bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II, multicenter, open-label study of trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): DESTINY-CRC01.
Authors: Siena Salvatore , Di Bartolomeo Maria , Raghav Kanwal Pratap Singh , Masuishi Toshiki , Loupakis Fotios , Kawakami Hisato , Yamaguchi Kensei , Nishina Tomohiro , Fakih Marwan , Elez Elena , Rodriguez Javier , Ciardiello Fortunato , Saxena Kapil , Yamamoto Eriko , Bako Emarjola , Okuda Yasuyuki , Shahidi Javad , Grothey Axel , Yoshino Takayuki
Published: May 2020

4000

Background: T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload. Early studies have shown promising activity in advanced HER2-expressing tumors. DESTINY-CRC01 (DS8201-A-J203; NCT03384940) is a phase 2, open-label, multicenter study of T-DXd in pts with HER2-expressing mCRC. Methods: Pts with centrally confirmed HER2-expressing, RAS–wild type mCRC that progressed on ≥ 2 prior regimens received T-DXd 6.4 mg/kg every 3 weeks (q3w) in 3 cohorts (A: HER2 IHC 3+ or IHC 2+/ISH+; B: IHC 2+/ISH−; C: IHC 1+). The primary endpoint was confirmed objective response rate (ORR) by independent central review in cohort A; secondary endpoints included, disease control rate (DCR; CR + PR + SD), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and ORR in cohorts B and C. Results: At data cutoff (Aug 9, 2019), 78 pts (A, 53; B, 7; C, 18) had received T-DXd. Median age was 58.5 y (range, 27-79 y), 52.6% of pts were male, and 89.7% had left colon or rectum cancer; median number of prior regimens was 4 (range, 2-11); all pts had prior irinotecan. Median treatment duration was 3.5 mo (95% CI, 2.1-4.3 mo; cohort A, 4.8 mo [95% CI, 3.9-5.8 mo]); 38.5% of pts remained on T-DXd treatment. The confirmed ORR was 45.3% (24/53 pts; 95% CI, 31.6%-59.6%) in cohort A, including 1 CR and 23 PRs; median DOR was not reached (95% CI, 4.2 mo-NE). The ORR in pts with prior anti-HER2 treatment was 43.8% (7/16 pts; 95% CI, 19.8%-70.1%). The DCR was 83.0% (44/53 pts; 95% CI, 70.2%-91.9%); median PFS was 6.9 mo (95% CI, 4.1 mo-NE); median OS was not reached. No responses were observed in cohorts B or C. Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 61.5% of pts (48/78); the most common (≥10%) were decreased neutrophil count (21.8%) and anemia (14.1%). Seven pts (9.0%) had TEAEs leading to drug discontinuation. Five pts (6.4%) had interstitial lung disease (ILD) adjudicated by an independent committee as related to T-DXd (2 grade 2; 1 grade 3; 2 grade 5 [the only drug-related deaths]). Conclusions: Overall, T-DXd 6.4 mg/kg q3w demonstrated remarkable activity in pts with HER2-expressing mCRC refractory to standard therapies, with a safety profile consistent with previous results. ILD is an important risk and requires careful recognition and intervention. Clinical trial information: NCT03384940 .
Overall survival (OS) and long-term disease-free survival (DFS) of three versus six months of adjuvant (adj) oxaliplatin and fluoropyrimidine-based therapy for patients (pts) with stage III colon cancer (CC): Final results from the IDEA (International Duration Evaluation of Adj chemotherapy) collaboration.
Authors: Sobrero Alberto F. , Andre Thierry , Meyerhardt Jeffrey A , Grothey Axel , Iveson Timothy , Yoshino Takayuki , Sougklakos Ioannis , Meyers Jeffrey P. , Labianca Roberto , Saunders Mark P. , Vernerey Dewi , Yamanaka Takeharu , Boukovinas Ioannis , Oki Eiji , Georgoulias Vassilis , Torri Valter , Harkin Andrea , Taieb Julien , Shields Anthony Frank , Shi Qian
Published: May 2020

4004

Background: In overall population, IDEA pooled analysis did not demonstrate non-inferiority (NI) regarding 3y DFS in pts with stage III CC receiving 3m vs. 6m of adj FOLFOX/CAPOX. However, in pts treated with CAPOX (especially in low-risk pts), 3m of therapy was as effective as 6m. Results of OS and 5y DFS are reported. Methods: OS was defined as time from enrollment to death due to all causes. OS NI margin was conservatively set to be Hazard Ratio (HR) = 1.11, which is equivalent to: the maximum acceptable loss of OS efficacy, by shortening treatment to 3m, was half of the OS efficacy gained in MOSAIC trial (i.e., 2.26% absolute reduction in 5y OS rate). Pre-planned sub-group analyses included by regimen and risk group for both OS and 5y DFS. NI was to be declared if the one-sided false discovery rate adjusted (FDRa) NI p-value < 0.025. Results: With an overall median survival follow-up of 72 m (range per study, 62 to 84 m), 2584 deaths and 3777 DFS events among 12,835 pts from six trials were observed. Across 6 studies, 39.5% of pts received CAPOX (rate by study, 0% to 75.1%). Overall, the 5y OS rate was 82.4% (3m) and 82.8% (6m), with estimated OS HR of 1.02 (95% confidence interval [CI], 0.95-1.11; FDRa NI p, 0.058) and absolute 5-y OS rate difference of -0.4% (95% CI, -2.1 to 1.3%). Overall, the 5y DFS rate was 69.1% (3m) and 70.8% (6m), with estimated DFS HR of 1.08 (95%CI, 1.01-1.15, FDRa NI p, 0.22). HRs (95% CI) within subgroups see table. Conclusions: 5y OS rate reported in IDEA trials was higher than historical rates, regardless of duration of therapy. While overall survival in IDEA did not meet prior statistical assumptions for NI in overall population, the 0.4% difference in 5y OS should be placed in clinical context. OS and 5y DFS results continue to support the use of 3m adjuvant CAPOX for the vast majority of stage III colon cancer pts. This conclusion is strengthened by the substantial reduction of toxicities, inconveniencies and cost associated with shorter treatment duration. Clinical trial information: NCT01150045; 2009-010384-16; NCT00749450; ISRCTN59757862; 2007-003957-10; UMIN000008543; 2007-000354 . [Table: see text]
Impact of high-risk features on disease-free survival (DFS) in patients (pts) with high-risk stage II colon cancer (CC) in ACHIEVE-2 trial as part of the IDEA collaboration.
Authors: Manaka Dai , Shiozawa Manabu , Kotaka Masahito , Gamoh Makio , Shiomi Akio , Makiyama Akitaka , Munemoto Yoshinori , Rikiyama Toshiki , Fukunaga Mutsumi , Ueki Takashi , Shitara Kohei , Shinkai Hiroshi , Tanida Nobuyuki , Oki Eiji , Yamazaki Kentaro , Sunami Eiji , Yamanaka Takeharu , Yoshino Takayuki , Ohtsu Atsushi , Maehara Yoshihiko
Published: May 2020

4011

Background: The IDEA collaboration for high-risk stage 2 colorectal cancer patients (pts) demonstrated that for CAPOX, 3 months was non-inferior to 6 months treatment, while for FOLFOX, 6 months was superior to 3 months treatment. We investigated the impact of high risk features on disease-free survival (DFS). Methods: ACHIEVE-2, one of the 4 IDEA studies (SCOT, TOSCA, ACHIEVE-2, HORG), was an open-label, multicenter randomized trial for high-risk stage II colon cancer. High risk features are defined as one or more: T4, inadequate nodal harvest < 12, poorly differentiated, clinical sign of obstruction and perforation or vascular invasion. The association of high risk features with DFS were measured by Cox regression analyses. Results: Between 2014 and 2017, ACHIEVE-2 enrolled 525 pts, out of whom 514 pts were the modified ITT (mITT) population; 432 received CAPOX (84.0%) and 82 did mFOLFOX6 (16.0%). High-risk features included 35.8% of T4, 12.8% of inadequate nodal harvest, 11.5% of poorly differentiated, 19.3% of obstruction, 6.4% of perforation and 87.5% of vascular invasion; 47.3% had one features, 35.2% had two, 14.6% had three, and 2.9% had four or more. With a median follow-up of 36.1 months, 3-year DFS rates were 88% in both arms, with a hazard ratio (HR) of 1.12 (95% CI, 0.67-1.87, p=0.67). In multivariate analysis, T4 (HR 3.77 [2.18-6.53], p< 0.0001) and inadequate nodal harvest (HR 2.98 [1.59-5.59], p= 0.0006) remained independent significant negative prognostic factors. The 3-year DFS rates in T4 and Non-T4 diseases were 78% and 94% (p<0.0001), while 3-year DFS rate in pts with inadequate and adequate nodal harvest were 77% and 90% (p=0.0059). No interaction was observed between treatment duration and T4 or inadequate nodal harvest. Conclusions: Our findings indicated the relative impact of high risk features on DFS varies across factors; T4 and inadequate nodal harvest < 12 were more significant than the others. Our results must be interpreted within the combined analysis as well as within the reproducibility of results across the 4 trials. Clinical trial information: 000013036 .
Improving the AJCC/TNM staging classification for colorectal cancer: The prognostic impact of tumor deposits.
Authors: Peacock Oliver , Limvorapitak Thitithep , Hu Chung-Yuan , Bednarski Brian K. , Taggart Melissa , Dasari Arvind , Kopetz Scott , Holliday Emma B. , Das Prajnan , You Y. Nancy , Chang George J.
Published: May 2020

4012

Background: Identification of tumor deposits (TD) currently plays a limited role in staging for colorectal cancer (CRC) other than for N1c designation. The aim of this study was to determine the prognostic impact, beyond AJCC N1c designation, of TD among primary CRC patients. Methods: Patients with stage 1 to 3 primary CRC diagnosed between 2010 and 2015 were identified from the Surveillance, Epidemiology and End Results (SEER) database. Cancer specific survival (CSS) stratified by TDs and nodal status was calculated, and Kaplan-Meier method and multivariable COX proportional hazards regression analyses were performed. Results: A total of 74,494 patients with primary CRC were identified. Mean age was 66.4 (SD+/-13.2) years, 36,988 (49.7%) were female and 40,651 (54.6%) were right-sided. TDs were present in 4,481 patients (6.0%) and 26,603 (35.7%) had lymph node metastases. The presence of TDs were significantly associated with adverse tumor characteristics including advanced pathological stage, nodal and metastasis status, higher grade and perineural invasion. Incorporating TDs into each nodal status was independently associated with worse CSS and supported reclassification of nodal status to incorporate TDs following multivariable regression analysis as outlined in the table. Following multivariable regression analysis, the proposed AJCC nodal reclassification incorporating TDs, in combination with tumor stage was a strong predictor of CSS, and also represents a new summary staging. Conclusions: TDs are an independent predictor of worse outcome in CRC. The presence of TDs have distinctly different CSS and these data support modification of the current N classification. This study proposes a reclassification of the AJCC system for CRC to incorporate TDs and informs an updated node and summary stage. [Table: see text]
FOxTROT: neoadjuvant FOLFOX chemotherapy with or without panitumumab (Pan) for patients (pts) with locally advanced colon cancer (CC).
Authors: Seligmann Jenny F. ,   FOxTROT Collaborative Group
Published: May 2020

4013

Background: FOxTROT has reported marked down-staging, reduced perioperative morbidity and a trend towards fewer recurrences with 6 wks of oxaliplatin-fluoropyrimidine neoadjuvant chemotherapy (NAC) in CC (Seymour, ASCO 2019 abstract 3504). Using updated data, we investigate the contribution of panitumumab (Pan) and tumour markers to efficacy of NAC. Methods: 1053 pts with radiologically-staged T3-4, N0-2, M0 CC were randomly allocated (2:1) to either 6 wks of NAC and 18 wks of postoperative adjuvant chemotherapy (AC) or 24 wks of AC. 279 pts with RAS-wt tumours were also randomised 1:1 to receive Pan or not with NAC. The primary endpoint was freedom from recurrence or residual disease at 2 years for NAC vs AC, and depth of extramural spread for the Pan randomisation; secondary endpoints include safety, histological downstaging, CC-specific survival and OS. Results: Of 699 allocated pre-and-postoperative chemotherapy, 674 (97%) started and 612 (88%) completed NAC. 684/699 (97.8%) pre-and-postoperative and 349/354 (98.6%) control patients underwent tumour resection. There was marked T- and N-down-staging and tumour regression with NAC (all p<0.001). There were fewer disease recurrences within 2 years in the NAC than AC group: 15.6% (109/698) vs 19.5% (69/354), RR=0.76 (95%CI 0.56-1.02), P=0.07. Response to NAC was significantly (p<0.001) less in MMR-deficient (dMMR) than MMR-proficient (pMMR) tumours: 7%(8/115) vs 23%(128/553) moderate or greater histological tumour regression. Reductions in 2-year recurrence were also seen only in pMMR tumours [RR=0.72 (0.52-1.00), p=0.05], with no apparent benefit in dMMR tumours: RR=0.94 (0.43 to 2.07), p=0.9]. Analyses of panitumumab will be presented. Conclusions: Six weeks of NAC for operable CC can be delivered safely, with marked histopathological down-staging, and may result in better disease control at 2 years in pMMR disease. Clinical trial information: 87163246 .
Pembrolizumab for previously treated advanced anal squamous cell carcinoma: Pooled results from the KEYNOTE-028 and KEYNOTE-158 studies.
Authors: Marabelle Aurelien , Cassier Philippe Alexandre , Fakih Marwan , Kao Steven Chuan-Hao , Nielsen Dorte , Italiano Antoine , Guren Tormod , Dongen Marloes Van , Spencer Kristen Renee , Bariani Giovanni M. , Ascierto Paolo Antonio , Santoro Armando , Hiret Sandrine , Ott Patrick Alexander , Piha-Paul Sarina Anne , Liu Chih-Chin , Leiby Melanie A. , Norwood Kevin , Delord Jean-Pierre
Published: May 2020

4020

Background: Patients (pts) with anal squamous cell carcinoma (ASCC) have poor outcomes and few treatment options. We report a pooled analysis of pembrolizumab (pembro) antitumor activity and safety in the ASCC cohorts of the multicohort studies KEYNOTE-028 (NCT02054806; phase 1b) and KEYNOTE-158 (NCT02628067; phase 2), providing a robust sample size and longer follow-up. Methods: Eligible pts were aged ≥18 y with histologically/cytologically confirmed metastatic/unresectable ASCC, had prior failure of/intolerance to standard therapy or no standard therapy options, measurable disease (RECIST v1.1), ECOG PS 0/1, and a tissue sample evaluable for PD-L1/biomarkers (KEYNOTE-028 required PD-L1 positivity). Baseline PD-L1 expression was assessed using a prototype IHC assay (QualTek) in KEYNOTE-028 and the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies) in KEYNOTE-158. Pts received pembro 10 mg/kg Q2W (KEYNOTE-028) or 200 mg Q3W (KEYNOTE-158) for 2 y or until PD/unacceptable AEs. The primary endpoint in both studies was ORR (per RECIST v1.1). Secondary endpoints were duration of response (DOR), PFS, OS, and safety. Results: 137 pts with ASCC were treated in KEYNOTE-028 (n = 25) or KEYNOTE-158 (n = 112) and were included in this analysis (median age, 61 y; 83.2% women; 73.0% had PD-L1–positive tumors). Median follow-up was 11.7 mo; 124 pts (90.5%) had discontinued treatment. ORR (95% CI) was 10.9% (6.3%–17.4%). 8 pts had CR and 7 had PR. ORR (95% CI) by PD-L1 status was 14.0% (7.9%–22.4%) in the PD-L1 positive group and 3.3% (0.1%–17.2%) in the PD-L1 negative group. Among all treated pts, median DOR was not reached (range, 6.0+ to 57.5+ mo). By Kaplan-Meier estimation, 84.6% of responders had a DOR ≥24 mo. Median PFS was 2.1 mo (95% CI, 2.0–2.1) and median OS was 11.7 mo (95% CI, 8.8–14.5). The 12-mo PFS and OS rates were 14.5% and 47.4%. 85 pts (62.0%) had +1 treatment-related AE, 24 pts (17.5%) with grade 3–4 events (no grade 5 events). 32 pts (23.4%) had immune-mediated AEs; 2 pts (1.5%) had infusion related reactions. Conclusions: In pts with previously treated advanced ASCC, pembro showed durable antitumor activity, particularly in pts with PD-L1–positive tumors, and manageable toxicity. Clinical trial information: NCT02054806 (KEYNOTE-028), NCT02628067 (KEYNOTE-158) .
Cetuximab/irinotecan/5-FU +/-oxaliplatin or FOLFOXIRI +/- bevacizumab in patients with colorectal cancer and nonresectable liver metastases (AIO CELIM2-study).
Authors: Folprecht Gunnar , Mende Marika , Liersch Torsten , Bechstein Wolf Otto , Kohne Claus-Henning , Stein Alexander , Kunzmann Volker , Ghadimi Michael , Neumann Ulf Peter , Nilsson Sven , Koenig Alexander , Pession Ursula , Troja Achim , Glados Manfred , Kleiss Mathias , Ubbelohde Ulrike , Weitz Juergen
Published: May 2020

4024

Background: EGFR based combinations and the triplet combination FOLFOXIRI are known to increase response rates compared to doublet combinations. Methods: Patients with colorectal cancer and non-resectable liver metastases were enrolled into the trial. RAS wild type patients were randomised to cetuximab/FOLFIRI or cetuximab/FOLFOXIRI, RAS/BRAF mutant patients were randomised to FOLFOXIRI with or without bevacizumab. The primary endpoint was response. Secondary endpoints included progression free and overall survival. The trial was closed early due to poor recruitment. Results: Between 2014 and 2018, ninety-two pts were enrolled into the study. 54 wild type pts were randomised into cetuximab based treatment with (28 pts) or without (26 pts) oxaliplatin, 38 RAS/BRAF mutant pts were randomised to receive FOLFOXIRI alone (18 pts) or plus bevacizumab (16 pts). Objective response was achieved in 21/26 pts (81 % [95 CI: 61 – 93 %]) with cet/FOLFIRI, 24/28 pts (86 % [95 CI: 67 – 96 %]) with cet / FOLFOXIRI, 13/1 8 pts (72 % [95 CI: 46 – 90 %]) with FOLFOXIRI and 14/20 pts (70 % [95 CI: 46 – 88 %]) with bev/FOLFOXIRI. Two pts with cet/FOLFOXIRI and one pat with FOLFOXIRI achieved CR according to imaging. The median PFS was 12.7 [95 % CI: 7.2 – 18.2], 15.0 [95 % CI: 11.3 – 18.7], 17.5 [95 % CI: 8.0 – 27.1] and 15.0 [95 % CI: 11.4 – 18.5] months with cet/FOLFIRI, cet/FOLFOXIRI, FOLFOXIRI and bev/FOLFOXIRI. The median overall survival was 42 mo. [95 % CI: 28 – 55], 55 [95 % CI:41 – 68], 28 [95 % CI: 22 – 36] and 44 [95 % CI: 0 – 94] months with cet/FOLFIRI, cet/FOLFOXIRI, FOLFOXIRI and bev/FOLFOXIRI. The frequency of grade ≥ 3 toxicity per arm (cet/FOLFIRI, cet/FOLFOXIRI, FOLFOXIRI and bev/FOLFOXIRI) was 29 %, 46 %, 56 %. 45 % for neutropenia/leukopenia, 11 %, 12 %, 28 %, 25 % for diarrhea and 29 %, 19 %, 6 % and 5 % for skin toxicities. Conclusions: High response rates were observed in patients with colorectal liver metastases with all regimens. The numerically highest response rate was observed in RAS wild type patients treated with cetuximab/FOLFOXIRI. Clinical trial information: NCT01802645 .
Fruquintinib combination with sintilimab in refractory metastatic colorectal cancer patients in China.
Authors: Gou Miaomiao , Yan Huan , E Liu Tie , Wang Zhikuan , Si Haiyan , Chen Shiyun , Pan Yuting , Fan Runjia , Qian Niansong , Dai Guanghai
Published: May 2020

4028

Background: Fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, is a new anti-cancer targeting drug independently developed in China for refractory metastatic colorectal cancer (mCRC). Because Regorafenib combined with nivolumab has a promising future in patients with refractory mCRC, we aim to evaluate the efficiency of combination of Fruquintinib with Sintilimab (a highly selective, fully human monoclonal antibody PD-1 mAb) in these patients. Methods: Fifty-two patients with refractory mCRC were given fruquintinib (3mg orally, once daily for 3 weeks, followed by 1 weeks off in 4 weeks cycles) and sintilimab (200mg intravenously, once every 3 weeks). Before treatment, peripheral blood samples were collected and next-generation sequencing was performed to detect the gene profile of patients. Results: The ORR was 15.38% (8/52), DCR was 57.6% (30/52), and mPFS was 108 days. The patients was divided into two groups according to their PFS: PFS ≥ 90 days and PFS <90 days. PFS was significantly worse in patients with the following mutations: AMER1 ( p=0.0073), DNMT3A ( p=0.0075), ETV5 ( p=0.012), EWSR1 ( p=0.016), FANCA ( p=0.019), IKBKE ( p=0.0073), NOTCH1 ( p=0.015), STAG2 ( p=0.012) and TCF7L2 ( p=0.0073). It was also significantly worse in the patients had the abnormalities of complexity and coagulation cascades ( p = 0.026) and pancreatic cancer pathway ( p = 0.0098). Conclusions: Fruquintinib combined with Sintilimab seemed not resulted in a significant increase in ORR, DCR and OS in refractory mCRC. Certain mutational genes and abnormal pathway caused by some frameshift mutations may affect the efficacy. It is suggested that targeting these mutational genes and signaling pathway may be helpful to improve the efficacy of Fruquintinib combination with Sintilimab.
Genomic aberration of chromatin regulatory BAF complex as predictive biomarker for immunotherapy in gastrointestinal adenocarcinoma.
Authors: QI Changsong , Ge Sai , Peng Zhi , Zhang Xiaotian , Xu Yu , Wang Guoqiang , Bai Yuezong , Shen Lin
Published: May 2020

4035

Background: SNF/SWI, a large ATP-dependent chromatin remodeling complex, is required for transcriptional activation of genes normally repressed by chromatin, and critical to tumor initiation and progression. Here, we analyzed the predictive utility of the mutations of the SNF/SWI members involved in BAF and PBAF complexes, and sought to explore the potential mechanisms. Methods: Clinical, genomic, transcriptional, and immunohistochemical data from immunotherapeutic cohort (MSKCC, n=185), Cancer Cell Line Encyclopedia (CCLE, n=92), The Cancer Genome Atlas (TCGA, n=925), and 3D Medicines database (3DMed, n=1812) were analyzed to explore the predictive effect of genomic aberration of BAF complex on the benefit from immunotherapy in patients with gastrointestinal adenocarcinoma. Results: In the MSKCC cohort involving 185 patients with gastrointestinal adenocarcinoma, the mutation of any member involved in BAF complex ( ARID1A, ARID1B, SMARCA4, SMARCB1, and SMARCD1) was significantly associated with prolonged OS of ICI treatment (HR 0.53, 95%CI 0.31-0.90, P=0.019), instead of the mutations of PBAF members including PBRM1 and ARID2. In addition, BAF mutation was not linked with better prognosis in TCGA database, indicating its predictive, not prognostic efficacy of immunotherapy. BAF-mutated samples exhibited higher tumour mutational burden (TMB, P<0.05, Table), and increased mRNA expression of immune-related genes including chemokines and granzyme A. In the 3DMed cohort where tumour samples received both genomic sequencing and PD-L1 immunohistochemical staining, BAF mutation was associated with higher PD-L1 positive rate in tumour cells (P<0.05, Table). Conclusions: Genomic aberration of members in chromatin regulatory BAF complex may serve as a predictive, not prognostic biomarker of ICI benefit in patients with gastrointestinal adenocarcinoma, partially underlying the mechanisms including higher mutational burden, transcription of immune-related genes, and protein-level PD-L1 expression. [Table: see text]
Pembrolizumab (Pem) in combination with stereotactic body radiotherapy (SBRT) for resectable liver oligometastatic MSS/MMR proficient colorectal cancer (CRC).
Authors: Deming Dustin A. , Emmerich Philip , Turk Anita Ahmed , Lubner Sam Joseph , Uboha Nataliya Volodymyrivna , LoConte Noelle K. , Mulkerin Daniel , Kim David H. , Matkowskyj Kristina A. , Weber Sharon M. , Abbott Daniel , Eickhoff Jens C. , Bassetti Michael Frederick
Published: May 2020

4046

Background: SBRT is used to treat liver metastatic CRC, causing an increase in immunogenic antigen release and influx of responding immune cells. We hypothesize that radiation enhances the immunogenicity of MSS CRC and potentiates the effectiveness of PD-1 blockade. This phase Ib study examines the safety and efficacy of the sequential combination of SBRT and Pem in patients (pts) undergoing resection of their disease. Methods: Eligibility criteria include MSS CRC with resectable liver-confined metastatic disease. Prior surgery and systemic chemotherapy are allowed. Subjects receive sequential SBRT and cycle 1 of Pem prior to operative management and adjuvant Pem. The primary objectives are to determine the safety/tolerability of this regimen and the recurrence free survival (RFS) at 1 year following clearance of metastatic disease. Correlative studies examined tumor infiltrating CD8+ T lymphocytes (TILs) and the accumulation and proteolysis of versican (VCAN), an immunoregulatory tumor matrix proteoglycan. Proteolysis of VCAN results in the release of an immunostimulatory fragment, versikine. Cancers with low VCAN and high versikine (VCAN proteolysis predominant (VPP)) are hypothesized to respond better to immunotherapies. Results: 15 pts (median age 58.2 [range 38-69]) have been enrolled. All pts had prior FOLFOX. SBRT median dose was 50 Gy (40-60 Gy) to a single lesion targeted in all pts. No DLTs were observed. AEs included one case of biliary tract injury and biloma, not related to immunotherapy. No grade 3/4 immunotherapy-related AEs have occurred. 10 pts have completed a minimum follow-up of 1 year post resection. In the intention to treat analysis, the 1 year RFS was 70% (historic control 50%). 2 of 3 pts with BRAF V600E mutations have had early recurrences. 2 pts had VCAN high tumors and both recurred prior to 1 year. 4 pts had VPP cancers and all were recurrence free at 1 year. TILs in the radiated lesions were > 2 times as abundant as in the pre-treatment (tx) tissue for 50% of pts. 3 of 4 pts who had non-radiated lesions available for analysis had TILs > 2 times pre-tx in the non-radiated lesions indicating a potential abscopal effect. Conclusions: The combination of SBRT with Pem and surgical resection is well tolerated with no signal of increased immunotherapy-related toxicity and preliminary evidence of potential enhanced efficacy. Clinical trial information: NCT02837263 .
Clinical and pathologic factors associated with survival in BRAFV600E colorectal cancers.
Authors: Morris Van K. , Kee Bryan K. , Overman Michael J. , Fogelman David R. , Dasari Arvind , Raghav Kanwal Pratap Singh , Shureiqi Imad , Johnson Benny , Parseghian Christine Megerdichian , Wolff Robert A. , Eng Cathy , Garg Naveen , Kopetz Scott
Published: May 2020

4047

Background: BRAFV600E mutations occur in fewer than 10% of all patients (pts) with metastatic colorectal cancer (mCRC) and arise from sessile serrated adenomas. Despite efficacy with targeted therapies against MAPK signaling and with immunotherapies in this population, survival outcomes for pts with BRAFV600E mCRC in general are poor. Characteristics distinguishing pts with BRAFV600E mCRC with favorable versus unfavorable outcomes have not been well annotated. Methods: Records of 188 pts with BRAFV600E mCRC evaluated at MD Anderson Cancer Center between 3/2010-1/2020 were reviewed. Pts with the shortest and longest metastatic survival (N = 25 for each group) were compared. Associations between prognostic group and clinical/pathologic features were measured by odds ratio and for median survival by log-rank testing. Results: Median metastatic survival differed between the 2 BRAFV600E mCRC populations (8.6 vs 84 months, p < .0001). Pts with poor survival more commonly had primary tumors arising from the hepatic flexure/proximal transverse colon (44% vs 16%, p = .04) and more frequent hepatic involvement (75% vs 28%, p = .001). Pts with favorable survival were more likely to develop metachronous metastases (52% vs 16%, p = .01), have fewer distant organ involvement (median 1 vs 2, p = .02), and undergo definitive locoregional therapy to metastatic disease (44% vs 0%, p = .01). Microsatellite instability (36% vs 4%, p = .008) and a history of tobacco use (44% vs 16%, p = .04) were associated with a favorable prognosis. Durable responses to MAPK-targeted therapies (5/25) and immunotherapy (3/25) were noted in the favorable group. Conclusions: Pts with BRAFV600E mCRC can achieve excellent long-term survival which belies conventional context and is driven by locoregional and systemic treatment options alike. Anatomic localization of the primary tumor and prior exposures may highlight environmental influences on tumor biology which account for the clinical heterogeneity of pts with BRAFV600E mCRC.
Evaluation of safety, immunogenicity, and preliminary efficacy of PolyPEPI1018 off-the-shelf vaccine with fluoropyrimidine/bevacizumab maintenance therapy in metastatic colorectal cancer (mCRC) patients.
Authors: Hubbard Joleen Marie , Cremolini Chiara , Graham Rondell P. , Moretto Roberto , Mitchell Jessica L , Wessling Jaclynn , Toke Eniko Rita , Csiszovszki Zsolt , Lőrincz Orsolya , Molnar Levente , Somogyi Eszter , Megyesi Mónika , Pantya Kata , Tóth József , Páles Péter , Miklós István , Falcone Alfredo
Published: May 2020

4048

Background: PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine containing 12 immunogenic epitopes derived from 7 cancer testis antigens (CTAs) frequently expressed in patients with CRC. Here we report the final results of the phase I study of PolyPEPI1018 vaccine as an add-on to maintenance therapy in mCRC patients. Methods: 11 patients with MSS mCRC were vaccinated with PolyPEPI1018 just after the transition to maintenance therapy with fluoropyrimidine/bevacizumab after first-line combo chemotherapy and bevacizumab. Part A: n = 5, single dose; Part B: n = 6, 3 doses, Q12W. Primary endpoint was safety. Immunomonitoring was performed at both blood and tumor levels, as well as prospectively predicted. Results: The vaccine was well tolerated; most common side effects were transient skin reactions. No vaccine-related SAE occurred. Pre-existing immune responses were boosted by the vaccine for 7/10 patients. De novo responses were also induced, overall, 80% of patients had CD8+ T cell responses against at least 3 CTAs. The magnitude of immune responses as well as the density and the ratio of CD8+/CD3+ tumor infiltrating T cells increased with multiple vaccine doses. Three patients had objective tumor response according to RECIST v1.1: one of them in the single dose group and two of them in the 3 doses group. Both patients in the 3 doses group qualified for curative surgery. One of them had no viable tumor cells in his primary tumor at the time of surgery. Post-trial follow-up revealed PFS of at least 12 months for 3 patients. mPFS was longer for patients receiving multiple doses (9.9 months) compared to single dose (6.1 months). Both measured and predicted multiantigenic immune responses tend to correlate with PFS and tumor volume reduction. Conclusions: PolyPEPI1018 was effective in restoring immunological responses to CTAs in patients’ with spontaneous immunity against. Treatment with PolyPEPI1018 vaccine and maintenance therapy was safe and demonstrated evidence of early clinical activity in MSS mCRC tumors. Data support further randomized trials with PolyPEPI1018. Clinical trial information: NCT03391232 .
Prognostic effect of specific RAS/BRAF mutations in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: George Ben , Taylor Bradley W , Lasowski Matthew , Ritch Paul S. , Shreenivas Aditya Varnam , Chakrabarti Sakti , Kamgar Mandana , Zimmermann Michael T , Reddi Honey V , Urrutia Raul , Thomas James P.
Published: May 2020

4050

Background: Somatic mutations in KRAS, HRAS, NRAS (extended RAS) and BRAF have prognostic and predictive impact in pts with mCRC. We analyzed the prognostic impact of specific somatic mutations in extended RAS and BRAF. Methods: We retrospectively reviewed the electronic medical records of pts with mCRC at our institution who underwent comprehensive genomic profiling (CGP) utilizing the Foundation One assay. DNA was extracted from clinical specimens and CGP was performed on hybrid-capture, adaptor ligation-based libraries for up to 315 genes plus 47 introns from 19 genes frequently rearranged in cancer. BRAF mutations were classified as class I, II and III according to accepted nomenclature. Fisher’s exact test and Kaplan Meier estimates were used for statistical analyses. This project was approved by the Medical College of Wisconsin Institutional Review Board. Results: 273 pts were identified - median age at diagnosis was 57, 48% were male. Somatic mutations in extended RAS were found in 138 (50%) pts, majority being mutations in KRAS (46%). Among pts with KRAS mutations, codon 12, 13, 61 and 146 mutations accounted for 73%, 11%, 4% and 6% respectively while KRAS G12C mutations accounted for 9%. BRAF mutations were detected in 22 (8%) pts - BRAF V600E and non–V600E mutations accounting for 4.4% and 3.6% respectively. Among pts with BRAF mutations, 17 (77%) were kinase domain mutations, 16 of which could be further classified as class I (12/16), II (1/16) and III (3/16). Median overall survival (mOS) for the entire cohort was 26.4 months (mo). KRAS mutated pts had a mOS of 25.8 mo; pts with KRAS G12C mutation had a mOS of 23 mo compared to 27.1 mo for pts with other KRAS mutations (p < 0.001).Pts with BRAF mutation had a mOS of 26.2 mo; pts with BRAF V600E mutation had a mOS of 14.1 mo compared to 30.6 mo for pts with BRAF non-V600E mutations (p = 0.1). Conclusions: The poor prognosis of pts with KRAS G12C and BRAF V600E mutations compared to pts with other KRAS and BRAF mutations merit further biologic characterization with functional assays. Individualized therapeutic strategies must be conceptualized for mCRC pts with specific RAS/BRAF mutations, considering their widely disparate prognosis and putative downstream signaling mechanisms. Dynamic molecular simulation to understand conformational changes in proteins associated with specific mutations will be pivotal to optimizing precision therapeutic strategies.
The mutation of homologous recombination repair genetics is a potential biomarker for immunotherapy in microsatellite stable colon cancer.
Authors: Wu Xueying , Mao Beibei , Zhang Henghui
Published: May 2020

4076

Background: Patients with microsatellite instability-high (MSI-H) colonic adenocarcinoma (COAD) are always immunotherapy-sensitive for the use immune checkpoint inhibitors, however, the vast majority of COAD patients (85%) are microsatellite stable (MSS). Homologous recombination deficiency (HRD) is demonstrated to be a response predictor to immunotherapies in gynecologic cancers, while limited studies were reported in colon cancer. We focus herein on the mutational pattern of HRR related genes in a large Chinese COAD cohort and further analyze the relationship between HRR-gene mutations and clinical response to immunotherapy in MSS COAD. Methods: The genomic profiling of Genecast cohort which is consisted of 406 Chinese patients with COAD were analyzed in a panel of 543 cancer related genes via next generation sequencing (NGS). The correlation between HRR-gene mutations and tumor immunity or clinical outcome using two COAD genomics datasets (TCGA and MSK-COAD) by the bioinformatic approach. Results: In Genecast Cohort, seventy of 406 (17.2%) patients were identified genomic alterations in HRR-gene, the most frequently mutated genes were ATM (9%), BRCA2 (4%), ATR (3%), RAD50 (3%) and BRIP1 (3%). In MSK-COAD cohort (treated with immune checkpoint inhibitors), HRR-mut group (n = 34) had a significantly better OS than HRR-wt group (n = 50) (log-rank test, P = 0.0087). From the analysis of TCGA cohort, we found that mutations of HRR-gene could increase immune activity in MSS COAD, including increased cytotoxic cells infiltration ( P = 0.035), increased exhausted CD8 T cells infiltration ( P = 0.0098) and higher IFN-g score ( P = 0.03). In contrary, similar results were not found in MSI-H COAD (all P > 0.05). Conclusions: Mutations of HRR-gene could significantly increase immune activity in patients with MSS COAD, implying the feasibility of using HRR-mut as a response predictor of immunotherapy in MSS-COAD.
Short-term results of VOLTAGE-A: Nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable and microsatellite instability-high locally advanced rectal cancer.
Authors: Yuki Satoshi , Bando Hideaki , Tsukada Yuichiro , Inamori Koji , Komatsu Yoshito , Homma Shigenori , Uemura Mamoru , Kato Takeshi , Kotani Daisuke , Fukuoka Shota , Nakamura Naoki , Fukui Makoto , Wakabayashi Masashi , Kojima Motohiro , Togashi Yosuke , Sato Akihiro , Nishikawa Hiroyoshi , Ito Masaaki , Yoshino Takayuki
Published: May 2020

4100

Background: Chemoradiotherapy (CRT) followed by radical surgery (S) is standard therapy for patients (pts) with locally advanced rectal cancer (LARC). Sequential use of an anti-PD-1 antibody after radiation demonstrates synergistic effects in in vivo models, and an anti-PD-1 antibody is effective in pts with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). We studied nivolumab (nivo) and radical S following CRT (50.4 Gy with capecitabine 1,650 mg/m2) in T3–4 NanyM0 LARC. Methods: After the quality-assured CRT, 240 mg q2 weeks x 5 cycles of nivo and radical S were investigated. In cohort A-1, for pts with microsatellite stable (MSS) LARC, the primary endpoint was a centrally confirmed pathological complete response (pCR) rate using AJCC tumor regression grading. The estimated required sample size assuming null and alternative hypotheses pCR = 10% and 30% was 37 pts, with a 1-sided alpha of 5% and power of 90%. In Cohort A-2, 5 pts with MSI-H LARC were included in an exploratory manner. Results: From Jan/2017 to Oct/2019, a targeted number of pts was included and assessed. In cohort A-1, 30% (11/37; 90% CI 18-44%) of pCR (AJCC grade (gr) 0) rate and 38% (14/37) of major pathological response (MPR) (AJCC gr 0+1) rate were observed. Clinical CR was observed in one additional pt (3%) refusing S after nivo. In cohort A-2, 60% (3/5) of pCR rate and 60% (3/5) of MPR rate were observed. As of Jan/2020, only 2 pts (1 local and 1 metastatic) in cohort A-1 and none in cohort A-2 recurred. Immune-related severe adverse events were observed in 3 pts (gr 3 myasthenia, gr 3 interstitial nephritis, and gr 2 peripheral motor neuropathy); all fully recovered and received radical S. During the follow-up period, one additional pt with gr 2 colitis was observed. No treatment-related deaths were observed. Conclusions: Promising pCR rates of 30% and 60%, with mild toxicities, were shown in MSS and MSI-H LARC pts treated with nivo plus radical S after CRT, suggesting the candidate therapy for the future non-surgical approach. Clinical trial information: NCT02948348 .
ARISTOTLE: A phase III trial comparing concurrent capecitabine with capecitabine and irinotecan (Ir) chemoradiation as preoperative treatment for MRI-defined locally advanced rectal cancer (LARC).
Authors: Sebag-Montefiore David , Adams Richard , Gollins Simon , Samuel Leslie M. , Glynne-Jones Robert , Harte Robert , West Nicholas , Quirke Philip , Myint Arthur Sun , Bach Simon P , Parsons Philip , Falk Stephen , Dhadda Amandeep Singh , Misra Vivek , Brown Nick , Brown Gina , Harrison Mark , White Laura , Duggan Marian , Lopes Andre ,   ARISTOTLE Trial Management Group
Published: May 2020

4101

Background: Phase II studies reported high pathological complete response (pCR) rates and acceptable toxicity using irinotecan and fluoropyrimidine chemoradiation in LARC (ISRCTN:09351447). Methods: This phase III, multicentre, open-label trial funded by Cancer Research UK, randomly assigned (1:1) patients with MRI defined LARC threatening or involving resection margins without metastases, to pre-operative radiotherapy (RT) 45Gy/25 fractions combined with either capecitabine 900mg/m2(CRT) or 650 mg/m2 bd weekdays with Irinotecan iv once-weekly 60mg/m2 weeks 1-4 (IrCRT). The primary endpoint is disease-free survival (DFS). Secondary endpoints include treatment compliance, safety and pCR. Results: 75 UK sites randomised 564 eligible patients from Oct/11 to July/18; 284 to CRT and 280 to IrCRT. 370 (66%) male; median age 61 years (range:29-83). Staging in both arms was similar: mrT3 (432/564(77%), mrT4 (89/564(16%); mrCRM involved (275/564(49%); threatened ≤1mm (215/564(38%). Compared with CRT, IrCRT patients were less likely to receive 45Gy RT (207/276(75%) vs 251/283(89%), p < 0.001) or receive ≥90% capecitabine dose in 188/276(68%) vs 253/283(89.4%)p < 0.001). A total of 204/276(74%) received ≥90% irinotecan dose. The grade 3-4 gastrointestinal adverse event rate was 21%(58/276) with IrCRT and 12%(34/283) with CRT (p = 0.004). Patients receiving IrCRT had significantly more diarrhoea 38/276(13.8%) vs 10/283(3.5%)p < 0.001) and neutropenia 27/276(9.8%) vs 3/283 (1.1%) p < 0.001). Two CRT and three IrCRT patients experienced a treatment related death. 237/276(86%) IrCRT and 241/283(85%) CRT patients had surgery. The median time from end of RT to surgery(10.6 weeks), the surgical procedure APE 262/478(55%), AR 189/478(40%), Hartmann’s 10/478(2%); and the surgical complications(any event) 38%(181/478) were similar in both arms. The pCR rate is available in > 95% patients and is 20.2%(46/228) for IrCRTvs.17.4%(40/230) for CRT (p = 0.45), A > 84% CRM-ve resection rate is similar in both arms. Conclusions: For patients with MRI defined high risk LARC low rates of CRM involvement were observed in both arms reflecting high quality multidisciplinary care. The addition of irinotecan did not significantly improve the pCR rate, was associated with a decrease in the RT and capecitabine compliance and a higher rate of adverse events. Surgical procedure or complications were unaffected. Longer follow-up is required to assess DFS and translational data. Clinical trial information: 09351447 .
Perioperative ramucirumab in combination with FLOT versus FLOT alone for resectable esophagogastric adenocarcinoma (RAMSES/FLOT7): Results of the phase II-portion—A multicenter, randomized phase II/III trial of the German AIO and Italian GOIM.
Authors: Al-Batran Salah-Eddin , Hofheinz Ralf Dieter , Schmalenberg Harald , Strumberg Dirk , Goekkurt Eray , Angermeier Stefan , Zander Thomas , Potenberg Jochem , Kopp Hans Georg , Pink Daniel , Siegler Gabriele Margareta , Schenk Michael , De Vita Ferdinando , Maiello Evaristo , Gaiser Timo , Sookthai Disorn , Bankstahl Ulli Simone , Pauligk Claudia , Goetze Thorsten Oliver , Homann Nils
Published: May 2020

4501

Background: Periop. FLOT has become SOC for resectable, esophagogastric adenocarcinoma. However, patient’s outcome is still poor. This trial evaluates the addition of the VEGF-R2 inhibitor ramucirumab (RAM) to FLOT for resectable patients (pts). Methods: This is a prospective, international, randomized, investigator-initiated phase II/III trial. Pts with resectable, Her2-negative, adenocarcinoma of the stomach and GEJ (≥ cT2 or cN+) were enrolled. Pts were randomized to 4 pre-and post-operative cycles of FLOT (docetaxel 50 mg/m²; oxaliplatin 85 mg/m²; leucovorin 200 mg/m²; 5-FU 2600 mg/m², q2w) alone (Arm A) or the same regimen with RAM 8mg/kg q2w, followed by 16 cycles RAM (Arm B, FLOT-RAM). Important endpoints of phase II (exploratory) were major pathological (complete and nearly complete) response, centrally assessed acc. to Becker criteria, R0-resection rate, and safety. GEJ type I tumors and pts requiring trans-thoracic esophagectomy were excluded for safety reasons during the conduct of the study. Results: In total, 180 pts were randomized. Baseline characteristics were similar between arms (male, 73%; median age, 60y; cT3/T4, 83%; cN+, 78%; GEJ, 54%; signet-ring cells, 40%). However, the FLOT-RAM arm included more unfavorable pts with T4 (9% vs. 4%), Siewert type I tumors (18% vs. 13%), impaired ECOG PS of 1 (34% vs. 20%), and concomitant disease (87% vs. 79%). 91% of pts with FLOT and 92% with FLOT-RAM completed the 4 pre- cycles. R0-resection (in the full set) could be achieved in 83% of pts with FLOT and 97% of pts with FLOT-RAM (p = 0.0049). The rate of major path response was similar in both arms and was 30% for FLOT and 27% for FLOT-RAM. Surgical morbidity was observed in 37% of pts with FLOT and 44% of pts with FLOT-RAM. Mortality was 2.5% with FLOT and 5.9% with FLOT-RAM including GEJ type I tumors and dropped to 2.9% in both arms after excluding type I tumors per amendment. There was bit more G≥3 adverse events with FLOT-RAM (78% vs. 89%). Conclusions: In this phase II trial, the addition of ramucirumab to perioperative FLOT significantly improved R0-resection rates without an impact on path response, mainly because more patients could proceed to operation. The FLOT-RAM is safe, when type I tumors are excluded. Clinical trial information: NCT02661971 .
ESPAC-5F: Four-arm, prospective, multicenter, international randomized phase II trial of immediate surgery compared with neoadjuvant gemcitabine plus capecitabine (GEMCAP) or FOLFIRINOX or chemoradiotherapy (CRT) in patients with borderline resectable pancreatic cancer.
Authors: Ghaneh Paula , Palmer Daniel H. , Cicconi Silvia , Halloran Christopher , Psarelli Eftychia Eirini , Rawcliffe Charlotte Louise , Sripadam Rajaram , Mukherjee Somnath , Wadsley Jonathan , Al-Mukhtar Ahmed , Jiao Long R. , Wasan Harpreet Singh , Carter Ross , Graham Janet Shirley , Ammad Farooq , Evans Jonathan , Tjaden Christine , Hackert Thilo , Buchler Markus W. , Neoptolemos John P. ,   European Study Group for Pancreatic Cancer (ESPAC)
Published: May 2020

4505

Background: Patients with borderline resectable pancreatic cancer have poor survival and low resection rates. Neoadjuvant therapy may improve the outcome for these patients. The aim of this trial was to determine the feasibility and efficacy of a comparison of immediate surgery versus neoadjuvant GEMCAP or FOLFIRINOX or CRT. Methods: Eligible patients with NCCN defined borderline resectable (following central review of the baseline CT scan) and biopsy proven pancreatic cancer were randomised (stratified by centre) to receive immediate surgery, or neoadjuvant therapy of either 2 cycles of GEMCAP, or 4 cycles of FOLFIRINOX or 50.4Gy capecitabine-based CRT in 28 daily fractions over 5 ½ weeks. Patients were restaged at 4-6 weeks and underwent surgical exploration if still borderline resectable. Resected patients received adjuvant therapy. Follow up was 12 months. There was quality assurance of surgery and CRT. Primary endpoints were recruitment rate and resection rate (R1/R0). Secondary endpoints included overall survival and toxicity. A target of 90 patients was set to determine feasibility and resection rates. Rates will be presented as point estimates and survival compared across treatment arms using a log-rank test. Analyses will be on an ITT basis. Results: Between August 2014 and December 2018, 90 patients were randomised with 88 included in the full analysis set (32 immediate surgery, 20 GEMCAP, 20 FOLFIRINOX, 16 CRT). Median age was 63 years, 44% were men. WHO performance status was 0 and 1 in 45% and 55% respectively. Median CA19-9 was 603 kU/L at baseline. 44 (79%) patients completed neoadjuvant therapy. Recruitment rate was 21 patients per year. Resection rate was 62% for immediate surgery and 55% for neoadjuvant therapy (p=0.668). R0 resection rate on resected patients was 15% and 23% respectively (p=0.721). One year survival rate was 40% [95% CI, 26% – 62%] for immediate surgery and 77% [95%CI, 66% - 89%] for neoadjuvant therapy. Log-rank analysis showed an HR=0.27 [95% CI, 0.13 – 0.55]; χ2 (1) = 14.91, P<0.001. 9 out of the 51 neoadjuvant patients included in the safety set reported 12 serious adverse events of grade 3 or above. Conclusions: There was no difference in resection rate between arms, however neoadjuvant therapy had a significant survival benefit compared with immediate surgery. Clinical trial information: 89500674 .