bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase Ib study of oral Chk1 inhibitor LY2880070 as monotherapy in patients with advanced or metastatic cancer.
Authors: Miller Wilson H. , Chu Quincy S. , Bouganim Nathaniel , Jonker Derek J. , Batist Gerald , Buhlaiga Najwa J , Lheureux Stephanie , Spratlin Jennifer L. , Alcindor Thierry , Smith Patricia S , Owen Joel , Zaknoen Sara L. , Stille John R. , Fortier Caroline , Vincett Darcy , Oza Amit M.
Published: May 2020

3579

Background: LY2880070 (LY) is an orally-administered, selective adenosine triphosphate-competitive inhibitor of checkpoint kinase 1 (Chk1). LY blocks the checkpoint response, and Chk1 inhibition results in mitotic catastrophe to produce apoptosis. Methods: This 2-part, open-label multi-center study explores the safety, pharmacokinetics (PK) and anti-tumor activity of LY in patients with advanced or metastatic cancers. The primary objective of this study was to determine the maximum tolerated dose (MTD) for multiple escalating oral doses of LY. Secondary objectives were to: 1) Characterize the dose-limiting toxicities (DLTs) and overall safety profile for LY; 2) Evaluate the PK of LY; and 3) Evaluate the anti-tumor activity of LY. Patients received LY orally in 21-day cycles in two treatment arms: 1) A multiple ascending dose (MAD) arm in patients with normal/intermediate CYP2D6 metabolism; or 2) An arm with LY administered as monotherapy to CYP2D6 poor metabolizers. Results: The MTD in normal/intermediate CYP2D6 metabolizers was 200 mg BID daily. A dose of 400 mg QD was not tolerated even with the use of anti-emetics. However, BID administration (same total daily dose) made LY tolerable. Dose-limiting toxicities were predominantly vomiting, nausea, and fatigue, and appeared to be correlated with Cmax. The mean half-life was 5.35 (+/- 2.3) hours. BID dosing provided maintenance of the AUC (3271.4 h∙ng/mL 200 mg BID vs 3377.9 h∙ng/mL 400 mg QD) while lowering Cmax (350.0 ng/mL 200 mg BID vs 691.9 ng/mL 400 mg QD) and increasing Cmin, compared to QD dosing of the same total daily dose. Importantly, BID administration of 200 mg LY resulted in a median Cmin at steady-state that remains above the IC80 for 12 h/day and above the IC50 for 24 h/day. Five patients had a best response of SD for a duration of ≥ 6 cycles. Conclusions: LY was tolerated in a daily BID schedule. The toxicity profile can be modulated by changing the dosing frequency from QD to BID while administering the same daily dose. LY may be a potential combination therapy with DNA damaging agents. Study #: NCT02632448 . This study is sponsored by Esperas Pharma Inc., 1255 boul. Robert-Bourassa #1610, Montreal, Qc, H3B 3X3. Clinical trial information: NCT02632448 .
Phase Ib/IIa study of GC1118 in combination with irinotecan or FOLFIRI in patients with metastatic solid tumors.
Authors: Lee Keun Wook , Han Sae-Won , Kim Ji-Won , Lee Dae-Won , Hong Yong Sang , Ahn Joong Bae , Bang Yung-Jue
Published: May 2020

3592

Background: GC1118 is a novel anti-EGFR monoclonal antibody which has a unique binding epitope and superior ligand inhibition potential. It showed promising antitumor activity as a single agent in the phase I study. This study aimed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of GC1118 in combination with irinotecan or FOLFIRI in metastatic solid tumors and evaluate the efficacy of GC1118 plus FOLFIRI as a second line therapy for RAS and BRAF wild-type metastatic colorectal cancer. Methods: Phase 1b part was designed to evaluate weekly GC1118 (starting from 3 mg/kg) in combination with biweekly irinotecan (180mg/m2) or FOLFIRI (irinotecan 180mg/m2, leucovorin 400mg/m2, 5-FU 400 mg/m2 bolus, and 5-FU 2400mg/m2 over 46hrs) in a 3+3 design. In the phase 2a part, the RP2D of GC1118 is administered in combination with FOLFIRI in a Simon’s two stage design with objective response rate (ORR) as the primary endpoint. Results: 13 pts were enrolled in phase 1b and received 3mg/kg of GC1118 with irinotecan (N = 6) or FOLFIRI (N = 7). DLT occurred in 2 pts (G4 neutropenia, G2 rash) in irinotecan arm and 1pt (G3 neutropenia) in FOLFIRI arm with 3mg/kg of GC1118 and it was determined as MTD and RP2D. Adverse events (AE) of grade ≥ 3 included neutropenia (61.5 %), skin rash (15.4 %) and diarrhea (15.4%). Dose reductions due to GC1118-related AE were required in 6 (46.2%) patients. Among 10 response-evaluable pts in phase 1b, best overall response was PR in 3 and SD in 6, and median PFS was 12 months. In stage 1 of phase 2a (N = 9), 4 PR and 5 SD were observed (ORR 44.4%, 95% CI 13.7 – 78.8). We moved to stage 2, and are currently enrolling additional 20 pts. AE of grade ≥ 3 included neutropenia (66.7%), skin rash (22.2%) and diarrhea (11.1%). Updated data of the phase 2a part will be presented at the meeting. Conclusions: The MTD and RP2D of weekly GC1118 in combination with irinotecan or FOLFIRI was 3mg/kg. Preliminary results of GC1118 and FOLFIRI as a 2nd line treatment in mCRC suggests promising antitumor activity and acceptable safety profile. Clinical trial information: NCT03454620 .
Safety and efficacy of pemigatinib plus pembrolizumab combination therapy in patients (pts) with advanced malignancies: Results from FIGHT-101, an open-label phase I/II study.
Authors: Gutierrez Martin , Subbiah Vivek , Nemunaitis John J. , Mettu Niharika B. , Papadopoulos Kyriakos P. , Barve Minal A. , Féliz Luis , Lihou Christine Francis , Tian Chenwei , Ji Tao , Silverman Ian M. , Chugh Rashmi , Saleh Mansoor N.
Published: May 2020

3606

Background: Pemigatinib (INCB054828) is a selective fibroblast growth factor receptor (FGFR) 1–3 inhibitor with demonstrated efficacy as monotherapy in phase 1/2 (FIGHT-101) and phase 2 (FIGHT-201, -202, -203) trials in pts with advanced cancer. Here, we present preliminary safety, efficacy, and pharmacokinetic (PK) data for pemigatinib (PEMI) combined with pembrolizumab (PEMBRO), a programmed cell death protein-1 (PD-1) inhibitor, in pts with refractory advanced malignancies enrolled in the ongoing FIGHT-101 trial (NCT02393248). Methods: FIGHT-101 includes monotherapy (part 1 and 2) and combination therapy (part 3) cohorts. This analysis is based on pts enrolled in the PEMI + PEMBRO combination dose finding (3a) and dose expansion (3b) cohorts. Eligible adults had advanced malignancies who had progressed after prior therapy and for whom PEMBRO treatment was relevant; pts in part 3b had FGF/FGFR alterations. Pts received oral PEMI at 9 mg or 13.5 mg QD on an intermittent dosing (ID) schedule (21-day cycle, 14-day on/7-day off), or 13.5 mg QD on a continuous dosing (CD) schedule, plus PEMBRO 200 mg IV on day 1 of each 21-day cycle. Results: At data cutoff (August 30, 2019), 23 pts had received PEMI + PEMBRO; 22 (96%) had discontinued therapy (disease progression, 70%). Most frequent tumors were NSCLC (n = 3), bladder (n = 3), pancreatic, testicular, and sarcoma (each n = 2). Of 19 enrolled pts with baseline FGF/FGFR data; 5 had FGFR mutations or rearrangements. No dose-limiting toxicities occurred with PEMI + PEMBRO. The recommended PEMI dose combined with PEMBRO was 13.5 mg QD. Most frequent all-cause, all-grade (Gr) adverse events for ID (n = 17) were hyperphosphatemia (n = 14 [82%]; Gr ≥3, n = 0), anemia (n = 9 [53%]; Gr ≥3, n = 3 [18%]), and decreased appetite (n = 9 [53%]; Gr ≥3, n = 0); for CD (n = 6), hyperphosphatemia (n = 5 [83%]; Gr ≥3, n = 0), and dry mouth (n = 4 [67%]; Gr ≥3, n = 0). One pt discontinued, 2 reduced dose, and 13 interrupted dose due to AEs (none for hyperphosphatemia; dose interruption mainly for gastrointestinal AEs [n = 5]). One fatal AE occurred (suicide, not treatment-related). PK parameters for PEMI in the PEMI + PEMBRO combination were comparable with those for PEMI monotherapy. Five pts had partial response (3 had FGFR rearrangements or mutations); 5 pts had stable disease. Conclusions: PEMI + PEMBRO combination therapy was tolerable with no new safety signals, and demonstrated preliminary antitumor activity in pts with advanced malignancies including those with FGF/FGFR alterations. Clinical trial information: NCT02393248 .
Phase I study of afatinib plus selumetinib in patients with KRAS mutation-positive colorectal, non-small cell lung and pancreatic cancer.
Authors: Huijberts Sanne , Brummelen Emilie Van , Van Herpen Carla M.L.- , Desar Ingrid M.E. , Opdam Frans , Geel Robin Van , Marchetti Serena , Steeghs Neeltje , Monkhorst Kim , Thijssen Bas , Rosing Hilde , Huitema Alwin , Beijnen Jos H. , Bernards Rene , Schellens Jan H. M.
Published: May 2020

3613

Background: Mutations in the KRAS gene result in a constitutively activated RAS-RAF-MEK-ERK (MAPK) pathway. In KRAS mutant tumors, the anti-tumor activity of MEK inhibitors is limited due to intrinsic resistance caused by feedback activation of upstream epidermal growth factor receptors (HER). This upstream activation not only reactivates MAPK, but also the phosphoinositide 3-kinase (PI3K)-AKT pathway in preclinical research. Based on these data, a phase I clinical trial was initiated with the combination of the orally administered pan-HER inhibitor afatinib and the MEK inhibitor selumetinib in patients with KRAS mutant and PIK3CA wildtype colorectal cancer (CRC), non-small cell lung cancer (NSCLC), or pancreatic cancer to determine the recommended phase 2 regimen (RP2R). Methods: In this multicentre study, patients received escalating doses of afatinib and selumetinib according to a 3+3 design starting with 20 mg afatinib once daily (QD) continuously and 25 mg selumetinib twice daily (BID) in a 21 days on/7 days off schedule. Continuous and intermittent dosing were explored to assess optimal exposure and tolerability. The primary aim was determining the RP2R. Secondary objectives included assessment of anti-tumor activity and the analyses of pharmacokinetic and pharmacodynamic parameters for target inhibition. Clinicaltrials.gov identifier: NCT2450656. Results: In total, 26 mostly heavily pretreated patients with CRC (n=19), NSCLC (n=6) and pancreatic cancer (n=1) were enrolled among 5 dose-levels. Dose-limiting toxicities (DLTs) occurred in 6 patients and consisted of grade 3 diarrhea (n=3), decreased appetite (n=1), nausea/vomiting (n=1), dehydration (n=2) and mucositis (n=1). Clinical efficacy was limited with no responses according to RECIST v1.1 and stable disease for 221 days in a patient with NSCLC as best response. Conclusions: The RP2R was determined at 20 mg afatinib QD continuously and 25 mg selumetinib BID 21 days on/7 days off for continuous dosing. The 3 patients treated in the escalation cohort of the ongoing intermittent dose-level with 20 mg afatinib QD and 25 mg selumetinib BID 5 days on/2 days off, experienced no DLTs. Pending the latest safety results of the expansion cohort for this ongoing dose-level, the RP2R of intermittent dosing has not been established at the moment. Clinical trial information: NCT2450656 .
BET inhibitor molibresib for the treatment of advanced solid tumors: Final results from an open-label phase I/II study.
Authors: Cousin Sophie , Blay Jean-Yves , Braña Garcia Irene , De Bono Johann S. , Le Tourneau Christophe , Moreno Victor , Trigo Jose Manuel , Hann Christine L. , Azad Arun , Im Seock-Ah , Ferron-Brady Geraldine , Datta Antara , Wu Yuehui , Horner Thierry , Kremer Brandon Edward , Dhar Arindam , O'Dwyer Peter J. , Shapiro Geoffrey , Piha-Paul Sarina Anne
Published: May 2020

3618

Background: Molibresib is an orally available, small molecule bromodomain and extra-terminal domain (BET) protein inhibitor under investigation for treatment of advanced solid tumors. Methods: This was an open-label, single- and repeat-dose, 2-part, Phase 1/2 study including patients (aged ≥16 years) with advanced solid tumors. Part 1: patients received different oral doses of molibresib (2–100mg QD; amorphous free-base formulation) to determine recommended Phase 2 dose. Part 2 (expansion cohort): patients with various tumor types received the bioequivalent besylate formulation (75mg) to explore clinical activity at recommended dose. Safety and efficacy (response rate [RR] based on RECIST 1.1 criteria, progression-free survival [PFS], and overall survival [OS]) were evaluated for the total cohort (patients from Part 1 and 2). Safety, pharmacokinetic, pharmacodynamic, and efficacy per tumor type were evaluated in Part 2. Results: Part 1 only data have previously been reported. Overall, 196 patients were included in the total cohort (1 patient in Part 1 was counted twice). In the all treated population, 195 patients (median age 58 years; 46% male) received ≥1 dose of molibresib (Part 1: n = 93; Part 2: n = 102). Adverse events (AEs) were experienced by 193/196 (98%) patients; 180/196 (92%) had a treatment-related AE (TRAE). AEs led to permanent treatment discontinuation in 38/196 (19%) patients. Of different tumor types in Part 2, NUT carcinoma (NC) had the lowest frequency of TRAEs (10/12 [83%]) and AEs leading to permanent treatment discontinuation (1/12 [8%]). In total cohort, 3/31 NC patients and 1/35 with castration-resistant prostate cancer (CRPC) achieved a confirmed partial response. A further 67/196 (34%) achieved stable disease (SD). In Part 2, RR in 12 NC patients was 8% (CI: 0.2–38.5); 50% had SD and median PFS was 4.8 months with median OS of 5.0 months. In CRPC patients, RR was 4% (CI: 0.1–21.9); 22% had SD; median PFS was 8.0 months with median OS of 9.1 months. Plasma concentrations for molibresib and active metabolites were similar between different tumor types. Gene expression analysis from pre- and post-dose biopsy samples collected from 10 mCRPC patients showed transcriptional downregulation of Myc target genes upon treatment with molibresib. Conclusions: Molibresib demonstrated a manageable safety and tolerability profile with single agent activity observed in selected patients with NC and CRPC. Clinical trial information: NCT01587703 .
Targeting G1-S phase cell-cycle alterations with CDK4/6 inhibitor-based genomically matched personalized therapy approach.
Authors: Adashek Jacob J. , Kato Shumei , Okamura Ryosuke , Khalid Noor , Lee Suzanna , Nguyen Van Thomas , Sicklick Jason K. , Kurzrock Razelle
Published: May 2020

3623

Background: Although CDK4/6 inhibitors are established as a standard treatment option for hormone receptor-positive, HER2-negative metastatic breast cancer patients, its benefit in other solid tumors is unclear. Moreover, no clear biomarker exists that predicts the response to CDK4/6 inhibitors. Herein, we investigated the factors associated with clinical outcomes from CDK4/6 inhibitor-based therapy, used alone or in combination with other therapies targeting genomic co-alterations, among diverse cancer patients with potentially sensitizing alterations in G1-S phase cell-cycle alterations (defined as CDK4/6 amplifications, CCND1/2/3 amplifications or CDKN2A/ B alterations). Methods: We interrogated molecular profiles of 2,457 patients with diverse solid tumors for G1-S phase cell-cycle alterations and co-altered genes using clinical-grade next generation sequencing (182-465 genes). Results: G1-S phase cell-cycle alterations occurred in 20.6% (507/2,457) of patients with 99% of those with cell cycle alterations (N = 501/507) harboring at least one characterized co-alteration (median, 4; range, 0-24). Significant improvement in median PFS was observed when CDK4/6 inhibitor-based therapies matched a larger proportion of tumor alterations, often by being given together with other drugs that were matched to genomic co-alterations, hence achieving a high Matching Score (high Matching Score [≥50%] vs. low Matching Score [ < 50%]: all cohorts including breast cancer [N = 58]: PFS: 6.2 vs. 3.2 months, P = 0.001; non-breast cancer cohort [N = 40]: PFS 6.2 vs. 2.0 months, P < 0.001 [multivariate]). (Matching Score roughly equivalent to number of alterations targeted divided by total number of characterized alterations). In contrast, targeting CDK4/6 alone in patients harboring cell-cycle pathway alterations along with other co-alterations, without targeting the genomic co-alterations, did not improve PFS even in patients who received matched CDK4/6 inhibitors as part of a combination regimen. Representative cases that were successfully treated with a matched combination strategy will also be presented. Conclusions: Most patients with G1-S phase cell-cycle alterations harbored co-genomic alterations. Our current study suggests that targeting co-alterations along with cell cycle molecular alterations may be necessary to achieve better clinical outcome. Further clinical investigation with larger numbers of patients are required.
Modeling differentially expressed genes in patient tumors to guide expression-based biomarker development.
Authors: Liu Derek , He Meng Xiao , Bi Kevin , Van Allen Eliezer Mendel , Liu David
Published: May 2020

3627

Background: Differential gene expression (DGE) methods, initially developed for analyzing bulk RNA changes in pure tumor cell lines under experimental settings, are commonly used to identify biomarkers in and infer biological differences between patient tumor samples, which are admixtures of tumor and non-tumor components. Methods to sensitively and accurately detect cell type-specific expression differences in admixed patient samples are not well characterized but may greatly affect emerging targeted and immunotherapy biomarker strategies. To address this issue, we developed a simulation framework to benchmark our ability to detect changes in tumor-intrinsic gene expression. Methods: Pseudobulk RNAseq melanoma cohorts were simulated by sampling from melanoma single cell RNAseq data. Simulation parameters were optimized to maximize concordance of gene expression means and variances (Spearman r = 0.81, 0.68, respectively) between the TCGA SKCM cohort (n = 462) and matched simulated cohort, and then validated in two independent melanoma cohorts (n = 42, 129; means Spearman r = 0.80, 0.78; variances Spearman r = 0.68, 0.63). Using this simulation framework, we benchmarked the effect of sample size, magnitude of differential expression, and differences in cell type proportions on the sensitivity and positive predictive value (PPV) of detecting true differentially expressed genes in the tumor-intrinsic compartment. Results: Reference cohorts of 50 total tumors (n = 10) were simulated to contain a 2 standard deviation tumor-intrinsic expression change in 50 randomly selected genes and a 11% difference in mean purity between two equally sized 25-tumor subgroups. DGE analysis using DESeq2 with an FDR q-value threshold of 0.1 yielded a sensitivity of 0.37 and PPV of 0.29. DGE analysis of the same simulated cohorts using a non-parametric Mann-Whitney U test with an FDR q-value threshold of 0.1 yielded a sensitivity of 0.13 and PPV of 0.76. Conclusions: Commonly used DGE methods for existing expression-based biomarker strategies have poor sensitivity and PPV in admixed tumor samples, limiting our ability to find meaningful transcriptional biomarkers in clinical cohorts. We are currently developing methods to more accurately detect true differentially expressed genes in admixed bulk RNAseq samples and applying these approaches for biomarker discovery in immunotherapy-treated patient cohorts and other clinical tumor cohorts.
Olaparib monotherapy in pretreated patients with BRCA1/2 alterations: Results of a DRUP trial cohort.
Authors: van der Wijngaart Hanneke , Hoes Louisa Rose , van Berge Henegouwen Jade Maxime , van Der Velden Daphne Liselotte , Zeverijn Laurien , Roepman Paul , Nguyen Luan , van Werkhoven Erik D. , de Leng Wendy W.J. , Jansen Anne M.L. , Mehra Niven , Robbrecht Debbie , Gelderblom Hans , Voest Emile E. , Verheul Henk M.W.
Published: May 2020

3633

Background: Extensive molecular profiling in cancer regularly reveals targets for which approved drugs are available in tumor types outside the registered label. Efficacy of off-label use of these drugs is unavailable. Access to these drugs for pts is challenging. In the Drug Rediscovery Protocol (DRUP, Van der Velden et al, Nature 2019), pts are treated based on their tumor molecular profile. Here, we present the results of the successful cohort “Olaparib for tumors with BRCA1/2 alterations”. Methods: Twenty five adult cancer patients (pts) who exhausted all treatment options and had BRCA1/2 loss of function (LoF) mutations (found in routine diagnostics) were included. No pts were eligible for on-label treatment with PARP inhibitors. Pts were treated with olaparib until disease progression or unacceptable toxicity. The primary endpoint was clinical benefit (CB: objective response or stable disease (SD) ≥ 16 weeks). Pts were enrolled using a Simon-like two-stage model, with 8 pts in stage 1 and up to 24 pts in stage 2 if at least 1 pt had CB in stage 1. A fresh frozen biopsy was obtained from each pt for whole genome sequencing (WGS) and target confirmation. Results: Fourteen pts (56%) had CB. The objective response rate was 32%. Nine different cancer types were included: prostate (n=11), breast (n=4), ovarian (n=2), pancreatic (n=3), colorectal (n=2), biliary tract (n=2), kidney (n=1), adrenal gland (n=1) and endometrial (n=1). WGS could be performed on 58% of baseline tumor biopsies, confirming the original BRCA1/2 mutations in 86%. CB was observed in pts with both somatic and germline BRCA alterations and across tumor types. CB was only observed in cases with biallelic loss of BRCA1/2 in the tumor and when classified as HRD by a pan-cancer homologous recombination deficiency classifier (CHORD), which relies on genome-wide SNV, indel, and SV mutational footprints for HRD detection. No evidence of complete BRCA loss and HRD was observed in 5 pts with PD, while 4 patients with effective BRCA complete loss and HRD also had PD. WGS analysis of these pts suggested resistance mechanisms due to other oncogenic drivers (e.g FGFR1 amplification, CTNNB1 stabilization, KEAP1 inactivation). Conclusions: Olaparib seems to be an effective treatment option for pts with BRCA1/2 LoF mutated malignancies, regardless of histology, for both germline and somatic alterations, which needs confirmation in an independent cohort. CB of olaparib was observed in malignancies showing biallelic loss of BRCA1/2 and when classified as HRD, indicating the importance of the BRCA/HRD signature status. Clinical trial information: NCT02925234 .
Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiation in patients with locally advanced rectal cancer: Final results of PRODIGE 23 phase III trial, a UNICANCER GI trial.
Authors: Conroy Thierry , Lamfichekh Najib , Etienne Pierre-Luc , Rio Emmanuel , FRANCOIS Eric , Mesgouez-Nebout Nathalie , Vendrely Veronique , Artignan Xavier , Bouché Olivier , Gargot Dany , Boige Valerie , Bonichon-Lamichhane Nathalie , Louvet Christophe , Morand Clotilde , De La Fouchardiere Christelle , Juzyna Beata , Rullier Eric , Marchal Frédéric , Castan Florence , Borg Christophe
Published: May 2020

4007

Background: PRODIGE 23 investigated the role of neoadjuvant mFOLFIRINOX before preoperative (preop) chemoradiation (CRT), with TME-surgery and adjuvant chemotherapy (CT) in resectable locally advanced rectal cancer. Methods: PRODIGE 23 is a phase III multicenter randomized clinical trial. Eligible pts had cT3 or cT4, M0 rectal adenocarcinomas <15 cm from the anal verge, age 18-75 years, and WHO PS ≤1. Randomization was stratified by center, T stage, N status, tumor location, and perirectal fat extramural extension. Primary endpoint was 3-yr disease-free survival (DFS). Main secondary endpoints were ypT0N0 rate, overall survival (OS) and metastasis-free survival (MFS). 460 pts were required to observe 136 events to show a gain in 3-year DFS from 75% to 85% (HR=0.56) with a 2-sided α=0.05 and 90% power. HR and 95% CI were estimated by a stratified Cox proportional hazard model. Arm A pts received preop CRT (50 Gy, 2 Gy/fraction [fr]; 25 fr + capecitabine), surgery, then adjuvant CT for 6 months (mos). Arm B pts received 6 cycles of mFOLFIRINOX (oxaliplatin 85 mg/m², leucovorin 400 mg/m², irinotecan 180 mg/m² D1, and 5-FU 2.4 g/m² over 46 h) every 14 days, followed by the same preop CRT, surgery and 3 mos of adjuvant CT. Adjuvant CT consisted of mFOLFOX6 or capecitabine, depending on the centre’s choice for all pts. Imaging work-up, operative and pathology reports were centrally reviewed. Results: (ITT) Between 6/2012 and 6/2017, 230 and 231 pts were randomly assigned in Arm A/B, respectively by 35 participating centers. Pts characteristics were well balanced. Neoadjuvant mFOLFIRINOX and CRT in both arms were well tolerated. Compliance to CRT and to adjuvant CT was not hampered by neoadjuvant CT. Surgical morbidity did not differ between the 2 arms. The ypT0N0 rate was 11.7 vs 27.5% in Arm A/B (p<0.001). Median follow-up was 46.5 mos. 136 DFS events was reported. 3-yr DFS was significantly increased in arm B (HR 0.69, 95% CI 0.49-0.97, p=0.034): 68.5% (CI: 61.9-74.2) vs 75.7% (CI: 69.4-80.8) in arm A/B. The subgroup analysis showed no evidence of heterogeneity of the effect size of treatment on DFS. 3-yr MFS was also significantly higher in arm B: 71.7 in arm A vs 78.8% (HR 0.64, CI 0.44-0.93, p<0.02) in arm B. 3-yr OS was 87.7 vs 90.8% (HR 0.65, CI 0.40-1.05, p=0.077) in arm A/B, with 54.2% of the pts with recurrence being alive. Conclusions: Neoadjuvant mFOLFIRINOX plus CRT is safe, and significantly increased ypCR rate, DFS and MFS. OS data are not mature. Clinical trial information: NCT01804790 .
Consensus molecular subtypes and CRCassigner classifications in metastatic colorectal cancer (mCRC): Prognostic and predictive impact in the TRIBE2 study.
Authors: Borelli Beatrice , Fontana Elisa , Giordano Mirella , Antoniotti Carlotta , Bergamo Francesca , Murgioni Sabina , Pietrantonio Filippo , Morano Federica , Tamburini Emiliano , Boccaccino Alessandra , Santini Daniele , Conca Veronica , Pella Nicoletta , Maiello Evaristo , Ugolini Clara , Fontanini Gabriella , Falcone Alfredo , Nyamundanda Gift , Sadanandam Anguraj , Cremolini Chiara
Published: May 2020

4016

Background: The TRIBE2 study (NCT02339116) recently demonstrated the superiority of upfront FOLFOXIRI/bevacizumab (bev) when compared to a pre-planned strategy of doublets/bev in molecularly unselected but mostly (74%) RAS/ BRAF mutant mCRC patients. The Consensus Molecular Subtypes (CMS) and CRCAssigner (CRCA) demonstrated prognostic value in multiple studies, but their predictive role has not been established so far. Given the poor prognosis associated with early stage mesenchymal/stem-like subtypes, we hypothesized that the CMS/CRCA classifiers could predict benefit from the upfront intensified strategy in patients included in the TRIBE2 study. Methods: Untreated formalin-fixed paraffin-embedded samples were classified into CMS/CRCA subtypes using a custom nCounter assay (NanoString Technologies). The impact of subtypes on progression free survival (PFS), progression free survival 2 (PFS2, defined as the time from randomization until the second evidence of disease progression) or overall survival (OS) was evaluated in the profiled population. Results: 426 and 428 (63%) patients enrolled in the TRIBE2 study were profiled according to CMS and CRCA classifications, respectively. The distribution of CMS/CRCA subtypes differed according to primary tumour site (both p < 0.001 for CMS/CRCA) and RAS/ BRAF mutational status (both p < 0.001 for CMS/CRCA). Significant associations of both CMS/CRCA classifiers with PFS, PFS2 and OS were demonstrated (Table). The effect of treatment intensification was independent of CMS subtypes (p for interaction for PFS/PFS2/OS: ns). Significant interaction effect between CRCA subtypes and treatment arm was reported in terms of PFS (p = 0.017), PFS2 (p = 0.010) and OS (p = 0.008). The benefit from the intensification of the upfront chemotherapy seemed more relevant in the stem-like (PFS, HR = 0.60; p = 0.03) and mixed subtypes (HR = 0.44; p = 0.002). Conclusions: CMS subtypes have a prognostic role in mCRC independently of RAS/ BRAF status. CRCA classification may help identifying subgroups of patients who may derive a more substantial benefit from upfront FOLFOXIRI/bev. [Table: see text]
Pembrolizumab monotherapy for patients with advanced MSI-H colorectal cancer: Longer-term follow-up of the phase II, KEYNOTE-164 study.
Authors: Diaz Luis A. , Le Dung T. , Kim Tae Won , Van Cutsem Eric , Geva Ravit , Jaeger Dirk , Hara Hiroki , Burge Matthew E. , O'Neil Bert H. , Kavan Petr , Yoshino Takayuki , Guimbaud Rosine , Taniguchi Hiroya , Elez Elena , Al-Batran Salah-Eddin , Boland Patrick M , Cui Yi , Mayo Carlos Alberto , Marinello Patricia , Andre Thierry
Published: May 2020

4032

Background: Pembrolizumab provides effective antitumor immunity and durable responses in patients (pts) with advanced, colorectal cancer (CRC) with microsatellite instability-high (MSI-H) tumors. We present data on antitumor immunity with pembrolizumab in pts from the phase 2, KEYNOTE-164 study who had approximately 3 years of follow-up, and in pts re-treated after disease progression. Methods: KEYNOTE-164 enrolled pts with metastatic MSI-H CRC, MSI-H status confirmed locally by IHC or PCR, and ≥2 (cohort A) or ≥1 (cohort B) prior lines of therapy (fluoropyrimidine, oxaliplatin, irinotecan, or anti VEGF/EGFR). Eligible pts received pembrolizumab 200 mg Q3W for 2y (35 administrations) or until progression, unacceptable toxicity, or withdrawal. Pts who stopped pembro due to a confirmed CR or after completing 2y of treatment and who progressed after stopping were eligible for re-treatment with up to 17 administrations in the second-course phase, at investigator discretion. Tumor response was assessed Q9W per RECIST v1.1 by independent review. The primary endpoint was ORR. Secondary endpoints included DOR, PFS, OS, and safety. The data cutoff date was Sep 9, 2019. Results: At data cutoff, the median follow-up was 31.4 mo (range, 0.2-47.8) for 61 pts in cohort A and 36.1 mo (0.1-39.3) for 63 pts in cohort B. ORR was 32.8% (3CR, 17PR; 95% CI% 21.3-46.0) for cohort A and 34.9% (8CR, 14PR; 95% CI 23.3-48.0) in cohort B. Median DOR was not reached (NR [range, 6.2-41.3+]) and not reached (range, 3.9+ to 37.1+), respectively. Fifteen pts in cohort A and 17 in cohort B had ongoing responses at data cutoff. Median PFS was 2.3 mo (95% CI 2.1-8.1) with 3-yr PFS rate of 31% in cohort A and was 4.1 mo (2.1-18.9) with 3-yr PFS rate of 34% in cohort B. Median OS was 31.4 mo (21.4-NR) with 3-yr OS rate of 49% in cohort A and was not reached (19.2-NR) with 3-yr OS rate of 52% in cohort B. Nine pts (6 in cohort A, 3 in cohort B) had a second course of treatment. The best response in second course was PR in 1 patient each in cohort A and B. Grade 3-4 drug-related adverse events occurred in 10 (16%) pts in cohort A and 8 (13%) pts in cohort B. No grade 5 drug-related events occurred. Conclusions: After approximately 3 y of follow-up, pembrolizumab continues to provide effective long-term antitumor immunity with durable responses, with small numbers of drug-related adverse events and no drug-related deaths in pts with advanced, MSI-H CRC. Clinical trial information: NCT02460198 .
Trifluridine/tipiracil or regorafenib in refractory metastatic colorectal cancer patients: An AGEO prospective “real life” study.
Authors: Coutzac Clélia , Trouilloud Isabelle , Artru Pascal , Henriques Julie , Masson Thérese , De La Fouchardiere Christelle , Doat Solene , Bouché Olivier , Coriat Romain , Saint Angelique , Moulin Valérie , Vernerey Dewi , Tougeron David , Taieb Julien
Published: May 2020

4036

Background: Regorafenib (R) and trifluridine/tipiracil (T) have proved their efficacy in patients (pts) with metastatic colorectal cancer (mCRC) refractory to standard chemotherapy and targeted therapies. However, it remains unclear which drug should be administered first. Methods: This observational study was prospectively conducted in 13 centers between 6/2017 and 9/2019 in France. All consecutive pts with chemoresistant mCRC and receiving T and/or R were eligible. The aim of this study was to describe efficacy and tolerability of T and/or R. Overall survival (OS) and progression-free survival (PFS) of pts receiving T then R (T/R) and the opposite sequence (R/T) were also assessed. Results: A total of 237 pts (25% R and 75% T) were enrolled (109 male, median age: 67 years (32-91), mean previous lines of treatment: 2.5 (1-7)). Baseline ECOG PS was 0-1 in 77% of pts. As compared to R pts, T pts were significantly older (68 years vs 63; p = 0.033) and with > 3 metastatic sites (44% vs 30%, p = 0.018). Median OS were 6.6 and 6.2. months in the T and R group, respectively (NS). Median PFS were 2.4 and 2.1 months in the T and R group, respectively (NS). After matching 46 paired pts according to primary tumor resection, age and number of metastatic sites, a trend to a longer OS (9.5 vs 6.8 months; p = 0.17) and a significantly longer PFS (2.8 vs 2 months; p = 0.048) were observed in the T group. Among the overall population, 24% of pts received R/T or T/R sequence. Median OS from first treatment were 10.7 months in the R/T group and 9.8 months in the T/R (NS). Treatment sequence was not an independent prognostic factor for OS or PFS in multivariable analysis. Tolerability profiles were similar to previously published data, but dose reductions were more frequent in the R group (44 vs 27%, p = 0.008). Conclusions: Efficacy and safety results in this real life prospective study are in line with those published phase III trials. Both treatments seem similar in term of efficacy favoring T for clinical use as shown by the higher number of patients receiving this drug.
Rectal cancer in young patients: Clinicoepidemiologic profile and treatment outcomes.
Authors: Goyal Pankaj. , Maheshwari Udip , Jain Parveen , Agrawal Chaturbhuj , Chaudhari Krushna A. , Goyal Sumit , Batra Ullas , Bothra Sneha J , Goel Varun , Talwar Vineet , Doval DC
Published: May 2020

4042

Background: Colorectal cancers are 3rd most common cause of cancer globally however studies of rectal cancers alone in younger patients are scarce. Rectal cancers in Asian patients present at a younger age and has an aggressive tumor biology. This study looks at rectal cancer in young patients, ≤30 years old, with the aim to report clinico-epidemiologic profile and treatment outcomes in this subgroup. Methods: Retrospective analysis was conducted at a tertiary care centre. Of total 845 rectal cancer patients between 2012-2017, 103 patients of young rectal cancers were enrolled. Kaplan Meier method was used for survival analysis and cox regression analysis was done to identify factors affecting survival. Results: Young rectal cancer patients constituted 12.2% of the total rectal cancer patients. Male: Female ratio was 2.3:1 and the mean age was 24.7 ± 3.9 years. Around 73.8 % patients had locoregional disease (stage I/II/III) at presentation.CEA levels were elevated in 36.9% of patients, while most common histology was signet ring cell histology which was present in 51.5% of patients. Of 76 patients with locoregional disease, 75% received neoadjuvant chemoradiotherapy, 7.9% received neoadjuvant chemotherapy alone while 3.9% received neoadjuvant radiotherapy alone. Of 76 patients with locoregional disease, 55 patients underwent surgery of which 53.9% underwent low anterior resection while 18.4% underwent abdomino-perineal resection. Pathologic CR rates were seen in 13.3%, while recurrences were seen in 55.4% of non-metastatic patients. Overall 5-year survival for the whole study group was 19.5%, while 1-year PFS and 3-year DFS for metastatic and non-metastatic disease were 5% and 43.8% respectively. On regression analysis elevated CEA levels and not achieving a pathologic CR (pCR) with neoadjuvant therapy had a trend towards worse overall survival (HR 2, 95% CI 1-4, p = 0.063), (HR 4.7, 95% CI 0.64-35.1, p = 0.125) respectively. Conclusions: Rectal cancers in Asia present at younger age and this younger population is associated with advanced stage, increased CEA at presentation, aggressive histology and poor survival. CEA raise and not achieving pCR were associated with trend towards worse survival.
Characterization of sociodemographic and clinicopathological features and associated outcomes of patients (Pts) with anal squamous cell cancer (ASCC): Analysis of 44,084 pts in the National Cancer Database (NCDB).
Authors: Young Joanna Alyse , Trufan Sally Jeanne , Worrilow William Mills , Musselwhite Laura W. , Nazemzadeh Reza , Kadakia Kunal C. , Chai Seungjean , Salmon John Stuart , Hwang Jimmy J. , Kim Edward S. , Raghavan Derek , Salem Mohamed E.
Published: May 2020

4052

Background: ASCC incidence is rising. There are limited data on the relationships between sociodemographic & clinicopathological features and outcomes of ASCC pts. Methods: Pts diagnosed with ASCC between 2004 and 2016 were retrospectively reviewed. Data obtained from the NCDB were used to examine the impact of sociodemographic status on clinicopathological features and outcomes. Pts were categorized based on low (median < $38,000) or high (≥$68,000) income and low ( > 21% with no high school diploma) or high ( < 7% with no high school diploma) education areas based on zip code at time of diagnosis. Logistic regression and chi-square were used to examine differences between groups. Results: In total, 44,084 pts with ASCC were identified: median age, 59 yrs, 86% white; 11% black; 64% female. Most pts (84%) resided in metro areas; 29.7% vs 19.8% lived in high vs low income areas; 22.9% vs 17.8% lived in high vs low education areas. Seven percent were uninsured, 50% had government (Gov), and 43% had private insurance. Male gender (HR 1.62, CI 1.41-1.85, p < 0.001), low income area (HR 1.28, CI 1.19-1.37, p = 0.014), and insurance status (Gov, HR 1.55, CI 1.32-1.82, p < 0.001 and uninsured, HR 1.37, CI 1.37-1.85, p = 0.039) were associated with a higher risk of death. After adjusting for age, sex, race, stage, grade, insurance status, and comorbidity, pts from low income/education (n = 6695) vs high income/education (n = 4316) areas had a 33 % increased risk of death (HR: 1.33, p < 0.001). Pts with stage IV ASCC in the low income/education (n = 227) vs high income/education (n = 295) groups had worse overall survival (mOS, 1.4 vs 1.9 yrs, p < 0.020). Of the 44,084 pts, 5461 (12.4%) had confirmed HPV status. Of these, 2658 (48.7%) were HPV+ (high risk subtypes) and 2803 (51.3%) were HPV-. Compared to the HPV- pts, HPV+ pts were more likely to be women (71.8% vs 67.8%, p = 0.001), have stage 3 (38.1% vs 33.6%) or 4 (7.9% vs 5.9%, p < 0.001) cancer, and have poorly differentiated (29.5% vs 25.6%, p < 0.001) tumors. There were no significant differences in race, education, income, metro area, insurance status, or comorbidity between the HPV+ and HPV- pts. Moreover, HPV status did not impact OS (HR 0.92, CI 0.81-1.04, p = 0.195). Conclusions: HPV status was not correlated to income, education or insurance status, and did not impact OS in ASCC pts. Male gender and insurance status were associated with increased risk of death. Pts living in low income and low education areas were associated with worse survival.
PDL1 expression predicts therapeutic outcome in non metastatic anal squamous cell carcinoma (NMASCC).
Authors: Iseas Ilma Soledad , Golubicki Mariano , Robbio Juan , Ruiz Gonzalo , Salanova Ruben , Mariani Javier , Slutsky Ezequiel , Vecchioni Daniela , Oviedo Ana , Guerra Florencia , Maquieira Julian , Basilletti Jorge , Picconi Alejandra , Roca Enrique , Mendez Guillermo , Coraglio Mariana
Published: May 2020

4054

Background: NMASCC is a rising incidence disease with up to 30% of treatment failure to achieve complete response (CR) after standard chemoradiotherapy (CRT) leading to severe morbidity and death. Stage III-TNM, p53 mutations, HPV negativity, HIV infection are linked to treatment failure. We investigated the predictive/prognostic role of TNM, CR, HPV, PDL1 positivity and CD3/CD8 densities in NM-ASCC from a single institution. Methods: All 79 eligible consecutive NMASCC pts (available FFPE pre-treatment samples) seen from October-2009 to April-2019 having completed definitive CRT (50.4 Gy Pelvic Radiotherapy with Mitomycin-C 12mg/m2/IV/d1-5 / FU 1000mg/m2/d1-4 d29-32 (28%), Mitomycin-C/Capecitabine 825 mg/m2/bid (38%), Cisplatin 60 mg/m2/IV d1-29 and 5FU (34%) were analyzed. Mean age: 59 (range 26-87), 72% female, Stage III: 59%, HPV positive: 86% (HPV-16: 80%);14% HIV positive. IHC assessed by two pathologist for PD-L1 expression (ClonSP263) and CD3-CD8+ TILS densities (Clone 2GV6, Clone SP57). HPV-DNA assessed by PCR (BSGP5+/6+ multiplexed with beta-globin). Kaplan-Meier survival, CR, DFS, OS and Univariate analyses were performed using Cox proportional hazard model. Results: CR achieved within 6 months of treatment completion was 68%( 53pts). Median follow-up after treatment completion: 35 months (range 6 –149). As of February 2020, 82% (65 pts) are alive, no evidence of disease:(57%) 46 pts, recurrence rate: 26%(22 pts), cancer death: 18% (14 pts). PDL1+ tumors ( > 1% positivity-CPS score): 56%, expression levels: 1-5% (57%,26p), > 10%-100% (43%,19p). PDL1+ had a strong association with CR (p = 0.021); higher PDL1+ levels had 8-fold of CR-likelihood than PDL1 negative.(OR 8.50 vs. 1.12). Significative Spearman correlation between PDL1 tumors with CR and CD3-CD8 TILS density was observed (R = 0.43,p = 0.0017 and R = 0.36,p = 0.00094 respectively), albeit CD3-CD8 failed to reach significance as prognostic factors for either CR, DFS or OS. Only CR and PDL1 positive were strongly significantly associated to DFS (HR 0.10 [IC 95% 0.04-0.28] p < 0.001 and HR 0.28 [IC 95% 0.11-0.73] p = 0.006) and OS (HR 0.12 [IC 95% 0.03-0.45] p < 0.001 and HR 0.15 [IC 95% 0.03-0.68] p < 0.004). Low prevalence of HPV negative, early tumors, HIV positive cases in our series probably impacted in statistical power for prognosis correlation. Conclusions: PDL1 positivity was the strongest predictive/prognostic factor in NM-ASCC. Alternative therapeutics options to standard CRT should be explored on poor-risk patients as HPV-negative, P53-mutated and PDL1 negative patients.
Impact of tumor side on clinical outcomes in stage II and III colon cancer with known microsatellite instability status.
Authors: Zakka Katerina Mary , Williamson Shayla , Jiang Renjian , Alese Olatunji B. , Shaib Walid Labib , Wu Christina , Behera Madhusmita , El-Rayes Bassel F. , Akce Mehmet
Published: May 2020

4068

Background: Microsatellite instability high (MSI-H) status indicates better prognosis in early stage colon cancer (CC) compared to microsatellite stable (MSS). However, the impact of tumor side, left side (L) versus right side (R), is not described on clinical outcomes based on MSI status. Methods: Patients with pathological stage II and III primary adenocarcinoma of the colon between 2010 and 2015 were identified in the National Cancer Database (NCDB) using ICD-O-3 morphology and topography codes: 8140-47, 8210-11, 8220-21, 8260-63, 8480-81, 8490 and C18.0, 18.2,18.3, 18.5,18.6, 18.7. Univariate (UVA) and multivariable (MVA) survival analyses were conducted, and Kaplan-Meier Curves were used to compare overall survival (OS) based on tumor location and treatment received with Log-rank test. Results: A total of 35,071 patients with stage II (n = 17,629) and III (n = 17,442) CC were identified. 51.3% female; 81.5% Caucasian; median age 66 (range, 18-90). Majority of stage II and III tumors were R, 61.2% (n = 10,794) and 56.0% (n = 9,763). MSI-H was more common in stage II compared to III, 23.3% (n = 4,115) vs 18.2% (n = 3,171) (p < 0.0001). Survival was better in stage II MSI-H compared to MSS, 5 year-OS 75.1% vs 71.8% (p = 0.0057). However, stage III CC survival was better in MSS compared to MSI-H, 5-year OS 60.5% vs 58.0% (p < 0.001). In stage II MSI-H CC R was more common than left, 78.3 % (n = 3223) vs 21.7% (n = 892). There was no significant difference in survival between stage II MSI-H L vs R (5-year OS 76.2% vs 74.7%, p = 0.1578). Stage II MSS CC R was more common than L, 56.0% (n = 7571) vs 44.0% (n = 5943), and survival was better in L vs R (5-year OS 73.2% vs 70.8%, p = 0.0029). Stage III MSI-H CC was more common in R than L, 75.6% (n = 2397) vs 24.4% (n = 774) and survival was better in L (5-year OS 62.5% vs 56.5%, p = 0.0026). Stage III MSS CC was more common in R than L, 51.6% (n = 7366) vs 48.4% (n = 6905), and survival was better in L vs R (5-year OS 67.0% vs 54.4%, p < 0.001). Conclusions: Survival was better in left sided tumors compared to right in stage II MSS, stage III MSS and stage III MSI-H CC.
Translational research of voltage-A1: Efficacy predictors of preoperative chemoradiotherapy and subsequent nivolumab monotherapy in patients with microsatellite-stable locally advanced rectal cancer.
Authors: Inamori Koji , Togashi Yosuke , Bando Hideaki , Tsukada Yuichiro , Suzuki Ayako , Suzuki Yutaka , Kotani Daisuke , Fukuoka Shota , Kojima Motohiro , Fukui Makoto , Yuki Satoshi , Komatsu Yoshito , Homma Shigenori , Uemura Mamoru , Kato Takeshi , Ito Masaaki , Nishikawa Hiroyoshi , Yoshino Takayuki
Published: May 2020

4073

Background: In VOLTAGE-A1, after 5 cycles of nivolumab (240 mg q2 weeks) plus radical surgery following chemoradiotherapy (CRT; 50.4 Gy with capecitabine 1,650 mg/m2), a major pathologic response is observed in 38% (AJCC tumor regression grade 0-1) of 37 patients with microsatellite-stable locally advanced primary rectal cancer. Here, biomarkers for predicting the efficacy of this treatment were investigated. Methods: Serial tumor biopsies and blood collections were performed at 4 time points; before CRT, after CRT, after 3 cycles of nivolumab, and before surgery. Tumor-infiltrating lymphocytes (TILs) and DNA/RNA were extracted from tumor samples, and peripheral blood mononuclear cells (PBMCs) were extracted from blood samples. We analyzed the immune status of the patients by flow cytometry using the collected TILs and PBMCs. Whole exome and RNA sequencing analyses were conducted using the extracted DNA and RNA, respectively. The PD-L1 status of tumor samples was also evaluated by in vitro diagnostic immunohistochemistry staining. Results: Among the 24 patients whose samples were serially collected, 11 (46%) were AJCC grade 0-1 and 13 were 2-3. Before CRT, effector regulatory T (eTreg) cells in TILs were higher in patients with AJCC grade 2-3, and both the CD8+ T cell/eTreg cell ratio in TILs and PD-L1-positive tumor cells (≥1%) were higher in patients with AJCC grade 0-1 (p = 0.047, p = 0.083, respectively). Ki67 expression by CD8+ T cells in TILs was higher before CRT in patients with AJCC grade 0-1 (p = 0.037) and increased after CRT in all patients. Patients with consensus molecular subtype (CMS) 1 and CMS3 achieved AJCC grade 0-1 at rates of 100% (2/2) and 60% (4/6), respectively. In contrast, patients with CMS2 and CMS4 achieved AJCC grade 0-1 at rates of 43% (3/7) and 29% (2/7), respectively. The tumor mutation burden of pre-CRT samples was significantly higher in patients with AJCC grade 0-1 (median 1.45/MB) than in patients with AJCC grade 2-3 (0.84/MB) (p = 0.016). Conclusions: A higher CD8+ T cell/eTreg cell ratio, PD-L1-positive, Ki67 expression by CD8+ T cells in TILs, CMS1 or 3, and higher tumor mutation burden are good predictors of the efficacy of the sequential combination of CRT and nivolumab. Further results will be reported in the meeting. Clinical trial information: NCT02948348 .