 (hepatitis). Conclusions: Targeted therapy with BRAF with or without MEK inhibition may serve as an important therapeutic tool for locally advanced Ameloblastoma with the potential of organ preservation treatment, and is an important example of oncological therapy assisting in non-cancerous tumors.
Contact x-ray brachytherapy (Papillon) in addition to chemoradiotherapy to improve organ preservation in early cT2-T3 rectal adenocarcinoma: The 3-year results of OPERA randomized trial (NCT02505750).
Authors: Gerard Jean-Pierre , Barbet Nicolas N. , Pacé-Loscos Tanguy , Magné Nicolas , Serrand Jessica , Mineur Laurent , Deberne Melanie , Zilli Thomas , Dhadda Amandeep Singh , Sun Myint Arthur
Published: June 2022

3512

Background: The OPERA trial was testing the hypothesis that Contact x-ray brachytherapy (CXB) 50 kV boost will increase the rectal preservation rate in early T2-T3ab rectal adenocarcinoma. We present the 3 years clinical results. Methods: Inclusion criteria were: Age > 18 years, PS: 0-1, adenocarcinoma, distal - middle rectum, cT2-T3ab cN0-N1 < 8mm staged using MRI, M0. Stratification: T < vs ≥ 3 cm diameter. Control arm (A) was chemoradiotherapy (CRT) 45Gy/ 5 weeks with concurrent chemotherapy (Capecitabine 825 mg / m2) and external beam radiotherapy boost (9Gy/ 5 fr/ 1 week). Experimental arm used the same CRT (Cape 45) but the boost used CXB (90 Gy/ 3 fr/ 4 weeks). CXB was given first (B1) for tumor < 3 cm and after cap 45 (B2) for tumor ≥ 3 cm. Response assessment was made at week 14 after treatment start using palpation, endoscopy and MRI. A new assessment could be made at week 20 and 24 with a second MRI.TME was recommended in case of Partial response, Watch& Wait in case of clinical complete response (cCR). Bowel function measurement used LARS score. Main end- point was: Rate of organ preservation at 3 years. The hypothesis (in 2014) was 20% arm A vs 40% arm B (HR:0.53). Results: Between 5-2015 and 6-2020, 144 patients were included (France 96, UK 44, Switzerland 4). The analysis was made in 01-2022 with a median Follow-up time of 34 months. Treatment compliance was good in ≥ 90% of patients. Table gives main patients characteristics and clinical outcome. At three years the OP rate (Kaplan Meier estimate) was respectively arm A vs B: 60% vs 81% (HR 0.34 [95% CI 0.19 – 0.73]; p= 0.005). At three years OP for group A1 and B1 were: 65% vs 97% (HR 0.081 [95% CI 0.01-0.64]; p= 0.02). Conclusions: A CXB boost, when combined with chemoradiotherapy, increases the rate of organ preservation in early rectal adenocarcinoma. Starting with CXB in T < 3 cm appears as an attractive option. A B A1 (T < 3cm) B1 (T < 3cm) N° patient 71 73 30 32 Median age 68 69 69 70 Gender M/F 45/26 43/30 18/12 18/14 T2/T3 45/26 47/26 25/5 29/3 Distal/middle 53/18 53/20 21/9 27/5 cCR (W 14-24) 61% 90% p < 0.001 70% 94% p = 0.027 TME 26 12 8 1 Death 2 2 1 0 LARS < 30 80% 83% 87% 86%.
Short-term outcomes of laparoscopy-assisted versus open surgery for low rectal cancer (LASRE): A multicenter, randomized, controlled trial.
Authors: Chi Pan , Su Xiangqian , Xu Jianmin , Qiu Huizhong , Wang Ziqiang , Kang Liang , Deng Haijun , Chen Weiping , Zhang Qingtong , Du Xiaohui , Yang Chunkang , Guo Yincong , Zhong Ming , Ye Kai , You Jun , Xu Dongbo , Li Xinxiang , Xiong Zhiguo , Tao Kaixiong , Ding Ke-Feng ,   The LASRE Trial Investigators
Published: June 2022

3516

Background: The efficacy of laparoscopic versus open surgery for low rectal cancer has not yet been established. We aimed to evaluate whether laparoscopic surgery is non-inferior to open surgery for low rectal cancer in terms of oncologic outcomes. Methods: LASRE trial (NCT01899547) is a multicenter, noninferiority, randomized controlled trial being conducted in 22 tertiary hospitals across China. Patients with low rectal cancer and without evidence of pelvic lateral lymph nodes or distant metastasis were randomly assigned (2:1) to laparoscopic or open surgery. The primary outcome was 3-year disease-free survival (DFS). Secondary outcomes included pathological outcomes, 30-day postoperative complications, 30-day mortality, overall survival (OS), and quality of life. The target sample size was 1065 patients. The short-term pathological, surgical, and postoperative recovery outcomes, analyzed in a modified intention-to-treat population (mITT). Results: Between November 12, 2013, and June 6, 2018, 1070 patients were randomized into laparoscopic (n = 712) or open surgery (n = 358) groups; 1039 were included in the mITT analysis (685 in laparoscopic and 354 in open group). Seventeen patients (2.5%) in the laparoscopic group required conversion to open surgery. There were no significant between-group differences in the rates of complete mesorectal excision (85.3% vs. 85.8%; p = 0.777), negative circumferential resection margins (98.2% vs. 99.7%; p = 0.085), negative distal resection margins (99.4% vs. 100%; p = 0.362), and numbers of retrieved lymph nodes (13.0 vs. 12.0; p = 0.394). The laparoscopic surgery group exhibited a shorter time to first flatus (40.4 vs. 44.8 hours; p = 0.006), time to first defecation (61.2 vs. 66.3 hours; p = 0.031), duration of analgesic use (45.0 vs. 48.0 hours; p = 0.001), and duration of hospitalization (8.0 vs. 9.0 days; p = 0.008) compared to the open surgery group. The postoperative complication rates were 13.0% and 17.2% in the laparoscopic and open surgery groups, respectively (p = 0.065). There was no incidence of 30-day mortality. Conclusions: In patients with low rectal cancer, laparoscopic surgery performed by experienced surgeons can provide pathological outcomes comparable with those of open surgery in terms of complete mesorectal excision and negative resection margins, rapid postoperative recovery, and fewer postoperative complications. Clinical trial information: NCT01899547.