bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I study of the combination of alisertib (MLN8237) and gemcitabine in advanced solid tumors.
Authors: Huynh Jasmine , Chen Justin , Kim Edward Jae-Hoon , Gandara David R. , Semrad Thomas John , Riess Jonathan W. , Li Tianhong , Wu Chun-Yi , Zhang Chao , Yu Aiming , Matsukuma Karen , Kelly Karen
Published: May 2020

3589

Background: Aurora Kinase A (AKA) is a key mitotic regulator overexpressed in multiple solid tumors. This open-label dose escalation and expansion phase I study evaluated the safety and tolerability of alisertib (MLN8237), an oral AKA inhibitor, in combination with gemcitabine. Methods: In dose escalation, patients (pts) > 18y with refractory solid tumors received 28-day cycles of gemcitabine on days 1, 8, 15 and alisertib twice daily on days 1-3, 8-10, and 15-17. Gemcitabine was given at 1000mg/m2. Four dose levels (DL) of alisertib (20-50mg) were given per 3+3 design to investigate dose limiting toxicities (DLT) in cycle 1, to determine maximum tolerated dose (MTD) and recommended phase II dose (RP2D). In dose expansion, advanced pancreatic adenocarcinoma pts received the MTD dose twice daily on a modified dosing schedule to allow for pharmacokinetic (PK) evaluation. Anti-tumor activity was assessed by response rate (RECIST 1.1) and progression-free survival (PFS). PK evaluation of plasma gemcitabine and alisertib was performed on all pts enrolled in the dose expansion. PK sampling was performed before treatment, immediately after gemcitabine infusion, and at other pre-specified post-infusion timepoints. Results: Twenty-six pts were treated in total: 21 pts in dose escalation and 5 pts in dose expansion. Overall, median age was 57y [42-82]; 50% male; 62% PS 1 (16 pts); 2 [0-7] median prior therapies. In the dose escalation phase, 9 tumor types were included and NSCLC was most common (7 pts). Maximum administered dose (DL4) achieved 900 mg alisertib per cycle and was tolerated (1 DLT in 6 pts). The dose expansion phase enrolled 5 pts with advanced pancreatic adenocarcinoma; median age 63y [48-82]; 60% male; 60% PS 1 (3 pts); 2 [1-2] median prior therapies. Grade ≥3 TRAEs were observed in 73% of all pts and were predominantly hematologic, including neutropenia (54%), leukopenia (50%), and lymphopenia (31%). Similar TRAEs were seen at DL4; all 14 pts experienced neutropenia with 64% experiencing grade ≥3 neutropenia. Fourteen of 23 evaluable pts (61%) had stable disease and 2 pts (9%) had partial response (PR) as best overall response. Median PFS was 2.9 months (95% CI 2.0-4.2). Analysis of PK data is ongoing and will be reported. Conclusions: Alisertib can be safely administered with gemcitabine. RP2D for alisertib is 50 mg PO BID in combination with full dose gemcitabine. Best response was at least stable disease in a majority of pts with PR observed in 9% of this heavily pretreated group of patients. Most grade ≥3 TRAEs were hematologic. Results of PK studies will also be reported. Clinical trial information: NCT01924260 .
TOOme: A novel computational framework to infer cancer tissue-of-origin by integrating both gene mutation and expression.
Authors: Gao Wei , Yang Jianwei , Zhuo Changhua , Yang Jialiang , Huang Sha , Tian Geng , Lin Jinyuan
Published: May 2020

3591

Background: Metastatic cancers require further diagnosis to determine their primary tumor sites. However, the tissue-of-origin for around 5% tumors could not be identified by routine medical diagnosis according. With the development of machine learning techniques and the accumulation of big cancer data from TCGA and GEO, it is now feasible to predict cancer tissue-of-origin by computational tools. Methods: Developed a computational framework to infer tumor tissue-o. Results: Applied TOOme to the TCGA data containing 7,008 non-metastatic samples across 20 solid tumors including BLCA, BRCA, CESC, COAD, GBM and so on. 74 genes by gene expression profile and 6 genes by gene mutation are selected by the random forest process, which can be divided into two categories: (1) cancer type specific genes, which are highly expressed or mutated only in one specific cancer and (2) those expressed or mutated in several cancers with different levels of expression or mutation rates. Function analysis indicates that the selected genes are significantly enriched in gland development, urogenital system development, hormone metabolic process, thyroid hormone generation prostate hormone generation and so on. According to the multiple-label classification method, random forest performs the best with a 10-fold cross-validation prediction accuracy of 96%. We also use the 19 metastatic samples from TCGA and 256 cancer samples downloaded from GEO as independent testing data, for which TOOme achieves a prediction accuracy of 89%. The cross-validation validation accuracy is better than those using gene expression (i.e., 95%) and gene mutation (83%) alone. Conclusions: TOOme provides a quick yet accurate alternative to traditional medical methods in inferring cancer tissue-of-origin. In addition, the methods combining somatic mutation and gene expressions outperform those using gene expression or mutation alone.
Tumor-targeted oncolytic adenovirus demonstrates high cytotoxicity for human lung and renal cell carcinomas independently of the level of tumor PD-L1 expression.
Authors: Yao Jia , Atasheva Svetlana , Young Cedrick , Master Viraj A. , Shayakhmetov Dmitry
Published: May 2020

3596

Background: Immuno-checkpoint (IC) inhibitors targeting PD1-PD-L1 pathway have proven highly effective at extending survival of cancer patients. However, the clinical benefits of IC inhibitors are limited to only about 20% patients who have moderate to high levels of tumor PD1 and/or PD-L1 expression. To develop therapeutics that would provide clinical benefits to a larger proportion of cancer patients, we engineered oncolytic adenovirus for targeted infection of human tumor cells via CD46 and integrins of α3β1 or α6β4 classes, overexpressed on many epithelial human cancers. Methods: Here, we analyzed the infectivity and cytotoxicity of this novel oncolytic virus in a panel of human non-small cell lung cancers (NCSLC) cell lines, primary patient derived NSCLC xenografts, and tumor surgical explants from patients with renal cell carcinoma (RCC). Results: The in vitro analysis of NSCLC cells lines (N = 17) demonstrated that over 60% of them were highly sensitive to virus infection. The genome-wide transcriptional profiling showed that only 3 out of 12 cell lines that were sensitive to oncolytic virus infection, expressed PD-L1 ( > 4.5 Log2 RPMK). Furthermore, although the pre-treatment of these cell lines with IFN-I activated PD-L1 expression, IFN-I treatment did not reduce the efficacy of tumor cell infection by the oncolytic virus. The analysis of virus infectivity on primary human tumor cells from patients with NSCLC (N = 4) and RCC (N-24) demonstrated that primary tumors were highly sensitive to oncolytic virus infection. Specifically, tumor-targeted oncolytic virus demonstrated strong cytotoxicity in 22 out of 24 analyzed primary isolated RCC cell samples. Next, we subcutaneously grafted PD-L1-negative NSCLC A549 cells to NSG mice, treated them with oncolytic virus intravenously, and the kinetics of tumor growth and animal survival was monitored. This analysis showed that after intravenous administration, oncolytic virus was able to infect tumor cells and suppress tumor growth. Whereas the median survival in mock-treated group was 26 days, all mice survived up to 100 days post oncolytic virus therapy (endpoint). Conclusions: Our study showed that tumor-targeted oncolytic adenovirus infects human tumor cell lines independently of their PD-L1 expression status and is not sensitive to IFN-I inhibition. This novel tumor-targeted oncolytic virus has the potential to provide clinical benefits to cancer patients, who do not respond or became resistant to ICI drugs.
Phase II trial of the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886 Hydrogen Sulfate) in adults with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN).
Authors: O'Sullivan Coyne Geraldine Helen , Gross Andrea M. , Dombi Eva , Tibery Cecilia , Carbonell Amanda , Takebe Naoko , Derdak Joanne , Pichard Dominique , Srivastava Apurva K. , Herrick William , Parchment Ralph E. , Martin Staci , Wolters Pamela , Whitcomb Patricia , Rubinstein Lawrence , Doroshow James H. , Chen Alice P. , Widemann Brigitte C.
Published: May 2020

3612

Background: NF1-related PN are locally invasive tumors characterized by increased activation of the RAS pathway causing significant morbidity including disfigurement, pain and functional limitations. Selumetinib has received breakthrough designation for NF1 PN based on phase I / II trials in children. We present results for the ongoing phase II study of selumetinib in adults with NF1 PN, which includes pharmacodynamic (PD) evaluation of serial tumor biopsies as well as functional/patient-reported outcomes (PROs). Methods: Open-label Simon 2-stage design. Eligibility: NF1 patients (pts) ≥18 years old with inoperable/symptomatic/progressive PN. First 2 pts received selumetinib 75 mg BID; subsequent pts received selumetinib 50 mg BID. Primary objective: response rate by volumetric MRI analysis (partial response [PR]; ≥20% volume decrease). Secondary objectives: PD studies on pre/on-treatment biopsies of PN and cutaneous neurofibromas, assessment of clinical benefit using PROs (Numeric Rating Scale-11, Pain Interference Index), and PN-specific functional assessments. Validated, fit-for-purpose, isozyme-specific measurements of pERK/ERK/pMEK/MEK performed using SOPs designed for labile phosphoproteins (PMID 27001313). Results: As of February 2020, 27 pts have enrolled. Outcomes are reported for 23 pts (74% male; median age 33 years, range 18-60). Most common PN-related morbidity: pain (19 pts). Sixteen pts achieved PR (69%), with 13/16 confirmed; no disease progression. Time to response: 11 months (range 5-25); median change in PN volume at best response: -22% (range -41% to +5.5%); median duration of treatment: 28 months (range 2-50). Selumetinib suppressed tumor pERK1,2/ERK1,2 but not pMEK1,2/MEK1,2 ratios from 1-10 hours following oral dosing (one t½). Pt-reported target tumor pain intensity and pain interference scores significantly improved (both p < 0.03). Pts 1 and 2 were dose-reduced due to grade 3 intolerable rash (n = 2) and pain (n = 1). Grade ≥3 drug-related toxicities on 50 mg (21 pts) include transaminitis (5 pts), rash (1 pt) and pancreatic enzyme elevation (1 pt). Two pts were dose reduced (rash = 1 pt, transaminitis = 1 pt). Two pts discontinued by choice, 2 pts withdrawn by PI (best interest of patient), and 1 pt each removed for transaminitis, surgical resection, serious concurrent medical illness, and non-compliance. Conclusions: Selumetinib shrinks the majority of adult PN and results in molecular target suppression and clinical benefit. Clinical trial information: NCT02407405 .
Quality of life of adults and children with TRK fusion cancer treated with larotrectinib compared to the general population.
Authors: Kummar Shivaani , Van Tilburg Cornelis M. , Albert Catherine M. , Berlin Jordan , Farago Anna F. , McDermott Raymond S. , Bielack Stefan S. , Doz Francois P. , DuBois Steven G. , Lassen Ulrik Niels , Leyvraz Serge , Mascarenhas Leo , Nagasubramanian Ramamoorthy , Keating Karen N , Chirila Costel , Childs Barrett H. , Laetsch Theodore Willis , Drilon Alexander E. , Hong David S.
Published: May 2020

3614

Background: NTRK gene fusions occur in diverse tumor types in adults and children. The selective TRK inhibitor, larotrectinib, has shown high response rates, durable disease control, and a favorable safety profile in patients (pts) with TRK fusion cancer. We report an expanded quality of life (QoL) analysis for pts treated with larotrectinib. Methods: QoL data were collected in two trials of larotrectinib in pts with TRK fusion cancer using EORTC QLQ-C30 (adults) and PedsQL (children) questionnaires, and were analyzed descriptively and longitudinally. EORTC QLQ-C30 global health scores (GHS) and PedsQL total scores range from 0 to 100, with higher scores indicating better QoL. We calculated the proportion of pts with normal/above and below normal QoL scores compared to values in the literature for the US general population. Results: By July 2019, 126 pts with TRK fusion cancer (74 adults, 24 children ≥2 yrs, and 28 infants <2 yrs) had received larotrectinib and completed baseline (BL) and ≥1 post-BL questionnaire. Most pts had clinically meaningful QoL improvements that reached or exceeded the minimally important difference (Table); a positive change from BL was also seen in infants: mean best change of 12.0 (SD 13.8). Of 52 adults with BL EORTC QLQ-C30 GHS at or above the population norm, 51 remained in this category on treatment and 1 moved into the below normal category. Of 22 adults with BL scores below the population norm, 20 moved into the normal/above normal category. All 9 children aged ≥2 yrs with BL PedsQL scores at or above the population norm remained in this category on treatment. Of 15 children with BL scores below the population norm, 10 moved into the normal/above normal category. Sustained QoL improvements (change from BL ≥0) occurred by 2 months of treatment in 69% of adults and 75% of children. Median duration of sustained improvement in EORTC QLQ-C30 GHS and PedsQL total score was 12.0 months (range 1.7–20.3) and not estimable (range 1.1–23.0), respectively. Conclusions: Adults and children with TRK fusion cancer treated with larotrectinib had rapid, clinically meaningful, and sustained improvements in QoL. Clinical trial information: NCT02576431, NCT02637687 . [Table: see text]
Pan-cancer analysis of FGFR1-3 genomic alterations to reveal a complex molecular landscape.
Authors: Krook Melanie A. , Silverman Ian M. , Murugesan Karthikeyan , Ernst Gabrielle , Reeser Julie , Wing Michele , Frampton Garrett M. , Newton Robert C , Jackson Jeffery Richard , Albacker Lee A. , Burn Timothy , Roychowdhury Sameek
Published: May 2020

3620

Background: Activating genomic alterations (GAs) in the fibroblast growth factor receptor (FGFR) gene family occur in many tumor types. FGFR1-3 mutations and rearrangements are of particular interest given evidence of clinical activity of selective FGFR inhibitors in patients (pts) with susceptible alterations. We queried FGFR1-3 GAs in patient tumor samples analyzed using comprehensive genomic profiling (CGP) and performed in vitro characterization of select novel alterations. Methods: Tumor samples were assayed by hybrid capture based CGP on 0.8-1.2 Mb of the genome to identify GAs in exons and select introns in up to 404 genes (Foundation Medicine, Inc, Cambridge MA). Cell lines were stably transduced with alterations of interest and transformation assays and drug sensitivity assays were performed to determine oncogenic potential and sensitivity to FGFR inhibition by pemigatinib. Results: GAs in FGFR1-3 were present in 6314 of 274,694 pt specimens (2.3%), of which 4091 (64.8%) were short variants and 2269 (35.9%) were rearrangements. Tumor types with the highest frequency of FGFR1-3 alterations were bladder cancer (17.9%), cholangiocarcinoma (11.1%), endometrial cancer (7.9%), and glioma (5.5%) (Table). We identified 270 unique FGFR1-3 short-variants, including 144 missense mutations and 94 truncating alterations. Of short variants, the most frequent were FGFR3 p.S249C (18.3%), FGFR2 p.S252W (9.9%) and FGFR1 p.N546K (6.9%). Truncating alterations were largely identified in exon 18, downstream of the kinase domain. We identified 476 unique FGFR1-3 rearrangement pairs ( FGFR1; n=77, FGFR2; n=338, FGFR3; n=61). FGFR3-TACC3 was the most prevalent FGFR rearrangement (29.0%), followed by FGFR2-BICC1 and FGFR2-N/A (both 9.7%). In vitro analysis of the transforming potential and drug sensitivity for select alterations will be reported. Conclusions: FGFR1-3 mutations and rearrangements are highly diverse and present at low to moderate frequencies across many cancers. Therefore, cataloging and characterizing these diverse alterations has the potential to facilitate precision medicine. Tumor-specific and -agnostic trials of selective FGFR inhibitors in pts with susceptible alterations are ongoing. [Table: see text]
Tumor genomic analysis for biomarker identification in a phase I trial of the Wee 1 inhibitor adavosertib (AZD1775).
Authors: Naqash Abdul Rafeh , Mittra Arjun , O'Sullivan Coyne Geraldine Helen , Chen Li , Das Biswajit , Kummar Shivaani , Do Khanh T , Chang Ting-Chia , Bruns Ashley , Juwara Lamin , Miller Brandon , Kinders Robert J. , Parchment Ralph E. , Rubinstein Larry V , Ji Jiuping Jay , Wilsker Deborah , Dull Angie B , Doroshow James H. , Chen Alice P. , Takebe Naoko
Published: May 2020

3624

Background: Adavosertib, a first-in-class Wee1 kinase inhibitor, abrogates G2/M cell cycle arrest causing premature mitosis and DNA replication stress, yielding enhanced DNA damage. Here we report on potential biomarkers of response from tumor genomic analysis in patients (pts) with solid tumors treated with adavosertib. Methods: Adavosertib was administered once daily on days 1-5 and 8-12 of a 21-day cycle. RECIST 1.1 was used to evaluate clinical response. Paired tumor biopsies were obtained for RNASeq gene expression profiling (GEP) and for whole-exome sequencing (WES) to evaluate gene mutation and copy number amplification (CNA). Fold change (FC) was calculated to define gene overexpression. To identify the frequency of CNA and mRNA overexpression for the genomic biomarkers of interest, cBioPortal analysis using TCGA and MSK-IMPACT datasets was performed. Differential GEP analysis of tumor and paired normal tissue was performed using the gene expression profiling interactive analysis (GEPIA) interface (Tang et al. 2017). Results: Out of 35 pts evaluable for response, 6 (17%) had partial response (PR; 4 ovarian carcinoma [OVC], 2 endometrial carcinoma [EC]). The median duration of response was 5.2 months (range 4.0-23.1). Eighteen pts (51.4%) had stable disease. Genomic analysis of tumor biopsies was available for 9 pts; 7 of these pts were evaluable for response, and 3 had PR (2 OVC, 1 EC). WES revealed TP53 mutations in 6 pts (66.6%; 3 pts with PR, 2 with progressive disease,1 not evaluable). On WES, tumor Cyclin E1 ( CCNE1) CNA was present in 1 of 3 PR pts while tumors from all 3 PR samples showed relatively high CCNE1 expression by RNAseq (FC = 4.07). In the MSK-IMPACT 2017 dataset, CCNE1 CNA was identified in 1.8% of pts (194 of 10336); of which, OVC (10.3%) and EC (8.7%) had the highest incidence of CCNE1 CNAs. In separate tumor-specific (OVC, EC) TCGA datasets having CCNE1 overexpression and/or CNA, overlap in CCNE1 overexpression with CCNE1 CNA was 35.5% (OVC) and 25.2% (EC). Compared to normal ovarian/ endometrial tissues, GEPIA analysis revealed significantly higher CCNE1 mRNA expression in OVC (FC = 3.5) and EC (FC = 3.8). Conclusions: CCNE1alterations (overexpression and/or CNA) tend to be enriched in OVC and EC with a limited fraction showing both overexpression and CNA. Tumor genomic analysis of additional OVC and EC pts treated with adavosertib is required to determine whether CCNE1 mRNA overexpression, regardless of CCNE1 CNA, is a potential biomarker of response to this drug in these tumor types. Funded by NCI contract No. HHSN261200800001E. Clinical trial information: NCT01748825 .
The landscape of predictive biomarkers for ATR inhibition in Chinese solid-tumor patients.
Authors: Shen Rong , Yang Qiuan , Liu Zimin , Wang Yongjie , Fan Xinglong , Li Lei , Hu Bo , Xiao Wenjing , Ma Meili , Chen Wei , Liu Xiaoyan , Shi Weiwei , Liu Angen
Published: May 2020

3626

Background: Ataxia Telangiectasia and Rad3-related (ATR) is one of the core regulators participating in DNA damage response as a sensor of replication stress. Besides, ATR also plays a role in cell cycle checkpoint activation and DNA replication regulation. Several ATR inhibitors (ATRi) have been demonstrated in anti-cancer clinical trials. Herein, we describe the distribution of selected biomarkers, which have been shown to predict a higher sensitivity to ATRi according to preclinical data, in Chinese cancer population. Methods: FFPE tumor tissues and matched blood samples from 10,194 Chinese patients with 25 different types of solid tumors were collected. NGS based 450 cancer genes panel assay were performed to detect genomic alterations, including SNV, short and long insertions/deletions, CNV and rearrangements/fusions. The testing was carried out by a CAP accredited and CLIA certified laboratory. Results: The prevalence of ARID1A mutations, ATM mutations, BRCA1/BRCA2 mutations, MYC amplification, and CCNE1 amplification accounted for 9.5%, 4.7%, 6.0%, 3.5% and 3.3% of this cohort respectively. The most common tumors with ARID1A mutations were endometrial carcinoma (EC, 34.4%), gastric carcinoma (GC, 19.4%), small bowel carcinoma (SBC, 19.3%), intrahepatic cholangiocarcinoma (19.3%), extrahepatic cholangiocarcinoma (17.7%) and urothelial carcinoma (UC, 16.7%). For ATM mutations, the prevalence was colorectal carcinoma (CRC, 8.9%), SBC (8.8%), pancreatic cancer (7.8%), UC (7.3%), gallbladder carcinoma (GBC, 7.1%) and GC (6.8%). For BRCA1/BRCA2 mutations, the prevalence was ovarian carcinoma (29.5%, Germline 23%), breast carcinoma (13.3%, Germline 7.1%), EC (11.5%, Germline 3.3%), UC (10.4%), melanoma (8.5%) and CRC (7.9%). For MYC amplification, the prevalence was breast carcinoma (10.2%), ovarian carcinoma (9.2%), esophageal carcinoma (7.2%), thymic tumor (6.1%), cancer of unknown primary (CUP, 5.8%) and gastrointestinal neuroendocrine tumor (GI-NET, 5.4%). For CCNE1 amplification, the prevalence was GC (11.9%), GBC (8.8%), bone sarcoma (7.7%), ovarian carcinoma (6.9%), CUP (4.2%) and GI-NET (4.1%). Conclusions: Our study reported the prevalence of gene mutations of ATRi sensitivity determinants in a large cohort of Chinese cancer patients. The results revealed the high prevalence and different distribution of these biomarkers across a wide spectrum of cancers. The genomic profile study also provided information for ATRi sensitivity assessment and the drug combinations with ATR inhibition.
Comprehensive analysis of HER2 status through genomic, transcription, and translation among 5,305 patients with diverse malignancies.
Authors: Mesleh Shayeb Akram , Kurzrock Razelle , Kato Shumei
Published: May 2020

3632

Background: HER2 alterations is a predictive biomarker for anti-HER2 regimen. Success in breast and gastric cancers with anti-HER2 therapies translated to explore their efficacy in other tumors. Currently, measurement of HER2 can be done by assessing the expression of protein [e.g. immunohistochemistry (IHC)] or gene amplification of copy number variation (CNV) [e.g. fluorescence in situ hybridization or next-generation sequencing (NGS)]. But little is known about the transcription level (mRNA) of HER2. Herein, we investigated HER2 mRNA expression and its association with gene and protein expressions among diverse cancer types. Methods: Between 2015-2019, HER2 status was evaluated using IHC, qRT-PCR and NGS by Paradigm Diagnostics (CLIA-certified laboratory). All tumors in the database were included for analysis. Correlations between all 3 tests were done. An illustrative patient who was treated with anti-HER2 therapy base on the mRNA testing is presented. Results: HER2 testing was performed on 5305 patients (pts) with diverse cancers including NSCLC (n=1175), breast (n=1040) and colon (n=566); 4.1% (161/3926) had amplification through NGS, 33.3% (615/1848) had mRNA overexpression and 9.3% (236/2533) had overexpression by IHC. Of 723 pts who had all three tests performed, we found 7.5% (54/723) of pts with all three HER2 markers being positive (CNV [+]/mRNA [+]/ IHC [+]). Meanwhile, variety of amplification/ expression patterns were seen (see Table). CNV positivity translated to protein expression in 95% of cases. While only 4% of pts were IHC positive when CNV and mRNA were negative. 20% (144/723) of pts had mRNA overexpression alone among diverse cancer types. Representative case of 70yo female with metastatic cholangiocarcinoma harboring mRNA overexpression (but negative for CNV, IHC unclear due to sample insufficiency) who had near complete response to anti-HER2 therapy with progression-free survival of 24+ months is presented. Conclusions: HER2 status can be discordant with different assays but NGS positivity has excellent correlation with mRNA and protein expression. Of importance, HER2 mRNA can be overexpressed in 20% of pts even when gene amplification and protein expression are negative. Further studies are warranted to determine the clinical utility of mRNA as a biomarker for HER2 and potential use for anti-HER2 targeted therapies. [Table: see text]
The skin types closely related to development of the facial acneiform rash and the therapeutic effects of EGFR inhibitors in RAS wild-type metastatic colorectal cancer: Ancillary analysis of FAEISS study.
Authors: Yoshikawa Syusuke , Yamazaki Naoya , Kiyohara Yoshio , Nozawa Keiko , Fukuda Haruhiko , Shibata Taro , Hasegawa Akiko , Takahashi Masanobu , Masuishi Toshiki , Kawazoe Akihito , Hamaguchi Tetsuya , Tsushima Takahiro , Machida Ryunosuke , Kikuchi Katsuko , Nakai Yasuo , Takatsuka Sumiko , Nisina Tomohiro , Mizutani Hitoshi , Takashima Atsuo
Published: May 2020

3637

Background: At ESMO2019, we reported the primary results of a randomized controlled trial (FAEISS study) investigating the efficacy of topical corticosteroid treatment to facial acneiform rash (AR) by EGFR inhibitors comparing groups starting with a very strong topical corticosteroid and the standard weak topical corticosteroid. As an ancillary analysis, we investigated the association between AR and the pre-treatment skin types, as well as between the skin types and therapeutic effects of EGFR inhibitors on the primary disease. Methods: Utilizing pre-treatment clinical photos of the face taken according to the method determined by FAEISS study protocol, we divided the skin types into categories including enlarged pore, oiliness, xerosis, wrinkles, skin color/redness, and allocated the score (1-3) by central review. The severity of AR occurred during the study was graded and was evaluated the association with the specific skin type by Fisher’s exact test. We also investigated the association between the skin types and the best overall response (RECISTv1.1) to EGFR inhibitor therapy on the primary disease using the Cochran-Armitage trend test. Results: Of the registered 172 cases of RAS wild-type metastatic colorectal cancer [104 men and 68 women, median age = 68 (26-79)], omitting the cases with unevaluable data, finally we analyzed 146 cases for associations between the skin types and AR and 147 cases for best overall response. Interestingly, AR developed 13.6% of enlarged pore score 1, 29% of score 2 and 45.8% of score 3, and patients with enlarged pore tended to have more AR (p = 0.058). Surprisingly, the response(CR/PR/SD) of the primary disease were 59.1% of the enlarged pore score 1, 70.6% of score 2 and 87.0% of score 3, and showed statistically significant trend(p < 0.038). Conclusions: This study suggested that a skin type (enlarged pore) is a possible marker predicting AR risk in EGFR inhibitor therapy for RAS wild-type metastatic colorectal cancer, and better therapeutic effects of EGFR inhibitors.
First-line FOLFOX plus panitumumab versus 5FU plus panitumumab in RAS-BRAF wild-type metastatic colorectal cancer elderly patients: The PANDA study.
Authors: Lonardi Sara , Schirripa Marta , Buggin Federica , Antonuzzo Lorenzo , Merelli Barbara , Boscolo Giorgia , Cinieri Saverio , Di Donato Samantha , Lobefaro Riccardo , Moretto Roberto , Formica Vincenzo , Passardi Alessandro , Ricci Vincenzo , Pella Nicoletta , Scartozzi Mario , Zustovich Fable , Zagonel Vittorina , Fassan Matteo , Boni Luca , Loupakis Fotios ,   Gono Group
Published: May 2020

4002

Background: Data on first-line treatment efficacy in elderly patients are limited. Many analyses adopt a questionable cut-off of 65 years and specific evidence with anti-EGFRs is low. FOLFOX-panitumumab (pan) is an option for RAS wild-type (wt) untreated mCRC patients. Guidelines recommend considering fluoropyrimidine monotherapy as an option for elderly patients, but no randomized studies have ever explored the role of the combination with an anti-EGFR. Methods: This is a prospective, open-label, multicenter phase II randomized trial. Unresectable and previously untreated RAS- BRAF wt mCRC patients aged ≥70 were randomized to receive FOLFOX-pan (arm A), or 5FU/LV-pan (arm B) for up to 12 cycles followed by pan maintenance until PD. The primary EP was PFS in both arms. Stratification criteria were age (≤75 vs > 75 years), ECOG PS (0–1 vs 2) and geriatric assessment with G8 Score (≤14 vs > 14). In each treatment arm, the null hypothesis for median PFS was set at ≤6 months. Assuming an expected median PFS time ≥9.5 months with both experimental regimens, a sample size of 90 patients in each arm granted to the study a power of 90%, with a type I error rate equal to 5% (1-sided Brookmeyer-Crowley test) for rejecting the null hypothesis. No formal comparison between the two arms was planned. Results: From Jul 2016 to Apr 2019 a total of 394 patients were screened, 211 were deemed eligible for inclusion and 185 were randomized (92 arm A and 93 arm B). Main pts’ characteristics were (arm A/B): males 66%/61%; median age 77/77y; PS≥1 49%/55%; right colon 23%/21%; G8 > 14 31%/30%. At a median follow up of 20.5 mos, 135 (arm A/B: 64/71) PD events were collected. Median PFS was 9.6 (95% CI 8.8-10.9) in arm A with FOLFOX-pan and 9.1 (95% CI 7.7-9.9) in arm B with 5FU/LV-pan. Response rates were (arm A/B): 65%/57%. Grade 3-4 toxicities were (arm A/B): neutropenia 9.8%/1.1%; diarrhea 16.3%/1.1%; stomatitis 9.8%/4.4%; neurotoxicity 3.3%/0%; fatigue 6.5%/4.4%; skin rash 25%/24.2%, hypomagnesemia 3.3%/7.7%. Conclusions: Large prospective randomized studies in molecularly selected elderly mCRC are feasible with multicenter collaborative efforts. Primary EP was met in both treatment arms. 5FU/LV plus panitumumab for up to 12 cycles followed by panitumumab maintenance until PD might be a reasonable option in elderly mCRC patients with RAS/BRAF wt tumors deserving further investigations in phase III trials. Clinical trial information: NCT02904031 .
Celecoxib in addition to standard adjuvant therapy with 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX) in stage III colon cancer: Results from CALGB/SWOG 80702.
Authors: Meyerhardt Jeffrey A. , Shi Qian , Fuchs Charles S. , Niedzwiecki Donna , Zemla Tyler J. , Kumthekar Priya , Guthrie Katherine A , Couture Felix , Kuebler J. Phillip , Bendell Johanna C. , Kumar Pankaj , Lewis DeQuincy Andrew , Tan Benjamin R. , Bertagnolli Monica M. , Grothey Axel , Hochster Howard S. , Goldberg Richard M. , Venook Alan P. , Blanke Charles David , Shields Anthony Frank
Published: May 2020

4003

Background: Aspirin and cyclooxygenase-2 (COX-2) inhibitors have been associated with a reduced risk of colorectal polyps and cancer in observational and randomized studies. CALGB/SWOG 80702 tested the effect of celecoxib, a COX-2 inhibitor, on reducing the risk of recurrence in stage III CC. Methods: CALGB/SWOG 80702 is a 2x2 randomized controlled phase III trial of 3 v 6 months of adjuvant FOLFOX (data previously reported as part of the IDEA collaboration) with concurrent celecoxib (400 mg daily) v placebo x 3 yrs for patients (pts) with resected stage III CC. The primary endpoint of the trial is disease-free survival (DFS), defined as time from randomization to recurrence or death from any cause. The trial was designed to provide 91% power to detect a hazard ratio (HR) of 0.79 in favor of celecoxib with 2-sided alpha = 0.05 (775 events required); due to slowing accumulation of events 4 years after complete accrual, power was lowered to 85% with same HR and alpha assumptions (696 events required). The DSMB released data on February 24, 2020 at median f/u of 5.6 yrs with 689 DFS events. Results: Between June 2010 and November 2015, 2,526 pts were consented and randomized to the trial. Treatment arms were well balanced by patient and tumor prognostic features, as well as low-dose aspirin use. Baseline characteristics included 45% female, 18% non-White, 8% Hispanic, 15% T4, 26% N2. 3-yr DFS for celecoxib was 76.3% v 73.3% for placebo (HR 0.89 [95% CI 0.77-1.04]; P = 0.14). 5-yr overall survival (OS) was 83.9% for celecoxib v 81.7% for placebo (HR 0.87 [95% CI 0.72-1.05]; P = 0.14). When considering the 4 treatment arms separately, 3-yr DFS was 77.0% for 12 months FOLFOX + celecoxib, 74.9% for 12 months FOLFOX + placebo, 75.5% for 6 months FOLFOX + celecoxib, and 71.9% for 6 months FOLFOX + placebo (log rank P = 0.22; P interaction = 0.64). There were no significant differences in grade 3-4 toxicity with celecoxib v placebo. Compliance with protocol celecoxib treatment, defined as 3 yrs of therapy completion or recurrence/death while on treatment, was 58.1% pts on celecoxib and 60.2% pts on placebo. Conclusions: The addition of celecoxib to standard chemotherapy did not significantly improve DFS or OS. Clinical trial information: NCT01150045 .
A randomized phase II/III trial comparing hepatectomy followed by mFOLFOX6 with hepatectomy alone for liver metastasis from colorectal cancer: JCOG0603 study.
Authors: Kanemitsu Yukihide , Shimizu Yasuhiro , Mizusawa Junki , Inaba Yoshitaka , Hamaguchi Tetsuya , Shida Dai , Ohue Masayuki , Komori Koji , Shiomi Akio , Shiozawa Manabu , Watanabe Jun , Suto Takeshi , Kinugasa Yusuke , Takii Yasumasa , Bando Hiroyuki , Kobatake Takaya , Kato Tomoyuki , Shimada Yasuhiro , Katayama Hiroshi , Fukuda Haruhiko
Published: May 2020

4005

Background: The role of adjuvant chemotherapy after hepatectomy is controversial for liver only metastases from colorectal cancer (LM). Current recommendations for oxaliplatin-containing adjuvant regimen (FOLFOX) for LM are based on extrapolation of the results of the EORTC intergroup trial 40983, which showed that perioperative FOLFOX confirmed a progression-free survival benefit but did not affect overall survival (OS) in LM patients. We conducted a randomized controlled trial to determine if adjuvant modified FOLFOX (mFOLFOX) is superior to hepatectomy alone for LM. Methods: Eligible patients aged 20-75 years who had histologically proven colorectal adenocarcinoma with an unlimited number of LM were randomly assigned (1:1) to receive either adjuvant mFOLFOX6 (oxaliplatin 85mg/m2, l-LV 200 mg/m2, 5-FU bolus 400 mg/m2 and 2400mg/m2 over 48 h), for 12 cycles after surgery (CTX arm), or surgery alone (S alone arm). When treatment compliance after 9 courses of CTX was as high as expected in phase II, the registration was continued in phase III. The primary endpoint of phase III was disease-free survival (DFS), and the secondary endpoints were OS, toxicity, and sites of relapse. The planned sample size was 150 patients (pts) per arm, with a one-sided alpha of 5%, and 80% power detecting a 5y-DFS difference of 12% (25% with S alone vs. 37% with CTX). Results: Between Mar. 2007 and Jan. 2019, 300 patients were randomized. 151 pts were allocated to CTX, and 149 pts to S alone. When the third interim analysis of phase III was performed in Dec. 2019, the DSMC recommended the early termination of the trial because a statistically significant difference in terms of DFS but the futility in terms of OS was found. With a median follow-up period of 54 months for disease-free surviving patients, the 3y-DFS was 52.1% (95% CI 43.2 – 60.2) with CTX and 41.5% (33.2 – 49.6) with S alone (hazard ratio 0.63 [0.45 – 0.89], one-sided p = 0.002 < 0.0163 for the one-sided alpha level at the interim analysis). However, the 3y-OS was 86.6% (79.2-91.4) with CTX and 92.2% (86.0 – 95.8) with S alone (hazard ratio 1.35 [0.84 – 2.19]). The 5y-OS was 69.5% (59.6-77.5) with CTX and 83.0% (74.5-88.9) with S alone. Median OS after recurrence was 38.4 months in the CTX arm and 87.6 in the S alone arm. Conclusions: DFS did not correlate with OS for LM. Postoperative chemotherapy with mFOLFOX6 improves DFS but worsens OS over surgery alone due to more deaths after recurrence in the CTX arm. Adjuvant mFOLFOX is not beneficial to patients after hepatectomy for LM. Clinical trial information: UMIN000000653 .
Circulating tumor DNA to detect minimal residual disease, response to adjuvant therapy, and identify patients at high risk of recurrence in patients with stage I-III CRC.
Authors: Tarazona Noelia , Henriksen Tenna V , Carbonell-Asins Juan Antonio , Reinert Thomas , Sharma Shruti , Roda Desamparados , Shchegrova Svetlana , Huerta Marisol , Roselló Susana , Renner Derrick , Sethi Himanshu , Zimmermann Bernhard , Aleshin Alexey , Cervantes Andres , Andersen Claus Lindbjerg
Published: May 2020

4009

Background: The clinical utility of tracking circulating tumor DNA (ctDNA) as a non-invasive biomarker for detecting minimal residual disease (MRD) and stratifying patients based on their risk of developing relapse has been well established in colorectal cancer (CRC). This study evaluates the detection and longitudinal monitoring of ctDNA in CRC patients pre- and post-operatively, during and after adjuvant chemotherapy (ACT). Methods: The prospective, multicenter cohort study recruited patients (n = 193) diagnosed with resected stage I-III CRC. Plasma samples (n = 1052) were collected at various timepoints with a median follow up of 21.6 months (4.6-38.5 months). Individual tumors and matched germline DNA were whole-exome sequenced and somatic mutations identified. Multiplex PCR assays were designed to 16 tumor-specific single-nucleotide variants to track ctDNA in plasma samples. The study evaluated the relationship between ctDNA status and clinical outcomes including radiologic imaging. Cox regression was used to calculate recurrence-free survival (RFS) in patients stratified by ctDNA status postoperatively and post-ACT. Multivariable analysis was performed with all clinical variables. Best model was selected according to Akaike Information Criterion. Results: Pre-operatively ctDNA was detected in 90% (n = 166/185) of the patients. Post-operative ctDNA status prior to ACT was assessed in 152 patients, of which 9.2% (14/152) were identified to be MRD-positive and 78.5% (11/14) eventually relapsed. In contrast, 10.1% (14/138) of MRD-negative cases relapsed (HR: 16.53; 95% CI: 7.19-38.02; p < 0.001). Longitudinal ctDNA-positive status, post-ACT (n = 84) and post definitive therapy (n = 139) was associated with a 27.92 HR (95% CI: 9.16-85.11; p < 0.001) and a 47.52 HR (95% CI: 17.34-130.3.; p < 0.001), respectively. In the multivariable analysis, longitudinal ctDNA status was the only significant prognostic factor associated with RFS (HR: 53.19, 95% CI: 18.87-149.90; p < 0.001). Serial ctDNA analysis detected MRD up to a median of 9.08 months (0.56-16.5 months) ahead of radiologic relapse with a sensitivity of 79.1% and specificity of 99%. Conclusions: Postoperative ctDNA analyses detect patients with high-risk of recurrence, with near 100% specificity. Early detection of MRD and longitudinal monitoring of ctDNA could guide treatment decisions. Intervention trials to assess the clinical benefit of ctDNA use are underway.
FOLFOXIRI/bevacizumab (bev) versus doublets/bev as initial therapy of unresectable metastatic colorectal cancer (mCRC): A meta-analysis of individual patient data (IPD) from five randomized trials.
Authors: Cremolini Chiara , Antoniotti Carlotta , Stein Alexander , Bendell Johanna C. , Gruenberger Thomas , Masi Gianluca , Ongaro Elena , Hurwitz Herbert , Falcone Alfredo , Schmoll Hans-Joachim , Di Maio Massimo
Published: May 2020

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Background: Several randomized trials demonstrated that intensifying the upfront chemotherapy in combination with bev is beneficial for mCRC patients with an increased incidence of some adverse events. All trials had primary endpoints other than OS, and a proper estimation of the magnitude of the OS benefit from FOLFOXIRI/bev versus doublets (FOLFIRI or FOLFOX)/bev is currently lacking. Within each trial, subgroup analyses failed to identify predictors of benefit from the intensified therapy. To test OS with higher power compared to single trials, and to explore interaction of treatment effect with main patients’ and disease characteristics, we performed an IPD meta-analysis. Methods: IPD were collected from 5 randomized trials: CHARTA (NCT01321957), OLIVIA (NCT00778102), STEAM (NCT01765582, only combined FOLFOXIRI/bev and FOLFOX/bev arms), TRIBE (NCT00719797) and TRIBE2 (NCT02339116). Primary endpoint was OS. Secondary endpoints included PFS, objective response rate (ORR), R0 resection rate, G3/4 adverse events, and subgroup analyses. All statistical analyses were by intention-to-treat, stratified by trial. Results: 1697 pts randomized to FOLFOXIRI/bev (N=846) or doublets/bev (N=851) were included. Among pts in the doublets/bev group, 595 (70%) received FOLFOX/bev and 256 (30%) FOLFIRI/bev. At a median follow up of 39.9 mos, pts assigned to FOLFOXIRI/bev reported significantly longer OS than those assigned to doublets/bev (median OS 28.9 vs 24.5 months; HR 0.81 [95%CI 0.72-0.91], p<0.001), with no significant heterogeneity among trials (p=0.39; I2=2%). The estimated 5-yr OS was 22.3% vs 10.7% (p<0.001). No significant interaction effect between treatment arm and OS was demonstrated in terms of metastatic spread (liver-limited vs. not liver-limited p=0.665), primary side (p=0.656), and RAS/BRAF status (p=0.337). Pts assigned to FOLFOXIRI/bev achieved longer PFS (median PFS 12.2 vs 9.9 months; HR 0.74 [95%CI 0.67-0.82], p<0.001), higher ORR (64.5% vs 53.6%, p<0.001), higher R0 resection rate (16.4% vs 11.8%, p=0.007), and experienced higher rates of G3/4 neutropenia (p<0.001), febrile neutropenia (p=0.019), mucositis (p=0.024), nausea (p=0.016), and diarrhea (p<0.001). Conclusions: FOLFOXIRI/bev determines a clinically and statistically significant improvement of mCRC patients’ OS vs doublets/bev with a meaningful effect also on 5-yr OS, PFS, ORR and R0 resection rate. No significant heterogeneity among explored subgroups was found.
First-line biological agents plus chemotherapy in elderly patients with metastatic colorectal cancer: A retrospective pooled analysis.
Authors: Garcia-Alfonso Pilar , Diaz-Rubio Eduardo , Abad Albert , Carrato Alfredo , Massuti Bartomeu , Rodríguez Alonso Rosa , Manzano Jose Luis , Muñoz Martín Andres J. , Durán Gema , García de Paredes Beatriz , Safont Aguilera Maria Jose , Ferreiro Monteagudo Reyes , Martinez de Castro Eva , González Flores Encarnación , Valladares-Ayerbes Manuel , Gravalos Castro Cristina , Alonso Orduña Vicente , Vieitez Jose María , Escudero Pilar , Aranda Enrique
Published: May 2020

4017

Background: Biological agents, in combination with chemotherapy, are recommended as first-line treatment of metastatic colorectal cancer (mCRC); however, evidence guiding appropriate management of elderly patients with mCRC is lacking. This study compared the efficacy and safety outcomes in older versus younger patients with mCRC who received first-line biological therapy. Methods: This retrospective analysis used pooled data from five Spanish TTD collaborative group studies of adults with advanced CRC who received first-line treatment with bevacizumab, cetuximab or panitumumab, stratified by age (≥65 vs < 65 years). Endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and safety. Results: In total, 999 patients from five studies were included in the analysis; 480 (48%) were aged ≥65 years and 519 (52%) were aged < 65 years; 733 (73.37%) were treated with bevacizumab, 189 (18.92%) received cetuximab and 77 (7.71%) received panitumumab. Median PFS did not significantly differ between patients aged ≥65 versus < 65 years (9.9 vs 9.4 months; hazard ratio [HR] 1.01; 95% confidence interval [CI] 0.88–1.17). Median OS was significantly shorter in older versus younger patients (21.3 vs 25.0 months; HR 1.21; 95% CI 1.04–1.41; P = 0.0132). There was no significant difference between older versus younger patients in ORR (59% vs 62%). Older patients experienced more treatment-related grade ≥3 adverse events. Conclusions: Biological agents are an effective first-line treatment option for elderly patients with mCRC, with comparable efficacy in PFS and ORR to that observed in younger patients and a manageable safety profile.
CodeBreak 100: Activity of AMG 510, a novel small molecule inhibitor of KRASG12C, in patients with advanced colorectal cancer.
Authors: Fakih Marwan , Desai Jayesh , Kuboki Yasutoshi , Strickler John H. , Price Timothy Jay , Durm Greg Andrew , Falchook Gerald Steven , Denlinger Crystal S. , Krauss John C. , Shapiro Geoffrey , Kim Tae Won , Park Keunchil , Coveler Andrew L. , Munster Pamela N. , Li Bob T. , Kim June , Henary Haby Adel , Ngarmchamnanrith Gataree , Hong David S.
Published: May 2020

4018

Background: Kirsten rat sarcoma viral oncogene homolog (KRAS) p.G12C mutation is associated with poor prognosis in colorectal cancer (CRC). AMG 510 is a first-in-class small molecule that specifically and irreversibly inhibits KRASG12C by locking it in the inactive guanosine diphosphate-bound state. In a previous interim analysis of the phase 1, first-in-human trial of AMG 510, we observed a favorable safety profile and preliminary antitumor activity in patients (pts) with advanced solid tumors harboring KRAS p.G12C. Here, we present updated data in pts with CRC. Methods: Key inclusion criteria were KRAS p.G12C mutation identified through molecular testing, measurable disease, and progression on standard therapy. Primary endpoint was safety. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), as assessed per RECIST 1.1, and overall survival (OS). Oral daily doses of 180, 360, 720, and 960mg were tested in the dose escalation phase, and 960mg dose was selected for the expansion phase. Results: As of Jan 8, 2020, 42 pts with CRC (21 female [50%], median age: 57.5 years [range: 33–82]) were enrolled and dosed (25 on 960mg). All pts received prior systemic therapies; 19 pts (45.2%) received > 3 prior lines. Median follow-up was 7.9 months (mos) (range: 4.2–15.9). 13 pts (31.0%) died, and 8 pts (19.0%) remained on treatment (tx). 22 (52.4%) and 8 (19.0%) pts had remained on tx for more than 3 and 6 months, respectively. Progressive disease was the most common reason for tx discontinuation. 20 pts (47.6%) had tx-related adverse events (TRAEs): 18 (42.9%) had grade 2 or lower TRAEs; 2 (4.8%) had grade 3 TRAEs, which were diarrhea (2.4%) and anemia (2.4%). There were no dose-limiting toxicities, fatal TRAEs, or TRAEs leading to tx discontinuation. Overall, ORR and DCR were 7.1% (3/42) and 76.2% (32/42), respectively. At 960mg, ORR and DCR were 12.0% (3/25) and 80.0% (20/25). 3 pts with PR had duration of response of 1.5, 4.2, and 4.3 months, respectively, and their responses were still ongoing at data cutoff. In all pts treated with all doses, median duration of stable disease was 4.2 mos (range: 2.5[+]–11.0). PFS/OS will be reported. Conclusions: In pts with heavily pretreated KRAS p.G12C mutant CRC, AMG 510 monotherapy was well tolerated, with the majority of pts achieving disease control. Study is ongoing. Clinical trial information: NCT03600883 .