bluuebunny/crossref_metadata_2025 huggingface dataset:
The prevalence of KRASG12C mutations utilizing circulating tumor DNA (ctDNA) in 80,911 patients with cancer.
Authors: Thein Kyaw , Banks Kimberly , Saam Jennifer , Raymond Victoria M. , Roszik Jason , Meric-Bernstam Funda , Janku Filip , Hong David S.
Published: May 2020

3547

Background: Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most commonly mutated proto-oncogene identified in cancer and still remains an arduous therapeutic challenge. Recently, KRASG12C mutation has become special interest since it has now been considered potentially druggable after the introduction of covalent small-molecule KRASG12C inhibitors. Advances in next-generation sequencing (NGS) and embracing utilization of ctDNA have uncovered more genetic alterations in many cancers. We present a comprehensive analysis on the prevalence of KRASG12C mutations identified by ctDNA. Methods: We conducted a 5-year (July 2014 to June 2019) retrospective review of ctDNA NGS analysis in the Guardant360 CLIA database inclusive of treatment-naïve and previously treated patients with metastatic solid tumors. Data were retrieved from the 80,911 unique patients with ctDNA detected. Clonality and co-occurrence of cancer type were analyzed. Clonality was defined as variant allele fraction(AF) / maximum somatic AF in the sample. Results: 80,911 patients, which included more than 100 tumor histologies, were identified. 2,985 patients (3.7%) with > 40 tumor types had KRASG12C mutations identified in ctDNA. KRASG12C prevalence by cancer type were as follows: sarcomatoid lung carcinoma (13.5%), lung cancer NOS (9%), large cell lung carcinoma (9%), lung adenocarcinoma (7.4%), NSCLC (6.9%), carcinoma of unknown primary (CUP) (4.1%), lung carcinoid (4%), CRC (3.5%), squamous cell lung carcinoma (2%), small cell lung carcinoma (1.5%), pancreatic ductal adenocarcinoma (PDAC) (1.2%), cholangiocarcinoma (1.2%), bladder cancer (0.6%), ovarian cancer (0.6%) and breast cancer (0.3%). 53 additional patients with KRASG12C were identified across 24 other tumor types. The KRASG12C mutation was found to be clonal (clonality > 0.9%) in the majority of patients with lung adenocarcinoma, NSCLC, CUP, squamous cell lung carcinoma, and PDAC, compared to patients with CRC and breast cancer who had bimodal distribution of clonal and sub clonal mutations. Conclusions: To our knowledge, this is the largest analysis on the prevalence of KRASG12C mutations identified by ctDNA. Our study demonstrated the feasibility of utilizing ctDNA to identify KRASG12C mutations across solid tumors with the highest prevalence in lung cancer as previously reported in tissue. The clonality information available from ctDNA-based genotyping may provide insights into the clinical efficacy of targeting KRASG12C in different tumor types.
Phase I study of mesothelin-targeted immunotoxin LMB-100 given as a long infusion with or without nab-paclitaxel.
Authors: Pegna Guillaume Joe , Ahmad Mehwish Iqra , Yu Yunkai , Yuno Akira , Lee Min-Jung , Peer Cody J. , Steinberg Seth M. , Cao Liang , Trepel Jane B , Figg William Douglas , Hassan Raffit , Pastan Ira , Alewine Christine Campo
Published: May 2020

3553

Background: LMB-100 recombinant immunotoxin consists of a mesothelin-binding Fab for targeting a modified Pseudomonas exotoxin A payload. Previous Phase 1 clinical testing of a 30-minute LMB-100 “short” infusion format identified a serum half-life of ~1 hour. Pre-clinical data suggested that extending infusion time could improve anti-tumor efficacy by increasing tumor cell duration of exposure to LMB-100. The primary objective of this study was to determine the safety and tolerability of administering LMB-100 in a long infusion format over 24-48 hours alone or with nab-paclitaxel chemotherapy in patients with mesothelin-expressing solid tumors. Methods: Patients (n = 15) with pancreatic adenocarcinoma and other mesothelin-expressing solid tumors (n = 3; mesothelioma, colon, and ampullary cancers) treated on 3 dose levels received long infusion of LMB-100 (65 or 100 mcg/kg/day) for 24 hour on Days 1 and 4 (n = 6) or 48 hour on Day 1 (n = 9) with or without a loading dose (40 mcg/kg over 30 minutes) for up to 2 cycles. In the second arm, patients (n = 5) with pancreatic adenocarcinoma were treated with LMB-100 over 24 hours on Day 1 concurrently with nab-paclitaxel (125 mg/m2) for up to 3 cycles. Results: DLT of proteinuria (grade 3) in one patient and acute kidney injury (grade 1) in one patient were observed amongst patients receiving 100 mcg/kg/day over 48 hours and 24 hours, respectively. No objective responses were seen but all patients receiving nab-paclitaxel had > 50% decrease in CA 19-9. Patients at all single agent dose levels (8 of 10 evaluable) developed high titer anti-drug antibodies (ADAs) against LMB-100. Those with ADAs (8 of 8) had undetectable cycle 2 peak plasma LMB-100 concentration. Development of high titer ADAs occurred more frequently with long infusion than seen previously with “short” infusion LMB-100. Most long infusion patients (19 of 20) developed increased serum IL-6 within 24 hours of LMB-100 infusion. However, the systemic inflammatory response to LMB-100 (as measured by increased serum CRP) which occurs in most “short” infusion patients was not observed. Conclusions: Long infusion format LMB-100 is generally well tolerated but immunogenicity limits treatment to 1 effective cycle. No anti-tumor efficacy of the single agent was observed. Clinical trial information: NCT02810418 .
Clinically aggressive malignancies associated with STK11 germline mutations (STK11GCa): A comprehensive genomic profiling (CGP) study.
Authors: Sokol Ethan , Danziger Natalie , Pavlick Dean , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Jonathan Keith , Lin Douglas I. , Ramkissoon Shakti H. , Severson Eric Allan , Hemmerich Amanda , Duncan Daniel , Edgerly Claire I. , Huang Richard , Chung Jon , Reddy Venkataprasanth P. , McGregor Kimberly , Venstrom Jeffrey , Schrock Alexa Betzig , Alexander Brian Michael , Ross Jeffrey S.
Published: May 2020

3558

Background: Germline mutations in the STK11 ( LKB1) mTOR pathway gene are associated with Peutz-Jehger’s Syndrome and a variety of malignancies of variable clinical aggressiveness. Recent evidence also links STK11 inactivation with failure to benefit from anti-cancer immune checkpoint inhibitor (IO) therapy in NSCLC. Methods: Using hybrid capture based CGP on extracted tumor DNA and a published “somatic-germline-zygosity” SGZ data analysis algorithm on 212,470 samples of clinically advanced malignancies, we identified 103 (0.05%) STK11GCa inactivating base substitutions or indels. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: 57 (55%) STK11GCa cases were NSCLC, 7 (7%) STK11GCa cases each were CRC, breast, pancreatic and unknown primary carcinomas, and 3 (3%) were gynecologic cancers. Amongst all samples included in this analysis, STK11 germline alterations were found in 0.15% NSCLC, 0.03% CRC, 0.03% breast, 0.08% pancreas, 0.06% unknown primary carcinoma and 0.03% of gynecologic cancers. Additional malignancies harboring STK11GCa included melanoma, gastroesophageal, HNSCC, bladder, HCC, lymphoma and mesothelioma. In STK11GCa, the median patient age at sequencing was 61 years (range 2 to > 89 years); gender distribution was 52% female and 48% male. STK11GCa cases had a median of 6.5 genomic alterations (GA)/tumor and KEAP1, another IO resistance gene, was co-altered in 10%. Currently untargetable GA were detected in TP53 (50%), KRAS (38% with 9% in potentially targetable G12C), CDKN2A (32%), CDKN2B (22%), SMARCA4 (19%), MYC (11%), and APC (10%). Potentially targetable GA, which have also been linked in some studies to IO efficacy, included GA in BRAF (10%), EGFR (9%) and PBRM1 (4%). No targetable gene rearrangements or fusions were identified. No MSI High cases were identified. The median TMB was 5 mut/Mb with 23 % >10 mut/Mb and 4% >20 mut/Mb. 15% of 20 evaluated STK11GCA cases were PD-L1 high (>50% tumor cell staining). Conclusions: STK11GCa include a wide variety of primary tumors with a paucity of co-occurring targetable GA. Although these tumors have significant PD-L1 staining and a subset harbor other markers of potential IO efficacy, the inactivated STK11 in these tumors may contribute to IO resistance and lack of responsiveness to immunotherapies.
A prospective study of prognostic role of plasma circulating tumor DNA (ctDNA) in patients (pts) with early-stage malignancies.
Authors: Fedyanin Mikhail , Boyarskikh Uljana , Polyanskaya Elizaveta , Aliev Vechaslav , Mamedli Zaman , Kechin Andrey , Oscorbin Igor , Shamovskaya Darya , Popova Anna , Polyakov Alexandr , Kudashkin Nikolay , Arzumanyan Alla L. , Trigolosov Arkadiy , Nikulin Maxim P. , Nered Sergey N. , Stilidi Ivan , Moroz Ekaterina , Chekini Antonio , Filipenko Maxim , Tjulandin Sergei
Published: May 2020

3559

Background: Recently, conflicting evidence has emerged showing the association of ctDNA level and cancer progression. The aim of our study was the development of a method for detecting ctDNA in plasma and the investigation of the prognostic value of ctDNA retention after surgery in the prospective way. Methods: This prospective, single-center, sample collection study; pts with early-stage malignancies of the different origin were included. Tumor somatic mutations were determined by target sequencing of DNA from FFPE tumor blocks. Sequencing was performed using the custom NGS panel covering regions of frequent somatic mutations in 50 genes. Tumor-specific mutations were monitored in plasma samples taken before and after surgery. The median time between surgery and plasma collection was 7 days (5-15). Mutations of plasma ctDNA were determined by ddPCR. The plasma sample was considered "positive" if the content of ctDNA was more than 0.5 copies of mutant DNA in ml plasma. We needed 265 pts for improving 1-year disease free survival (DFS) from 60% to 80% with α=0.01, β=0.1, 10% loss of f.-up and duration of the study for 2 years. Results: The study comprised 271 pts with various cancers including colorectal – 91 (33,6%), pancreatic – 37 (13,7%), breast – 66 (24,4%), lung – 35 (12,9%) and gastric cancer – 42 (15,5%). Pts with stage I was 50 (18,5%), stage II – 118 (43,5%) and stage III – 103 (38%). The median time of the f.-up was 9 mos. (1-37). No significant association was found between the level of ctDNA before surgery and DFS either in the general group or in groups stratified by tumor sites (HR 2.4, 95%CI 0.8-7.1, р=0.12 and HR 1.5, 95%CI 0.4-6.3, р=0.5, correspondingly). ctDNA was detected in the plasma after surgery in 57 (10%) pts: 9 (9.9%) cases of colorectal, 10 (27%) - pancreatic, 9 (13.6%) - breast, 19 (54.3%) - lung, and 10 (23.8%) - gastric cancer. Progression of the disease was detected in 28/57 (49%) pts with ctDNA(+) and 17/214 (8%) - in ctDNA(-) pts (p<0.001). One-year DFS in ctDNA(+) and ctDNA(-) pts were 57% and 87%, respectively (HR 6.1, 95%CI 3.3-11.2, p<0,001). ctDNA positivity after surgery was an independent negative prognostic factor according to Cox regression model fitted to T, N, and adjuvant chemotherapy (HR 5.7, 95%CI 3.1-10.8, p <0.001). Conclusions: These results demonstrate the prognostic significance of ctDNA persisting after surgery in pts with the early stage of the different malignancies. Further clinical validation of this approach is required in trails with modifications of the adjuvant treatment, according to the content of ctDNA.
Platform comparison of HTG EdgeSeq and RNA-Seq for gene expression profiling of tumor tissue specimens.
Authors: Ran Di , Moharil Janhavi , Lu James , Gustafson Heather , Culm-Merdek Kerry , Strand-Tibbitts Kristen , Benjamin Laura , Navratil Marian
Published: May 2020

3566

Background: Clinical biomarker studies are often hindered by the availability of tissue specimens of sufficient quality and quantity. While RNA-Seq is often considered the gold standard for measuring mRNA expression levels in cancer tissue, it typically requires multiple formalin-fixed paraffin-embedded (FFPE) tissue sections to extract a sufficient amount of quality RNA for subsequent gene expression profiling analysis. The HTG EdgeSeq technology is a gene expression profiling platform that combines quantitative nuclease protection assay technology with next-generation sequencing detection. Unlike RNA-Seq, the HTG EdgeSeq technology does not require RNA extraction, and can use small amounts of tissue material, typically several mm2, to generate reproducible gene expression profiles. Methods: This study compares the performance of RNA-Seq and HTG's profiling panel, the HTG EdgeSeq Precision Immuno-Oncology Panel (PIP), which is designed to measure expression levels of 1,392 genes focused on tumor/immune interaction. Approximately 1,200 samples from three tumor indications (gastric cancer, colorectal cancer and ovarian cancer) were tested using both technologies. Results: Up to four FFPE slides were used for RNA extraction to support RNA-Seq testing; out of the 1,202 samples processed, 1,099 generated extracted RNA of sufficient quality and quantity (as measured by RNA concentration, RIN score and %DV200) to proceed to sequencing, which resulted in a pass rate of 91.4% for RNA-Seq. The HTG EdgeSeq PIP panel resulted in a pass rate of 97.3% (samples passing QC metrics) when the same 1,200 samples were tested, and required only a single FFPE section owing to the small sample requirement. The t-SNE (a non-linear dimensionality reduction method) analysis of the common 1,358 genes revealed similar clustering of the three cancer indications between the two methods. Correlations across individual genes by sample resulted in the mean Spearman correlation coefficient of 0.73 (95% confidence interval of 0.61 - 0.80). Additionally, gene-wise comparisons across all samples were also evaluated. Conclusions: These data demonstrate that HTG EdgeSeq gene expression panels can be used as a competitive alternative to RNA-Seq, generating equivalent gene expression results, while offering the added benefits of a small sample size requirement, lack of RNA extraction bias, and fully automated data analysis pipeline.
Genomic analysis of driver-negative lung adenocarcinoma (LA) in lifetime never smokers.
Authors: Fares Aline Fusco , Martins-Filho Sebastiao N. , Li Quan , Seto Andrew , Stewart Erin L. , Zhang Tong , Lau Sally CM , Ravi Deepti , Weiss Jessica , Patel Devalben , Pham Nhu-An , Sacher Adrian G. , Bradbury Penelope Ann , Stockley Tracy , Leighl Natasha B. , Shepherd Frances A. , Tsao Ming Sound , Liu Geoffrey
Published: May 2020

3571

Background: Genomic events giving rise to driver negative LA in never smokers remain elusive. Here we report results of whole exome sequencing (WES) and targeted RNA sequencing in NS who had no mutation drivers found on routine clinical testing by targeted next generation sequencing (NGS). Methods: The cohort of never smokers with EGFR/ALK negative LA by clinical biomarker testing at Princess Margaret Cancer Centre, were first subjected to various clinical NGS profiling platforms (table). Where tissue was available, those negative for potential drivers in the clinical NGS then underwent WES (mean coverage > 200x) and Oncomine comprehensive v.3 RNA sequencing. We analyzed mutational signatures (MS) of the driver negative cohort based on the COSMIC catalog and assessed the median tumor mutation burden (mTMB mut/Mb -Megabase) in cases without a smoking MS, to avoid confounders. Results: Of 159 never smokers profiled with clinical NGS, potential drivers were found in 86 (54%): 75 (87%) with mutations in known LA driver genes and 11 (13%) with fusions. Among the remaining never smokers that tested negative by clinical NGS, 35 (48%) had available tissue for further testing. The Oncomine panel identified 9 cases (25%) with fusions or MET exon14 mutation (n = 7). Within the driver negative group, 24 (92%) underwent WES. Three tumors had WES base substitution patterns that were consistent with a smoking-related MS (MS4). Twenty-one patients exhibited signatures found common across all cancer types (MS 5), associated with DNA mismatch repair (MS 6, MS 20) or APOBEC over-activation (MS 2, MS13). In the driver-negative group, we identified 7 pts with somatic mutations in the KMT2 family (4 KMT2C, 4 KMT2A, 1 KMT2D), known for putative tumor suppressors and histone methyltransferases. mTMB on the driver negative group was 1.92, while one outlier with APOBEC MS and KMT2C/A mutations had a TMB of 16.8. Conclusions: Never smokers with driver negative LA are a heterogeneous group, with different MS and a wide TMB range. Mutations on KMT2 family are frequently found in driver negative LA in never smokers and warrant further investigations. [Table: see text]
Phase I study of regorafenib and sildenafil in advanced solid tumors.
Authors: Poklepovic Andrew Stewart , Gordon Sarah W. , McGuire William P. , Thacker Leroy R. , Deng Xiaoyan , Tombes Mary Beth , Shrader Ellen , Ryan Alison A. , Kmieciak Maciej , Dent Paul
Published: May 2020

3593

Background: Regorafenib (R) is an oral multikinase inhibitor with anti-angiogenic properties approved for use in several solid tumors. Sildenafil (S) is an oral phosphodiesterase-5 (PDE5) inhibitor that interacts synergistically with R in both short-term and colony formation assays to kill multiple cancer cell types. Mechanistic studies identified that PDE5 knockdown enhances R lethality, suggesting a direct target effect for S. Methods: A single-center, open-label, dose-escalation study was conducted in adults with advanced solid tumors. Patients (pts) took R (120 or 160 mg) and S (50 or 100 mg) once daily days 1 through 21 of each 28-day cycle. Pts remained on study treatment until progression or excessive toxicity, with response assessments every 8 wks. The maximum tolerated dose (MTD) was defined as the maximum tested dose with ≤1/6 pts experiencing dose-limiting toxicity (DLT), with Cycle 1 as the DLT observation period. Results: 32 pts were enrolled and 29 treated at 3 dose levels (DLs). Median duration of treatment was 8 (range 2 – 101) wks. One of 6 evaluable pts treated at DL2 (160 mg R + 50 mg S) experienced DLT (grade 4 lipase increase). One of 12 evaluable pts treated at DL3A (160 mg R + 100 mg S, the MTD) experienced DLT (grade 3 rash and grade 3 muscle pain). The toxicity profile was generally consistent with that seen in R monotherapy at FDA-approved doses. 10 pts had a best response of progressive disease (PD). 14 pts had a best response of stable disease (SD), 5 of whom had stable disease duration > 24 wks. 5 treated pts were not evaluable for response. Notably, 2 pts with ovarian cancer and 1 with cervical cancer had stable disease > 24 wks. Analyses of correlative studies to examine pharmacokinetics and drug combination pharmacodynamic effects are underway. Conclusions: The combination was well-tolerated. The recommended phase 2 dose is 160 mg R + 100 mg S. Objective responses were not observed, but prolonged stable disease was seen in a subset of pts. Encouraging disease control was seen in gynecologic cancers. Dosing up to 100 mg S is safe concurrently with standard doses of R, and may be considered as an adjunct to R in future trials. Evaluation of R+S in gynecologic cancers warrants further consideration. Clinical trial information: NCT02466802 . [Table: see text]
Myelodysplastic syndrome and acute myeloid leukemia as side effect of PARP inhibitors.
Authors: Master Samip R. , Mansour Richard P.
Published: May 2020

3601

Background: Acute myeloid leukemia(AML) and myelodysplastic syndrome(MDS) have been rarely noted in patients on PARP inhibitors. The actual incidence is unknown and it has been put has warning/precaution of FDA label for olaparib, niraparib and rucaparib. Methods: The FDA has made the data on the adverse effects of various treatments available to the general public through the FDA Adverse Events Reports System (FAERS) public dashboard. We investigated the adverse events reported for PARP inhibitors like olaparib, niraparib and rucaparib for the years 2017-2019 to find out the number of patients who had acute leukemia or myelodysplastic syndrome reported while on those medications. Results: A total of 8151 adverse events were reported between 2017 and 2019 for olaparib, niraparib and rucaparib. Out of which, 6077 were serious and 1121 deaths were reported. There were 237 reports of AML and MDS, which compromise 2.9 % of total events reported. We also looked that cyclophosphamide data for comparison purposes during the same period. There were 29,162 adverse events reported for cyclophosphamide, out of which 963 i.e. 3.3% were AML and MDS. For olaparib, 2523 adverse events were reported and 173 (6.8%) were MDS/AML. For niraparib, 5496 adverse events were reported and 41(0.7%) were MDS/AML. For rucaparib, 153 adverse events were reported and 4 (2.6%) were MDS/AML. Conclusions: Based on this retrospective data, AML/MDS is an adverse event in pts of PARP inhibitors and needs to be monitored. Pts on olaparib seem to have high risk of AML/MDS compared to other two to PARP inhibitors.
Results of a phase Ib trial evaluating the safety and clinical activity of sapanisertib (TAK 228) in combination with serabelisib (TAK 117) and paclitaxel in patients with advanced ovarian, endometrial, or breast cancer.
Authors: Williams Casey B. , Williams Kirstin Anne , Krie Amy K. , De Pradip , Dey Nandini , Leyland-Jones Brian , Starks David , Rojas-Espaillat Luis Alexander
Published: May 2020

3604

Background: The link between taxane resistance and activation of PI3K/AKT/mTOR signaling suggests that by inhibiting this pathway in combination with anti-microtubule agents like paclitaxel may improve treatment outcomes in many malignancies. To investigate this further we combined the TORC 1/2 inhibitor sapanisertib (TAK-228), the PI3Kα isoform inhibitor serabelisib (TAK-117), and paclitaxel in a phase I trial to determine the safety, efficacy, and RP2D. Methods: Open label, cohort study using a traditional 3+3 dose escalation design with a maximum of 5 dosing cohorts. A dose expansion of cohort 4, the recommended RP2D, is planned for February 2020. Results: Enrollment to the DLT evaluation has been completed and the clinical results are summarized in Table. Sixteen patients have been enrolled; a majority were heavily pretreated and resistant to paclitaxel. Overall, the combination was safe and tolerable. One DLT occurred due to renal dysfunction in cohort 5. 360 adverse events have been reported, but only 28 (8%) grade 3 or 4 events. The most common events were leukopenia and non-febrile neutropenia. Two patients required dose reductions as a result of pneumonitis. The ORR is currently 46% in 13 evaluable patients. CBR is 69% and PFS is currently at 10 months. Two patients achieved a CR and three patients remain on treatment. Conclusions: The combination proved to be well tolerated in the doses and schedules used in cohorts 1-4 and exhibited very promising clinical activity in heavily pretreated patients. This regimen could prove to be a highly effective treatment option and a phase 2 study is warranted at the RP2D. Clinical trial information: NCT03154294 . [Table: see text]
Results of a completed first-in-human phase Ib dose-escalation study of oral CBL0137 in patients with advanced solid tumors.
Authors: Fedyanin Mikhail , Tryakin Alexey , Lisyanskaya Alla Sergeevna , Solovyeva Ekaterina , Fadeeva Natalia , Gladkov Oleg , Moiseyenko Vladimir , Cheporov Sergey V. , Shpigotskaya Polina , Purmal Andrei , Miller Langdon L. , Leonov Andrey , Zakurdaeva Kristina , Gurova Katerina , Gudkov Andrei , Tjulandin Sergei
Published: May 2020

3607

Background: Curaxin CBL0137 is a novel compound with broad anticancer activity in animal models. The drug is a non-genotoxic DNA intercalator that interferes with histone/DNA binding causing decondensation of chromatin in tumor cells, functional inactivation of histone chaperone FACT, activation of p53 and IFN responses, and inhibition of pro-cancer transcriptional factors, MYC, NF-kB, HSF1, and HIF1a. Methods: The study enrolled adults with advanced chemorefractory solid tumors, ECOG PS ≤2, and adequate organ function. The primary objective was to find the maximum tolerated dose (MTD) and recommended dosing regimen (RDR). Secondary objectives were to evaluate CBL0137 safety, pharmacokinetics, and efficacy. CBL1037 was given orally once daily (QD) for the first 14 days of repeated 28-day cycles. A 3+3 dose escalation determined the MTD, defined as the highest dose at which ≤1 of 6 pts had Cycle 1 dose-limiting toxicity (DLT). Pharmacokinetics were assessed on Days 1 and 13. Efficacy was evaluated every 8 weeks. Results: 60 pts were enrolled (females/males [n]: 42/18; median [range] age 56 [25-76] years; ECOG PS [n] 0/1/2: 8/49/3); cancer types [n]: ovarian cancer [15], colorectal cancer [14], breast cancer [11], others [20]) over 16 dose levels ranging from 4 mg to 200 mg QD. Durations of therapy ranged from 6 to 342 days. Three DLTs were observed: prolongation of QTc Gr 3 (88 mg QD), neutropenia/thrombocytopenia Gr 4 (200 mg QD), and LV dysfunction Gr 3 (200 mg QD). Dose-dependent nausea/vomiting was observed and was Gr 2-4 at 200 mg QD. Gr 1/2 photosensitization occurred in 11 subjects across doses from 48 to 200 mg QD but was successfully managed with sun protection and resulted in no dose modifications or discontinuations. On Day 1, mean (range) plasma CBL0137 Tmax values were 5.1 (1-10) hrs. Generally linear increases in AUC occurred with increasing CBL0137 dose. Mean (range) t1/2 values were 25.6 (0.3-166) hrs, with minor dose dependency. Mean (range) Day 13/Day 1 Ctrough ratios showed 3.6 (1.7-7.2)-fold accumulations. Disease control was registered in 11 pts who had stable disease (SD). Target lesion regressions up to 21% were documented in 4 patients with breast cancer (2), sarcoma (1), and ovarian cancer (1). Pts with breast cancer (1) and sarcoma (1) had SD for > 36 weeks. Conclusions: The Phase 2 RDR for oral CBL0137 was established as 180 mg QD x 14 days in 28-day cycles based on bone marrow and gastrointestinal DLTs at 200 mg QD. CBL0137 showed a manageable safety profile with efficacy signals. Further study as a component of combinations is planned. Clinical trial information: 847 .
Identifying pan-cancer transcriptomic determinants of perineural and lymphovascular invasion using machine learning.
Authors: Guo Jimmy , Hoffman Hannah I. , Hwang Peter G , Kim Daniel Y , Alshalalfa Mohammed , Mahal Brandon Arvin Virgil , Hong Theodore S. , Hwang William L.
Published: May 2020

3621

Background: Tumor invasion of nerves, blood vessels, and lymphatics are a primary means of local recurrence and escape from the local microenvironment, resulting in metastases and poor clinical outcomes. However, the genetic drivers that are most pertinent to these malignant processes are not well understood, and few therapeutics successfully target perineural invasion (PNI) and lympho-vascular invasion (LVI). Identifying genetic drivers and biomarkers can be valuable for therapeutic targeting and prognostication. Methods: We analyzed surgical pathology reports and bulk RNA-seq data of 1,624 patients across 12 cancer types from The Cancer Genome Atlas (TCGA). Differential gene expression analysis between patients with and without PNI/LVI was performed using DEseq2 in Python while adjusting for age, sex, race, and cancer type. Genes with an adjusted p-value < 0.001 were then used to derive parsimonious signatures using random forest classifier and recursive feature selection algorithms. Results: To assess whether these invasive histological phenotypes have clinical ramifications, we examined outcomes data and found that patients with PNI or LVI have reduced overall (OS) and disease-free survival (DFS) ( p < 0.05) relative to those without. In addition, patients with both PNI and LVI have the lowest DFS from our pan-cancer analysis, suggesting that each may have non-redundant contributions to poor outcomes. From the differential gene expression analysis, we identified a set of 621 and 606 genes that were highly associated with PNI and LVI, respectively (padj < 0.001). Many of these genes such as TEKT5 (padj = 3.18 x 10−64), which is canonically associated with ciliary and flagellar microtubules, and SCRIB (padj = 1.60 x 10−21), which helps establish apico-basal cell polarity, have not been described previously in relevance to PNI and LVI, and warrant further scientific and clinical investigation. These genes were ultimately condensed into a signature that optimizes for both model simplicity and goodness of fit with up to 90% accuracy as determined by trials on both a logistic regression and neural network model. Conclusions: We concluded from a pan-cancer analysis that PNI and LVI are associated with poor outcomes, and we were able to robustly identify sets of genes that characterize each invasive mechanism for further functional investigation.
Increased tumor purity and improved biomarker detection using precision needle punch enrichment of pathology specimen paraffin blocks: Method validation and implementation in a prospective clinical trial.
Authors: Killian Jonathan Keith , Wright Chris , Chan Lindsay , Danziger Natalie , Elvin Julia Andrea , Vergilio Jo-Anne , Lin Douglas I. , Williams Erik Abraham , Ramkissoon Shakti H. , Severson Eric Allan , Hemmerich Amanda , Duncan Daniel , Edgerly Claire I. , Tse Julie Y , McGregor Kimberly , Schrock Alexa Betzig , Alexander Brian Michael , Ross Jeffrey S. , Redman Mary Weber , Herbst Roy S.
Published: May 2020

3622

Background: While many sequencing assays may be geared for short variants (SV), more complex biomarkers such as genomic loss of heterozygosity (gLOH) score, also referred to as homologous recombination deficiency (HRD) score, require higher tumor purity for confident detection. Practical methods to increase tumor nuclei percentage (TN%) from pathology specimens are needed to achieve biomarker results to maximize patient matching to approved therapies and/or clinical trial enrollment. Methods: Tumor purity of specimens was determined by the computational analysis pipeline component of the FDA-approved NGS assay, FoundationOneCDx. In the validation study, specimen purities for each tissue block were compared following either no enrichment (UnE, n=46), pathologist-directed enrichment by straight razor blade (RBE, n=30) or precision needle punch (NPE, n=47). Post-enrichment H&E slides confirmed target region sampled for the NPE arm. Based upon validation data, the needle punch process was implemented for the Lung-MAP prospective clinical trial (LM-NPE). TN% was compared between the first 55 tested LM-NPE specimens and the validation study to assess performance on real-world samples outside of a controlled validation experiment. Results: The mean computational TN% in the 4 groups were: UnE: 33%; RBE: 30%; NPE: 52%; and LM-NPE: 48%. In the validation study, NPE had significantly higher purity than both UnE and RBE (p<0.001); in the trial arm, LM-NPE performed equivalently to NPE (p=0.344). Based upon a 30% tumor purity cutoff, gLOH could be determined for 52% UnE, 50% RBE, 89% NPE and 71% LM-NPE. Comparing NPE and LM-NPE groups reveals no statistical difference in Pass/Fail rates for gLOH determination (p=0.883; Fisher’s Test). Conclusions: Precision needle punch cores from tissue blocks have elevated tumor purity, and consequently, a greater number of successful gLOH determinations. Moreover, this process is rapid and inexpensive. Precision punches may constitute best practice with respect to enriching tumor cells from low-purity specimens for biomarker detection in a routine laboratory specimen-processing setting. [Table: see text]
Survival associated with mutations in SWI/SNF chromatin remodeling complex genes.
Authors: Hassett Michael J. , Tramontano Angela , Zhang Zilu , Kehl Kenneth L. , Schrag Deborah
Published: May 2020

3643

Background: The SWI/SNF (SWitch/Sucrose NonFermentable) chromatin remodeling complex (CRC) - a combinatorial assembly of products from multiple genes - alters histone/DNA interactions and thereby impacts transcription, DNA replication/repair, and cell division. Studies suggest that over 20% of human cancers contain mutations in at least one SWI/SNF gene, implying that it is the most highly mutated CRC in human cancer. To address existing knowledge gaps, we sought to evaluate the association between SWI/SNF mutations and overall survival (OS). Methods: We identified adult cancer patients who consented to have OncoPanel testing (Dana-Farber/Brigham & Women’s Hospital’s next generation sequencing platform) from June 2013-August 2019. These data were merged with institutional electronic health records and National Death Index vital status. We determined mutation frequency and co-occurrence for the nine SWI/SNF genes included in OncoPanel (ARID1A, ARID1B, ARID2, BCL11B, PBRM1, SMARCA4, SMARCB1, SMARCE1, and SS18). We assessed the association between mutation and OS (from time of OncoPanel testing) for cancers with at least 500 analyzed and 20 mutated cases, controlling for age and TP53 status. Exploratory analyses were conducted using cBioPortal and SAS (no multiple comparison adjustment). Results: Among 25,434 samples from 24,648 patients, a mutation in at least one evaluated SWI/SNF gene was identified in 26% of cases (ARID1A 10.5%, ARID1B 7.2%, SMARCA4 5.5%, PBRM1 4.9%, ARID2 4.8%, BCL11B 3.5%, SMARCE1 1.1%, SMARCB1 1.0%, and SS18 0.7%). The most frequently mutated cancers included small bowel (52%), endometrial (49%), ampullary (48%) and bladder (45%). Co-occurrence was common (30 of 36 potential gene-pairs), with the largest associations (odds ratio; all P < .05) seen for SMARCB1:BCL11B (4.19), ARID1B:BCL11B (3.87), ARID2:BCL11B (3.85), and SMARCA4:BCL11B (3.78). Associations between having a mutation and OS were seen for the following cancers/genes (odds ratio; all P < .05): ARID1A (colorectal 0.72, pancreatic 1.46), ARID1B (melanoma 0.32), SMARCA4 (esophagogastric 1.48, non-small cell lung 1.89, ovarian 0.43), SMARCB1 (non-small cell lung 2.04), and SS18 (soft tissue sarcoma 2.06). Conclusions: Mutations in SWI/SNF genes are widespread, with mutation rates varying by cancer type. Co-occurrence was common, especially with BCL11B. Associations with OS were both favorable and unfavorable, with variability seen by gene and cancer type. Future research should explore the mechanisms by which mutations in SWI/SNF genes influence treatment response/OS.
Tailored treatment strategy for locally advanced rectal carcinoma: Five-year results of the French phase II, randomized, multicenter GRECCAR4 trial.
Authors: Rouanet Philippe
Published: May 2020

4014

Background: Preoperative radiochemotherapy and total mesorectal excision are the standard-of-care for locally-advanced rectal carcinoma, but some patients are over- or undertreated. Our phase II study assessed the feasibility of tailored radiochemotherapy, based on tumor response to induction high-dose chemotherapy (FOLFIRINOX). Methods: We enrolled 206 patients; good responders after chemotherapy (≥75% tumor volume reduction) were randomly assigned to immediate surgery (arm A) or standard radiochemotherapy (Cap 50: 50 Gy and oral capecitabine daily) plus surgery (arm B). Poor responders were randomly assigned to Cap 50 (arm C) or intensive radiochemotherapy (Cap 60 (60 Gy irradiation), arm D) before surgery. Results: After induction treatment, 194 patients were classified as good (n=30, 15%) or poor (n=164, 85%) responders, and included in arms A and B (16 and 14 patients) or C and D (113 and 51 patients). The primary objective was obtained: (90% CI) R0 resection rates in the four arms respectively were 100% (74–100), 100% (85–100), 83% (72–91), and 88% (77–95). At 5 years: overall survival 90% (CI: 47.3-98.5), 93.3% (CI: 61.3-99.0), 84.3% (CI: 71.0-91.8), 86.1% (CI: 71.6-93.5); disease-free survival 80% (CI: 40.9-94.6), 89.5% (CI: 64.1-97.3), 72.9% (CI: 58.5-82.9), 72.8% (CI: 57.7-83.2); local recurrence 0, 0, 2.1% (CI: 0.3-13.9), 9.3% (CI: 3.6-23.0); metastasis 20% (CI: 5.4-59.1), 10.5% (CI: 2.7-35.9), 18% (CI: 31.8-94.6), 18.8% (CI: 10.2-33.0). Late morbidity and quality of life evaluations showed no significant difference between arms. Conclusions: Tailoring preoperative radiochemotherapy based on induction treatment response is safe and promising. Early tumoral response to induction chemotherapy can discriminate tumor prognosis. Clinical trial information: NCT01333709 .
Pre- versus postoperative CAPOX plus bevacizumab (CAPOX-Bev) for resectable liver metastases from colorectal cancer (CLM): A randomized phase II/III trial (HiSCO-01).
Authors: Takakura Yuji , Shinozaki Katsunori , Ikeda Satoshi , Egi Hiroyuki , Hirata Yuzo , Shimomura Manabu , Oshiro Takafumi , Hinoi Takao , Sumitani Daisuke , Nakahara Masahiro , Yoshimitsu Masanori , Honmyo Naruhiko , Kobayashi Tsuyoshi , Ohdan Hideki
Published: May 2020

4021

Background: The role of neoadjuvant chemotherapy, particularly for those with initially resectable CLM, is controversial. And the optimal regimen and duration to be used in the neoadjuvant setting is not established. We conducted prospective, multicenter, randomized phase II/III study to assess pre-operative 8 cycles of CAPOX-Bev (arm A) plus radical surgery compared with post-operative 8 cycles of CAPOX-Bev (arm B) for patients (pts) with resectable CLM. Methods: The primary endpoint in the Phase II was completion rate of protocol treatment (more than 6 cycles of CAPOX-Bev plus R0 surgical resection) and PFS in the Phase III. The secondary endpoints were OS, ORR (arm A), liver damage (arm A), safety. The Phase III part was terminated due to slow enrollment. Results: 81 pts were enrolled from 10 centers between November 2010 and November 2017. The full analysis set consisted of 76 pts who started protocol treatment (arm A 37 vs. arm B 39). 76 pts had the following characteristics: median age 66 (27-80), median number of liver metastases 2 (1-14), 69.7% male, 67.1% synchronous and 94.7% primary resected. Completion rate of protocol treatment was 89.2% in arm A and 71.8% in arm B (p = .06). ORR was 63.9%, including 2 pts who had pathologically complete response (5.6%). Only 1 pts in arm A could not undergo surgery due to progression of disease. In the chemotherapy safety population, arm B was associated with more grade 3 neutropenia and grade 3 gastrointestinal disorder than arm A. The most frequent surgical adverse event was biliary fistula, with an incidence of 0% in arm A and 10.3% in arm B (p = .02). No patient died from treatment-related adverse events. The median follow-up time was 40 months. The rate of PFS at 3 years was 32.2% in arm A versus 38.5% in arm B (p = .99). Conclusions: Pre-operative 8 cycles of CAPOX-Bev is compatible with radical surgery, but may have no impact on progression-free survival compared with post-operative chemotherapy. Clinical trial information: UMIN000003783 .
High amphiregulin mRNA expression is a strong prognostic biomarker with response to cetuximab in FIRE-1, CIOX, and FIRE-3.
Authors: Stahler Arndt , Stintzing Sebastian , Modest Dominik Paul , Ricard Ingrid , Kapaun Christine , Ivanova Boryana , Vehling-Kaiser Ursula , Fischer von Weikersthal Ludwig , Schalhorn Andreas , Stauch Martina , Kiani Alexander , Neumann Jens , Kirchner Thomas , Heinemann Volker
Published: May 2020

4026

Background: Amphiregulin ( AREG) and epiregulin ( EREG) were discussed as biomarkers for treatment of metastatic colorectal cancer (mCRC). Data from randomized controlled trials (RCT) are limited. Methods: AREG and EREG mRNA expression by RTqPCR in relation to housekeeping genes were available from 688 patients of three RCT (FIRE-1, n = 192, FUFIRI vs. mIrOx; CIOX, n = 113, cetuximab + CAPIRI/CAPOX; FIRE-3, n = 383, FOLFIRI+cetuximab/bevacizumab) and were normalized to their respective range of each trial with median and 3rd quartile as threshold values. Kaplan-Meier estimated overall survival (OS) and progression-free survival (PFS). Cox regression analysis calculated hazard ratio (HR) and 95% confidence interval (95% CI). Overall response rate (ORR) was compared by chi square test. Results: Across all trials, high AREG mRNA expression appeared as strong prognostic biomarker for OS, PFS and ORR for all threshold values. In RAS wildtype patients, high AREG expression was associated with better OS and PFS for cetuximab but not bevacizumab treatment. (Table) No effects were seen for epiregulin when all trials were analysed together. Conclusions: High AREG mRNA expression appeared as strong prognostic biomarker in mCRC. Positive predictive information might exist for cetuximab treatment. [Table: see text]
Real-world outcomes of patients with BRAF-mutated mCRC treated in the United States.
Authors: Braithwaite Matthew , Nevala-Plagemann Christopher Duane , Baron Kelsey , Haaland Benjamin , Pappas Lisa M. , Garrido-Laguna Ignacio
Published: May 2020

4030

Background: BRAF mutations portend a poor prognosis in metastatic colorectal cancer (mCRC). Recent trials have hypothesized that using more aggressive triplet-based chemotherapy regimens such as FOLFOXIRI in the frontline setting may improve outcomes in this patient population. In this study, we utilized real-world data to assess whether FOLFOXIRI is being used in the United States (US) and compared survival outcomes in BRAF mutated (BRAFmt) mCRC stratified by first line (1L) therapy. Methods: The nationwide Flatiron Health EHR-derived de-identified database was reviewed for patients diagnosed with mCRC between 2013 and 2018. Patients who had documented BRAF mutation testing and received a standard 1L therapy were included for analysis. Patients who did not have a visit or medication order within 90 days of metastatic diagnosis were excluded to ensure patients were engaged with care at the data-providing institution. Kaplan-Meier and Cox proportional hazard modeling were used to compare survival outcomes stratified by BRAF mutation status and 1L therapy received. Results: A total of 4,454 patients with documented BRAF mutational status were included, of which 3,988 (89.5%) were BRAF wild type (BRAFwt) and 466 (10.5%) were BRAFmt. Median OS was 15.4 months (mo) in the BRAFmt group compared to 28.1 mo in the BRAFwt group (HR 0.48, 95% CI 0.41- 0.56, p < 0.001). Only 3% (n = 16) of BRAFmt patients received 1L FOLFOXIRI +/- bevacizumab with a median OS of 13.8 mo compared to 15.5 mo in patients receiving a chemotherapy doublet (FOLFOX, CAPEOX, or FOLFIRI) +/- bevacizumab (95% CI 4.9 – not reached vs 14.3 – 19.0, p = 0.38). In BRAFmt patients, multivariate analysis (MVA) did not detect a significant improvement in OS with the use of FOLFIRI plus bevacizumab (HR 0.88, 95% CI 0.50-1.56, p = 0.67) or FOLFOX/CAPEOX plus bevacizumab (HR 0.89, 95% CI 0.59 – 1.34, p = 0.58) when compared to chemotherapy doublet alone. A MVA comparing 1L therapies in the BRAFwt group did not detect a significant improvement in OS with bevacizumab plus chemotherapy doublet compared to chemotherapy doublet alone. When stratified by 1L treatment regimen, similar proportions of BRAFmt patients received second line therapy. Conclusions: This analysis of real-world data confirms the negative prognostic impact of BRAF mutations in mCRC and suggests that FOLFOXIRI has not been widely adopted in the management of these patients in the US. We were unable to demonstrate any significant difference in OS of patients with BRAFmt mCRC based on type of 1L therapy received.
Results from the safety lead-in for a phase II study of pembrolizumab in combination with binimetinib and bevacizumab in patients with refractory metastatic colorectal cancer (mCRC).
Authors: Lieu Christopher Hanyoung , Davis Sarah Lindsey , Leong Stephen , Leal Alexis Diane , Blatchford Patrick Jud , Sandhu Gurprataap Singh , Purcell William T. , Kim Sunnie S. , Van De Voorde Zoe , Telles Rachel , Martin Anne , Cull Tiffany , Waring Meredith , Reed Colin , Lee Chimmoua , Siedem Amanda , Lee Matthew R , Pitts Todd , Eckhardt S. Gail , Messersmith Wells A.
Published: May 2020

4031

Background: The majority of pts with mCRC have microsatellite stable (MSS) tumors with minimal response to PD-L1/PD-1 blockade. MEK inhibition and VEGF inhibition have immunomodulatory effects (upregulation of tumor major histocompatibility complex-I expression, enhanced T-cell infiltration, reduced MDSCs and Tregs in tumors) supporting clinical evaluation of combined MEKi (B), anti–PD-1 (P), and anti-VEGF (BV) in pts with mCRC. We hypothesize that the combination of binimetinib, pembrolizumab, and bevacizumab (BPBV) will result in greater clinical benefit than pembrolizumab alone. Methods: Patients with chemotherapy-refractory mCRC were evaluated (20 planned in the safety lead-in and 50 planned for total accrual). B was dosed at 45mg PO BID, P was administered at 200mg IV Q21 days, and BV was administered at 7.5mg/kg IV Q21 days. Primary objectives were safety, tolerability, and investigator-assessed ORR by RECIST 1.1. Clinical benefit rate (CR+PR+SD) and progression-free survival were secondary endpoints. Descriptive statistics were used to summarize safety and clinical activity. Results: As of January 9, 2020, 21 pts (10 KRAS/NRASmt, 11 RASwt, 21 MSS) were enrolled into the safety lead-in and were evaluable. The median number of prior therapies was 6. The BPBV combination was tolerable. Treatment-related Gr 1-2 and Gr 3-4 AEs occurred at 60% and 38%, respectively. The most frequent related Gr 3-4 AEs were aceniform rash, diarrhea, and hypertension (19%, 14%, 14% respectively). No treatment-related Gr 5 AEs occurred. A total of 17 patients were evaluable for response. Confirmed PR was observed in 2 pts (12%). SD was noted in 14 patients (82%) leading to a clinical benefit rate of 94%. 1 patient had PD as the best response to treatment. Median PFS was 6.4 months (95% CI 4.2-8.9). Molecular determinants, immune biomarkers, and updated tumor assessments of response will be presented. Conclusions: B + P + BV demonstrated a tolerable safety profile and improvements in ORR and clinical benefit rate compared to those reported with SOC in heavily pretreated pts with mCRC. Objective responses observed in pts were durable, suggesting benefit of this novel combination in a patient population refractory to immune therapies. Clinical trial information: NCT03475004 .