bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction of olaparib sensitivity for variants of unknown significance in homologous repair genes.
Authors: Chevrier Sandy , Desmoulins Isabelle , Favier Laure , Ghiringhelli François , Bengrine Leila , Arnould Laurent , Boidot Romain
Published: May 2019

3108

Background: the recent use of PARP inhibitors in clinical practice gives very interesting outcome for ovary tumors with BRCA1 or BRCA2 mutation but also in other tumors with homologous repair deficiency. Nevertheless, no hotspot mutations are present, consequently, more than 85% of observed variants have unknown significance, blocking the use of PARP inhibitor. Methods: Exome analysis was performed on a cohort of 27 patients treated with olaparib. After bioinformatics analyses, variant interpretation was performed by interrogating different databases. For variants of unknown significance (VUS), PROVEAN software and allelic frequency normalized with tumor cellular content were used to classify VUS as potentially benign or potentially deleterious. Results: Among the 27 patients analyzed, 16 harbored already classified variants (3 benign and 13 pathogen variants) and 11 had VUS. The first Progression Free Survival (PFS) analysis showed that benign variants did not respond to olaparib with a median survival of 62 days, whereas pathogenic variants had a median of 109 days. Surprisingly, VUS had a median of 136 days, suggesting that some of them could be classified as potentially deleterious. On the subset of 11 patients with VUS, we applied PROVEAN prediction classifying 5 variants as benign and 6 variants as deleterious, with a median PFS of 54 days and 140 days ( p=0.3235), respectively. With the second prediction, based on variant allelic frequency, we obtained PFS of 73.5 months for benign variants and 210 days for deleterious ones ( p=0.29). By combining both predictions, we classified as benign, VUS predicted benign with both predictions, and as deleterious, VUS predicted as deleterious with at least one prediction. Consequently, we perfectly discriminated benign from deleterious variants with a median PFS of 36 days for predicted benign and 177 days for predicted deleterious ( p=0.0084). From all patients, PFS were significantly different ( p=0.0003) between benign (n=6, 56 days) and deleterious variants (n=21, 140 months). Conclusions: Our work tends to show that VUS of homologous repair genes could be predicted as benign or deleterious, and could increase the number of patients eligible for a treatment by PARP inhibitors. The number of patients needs to be increased in order to validate our prediction algorithm.
Long-term follow-up of pharmacokinetics (PK) and immunogenicity of the anti–PD-1 antibodies nivolumab (Nivo) and pembrolizumab (Pembro) in real-world practice.
Authors: Fukudo Masahide , Mishima Kazuto , Kimura Norihisa , Shinden Yuichiro , Sasaki Takaaki , Okumura Shunsuke , Ohsaki Yoshinobu , Uehara Jiro , Yamamoto Akemi , Tamaki Gaku , Kakizaki Hidehiro , Kishibe Kan , Takahara Miki , Hayashi Tatsuya , Harabuchi Yasuaki , Shonaka Tatsuya , Hasegawa Kimiharu , Ono Takashi , Tasaki Yoshikazu
Published: May 2019

3120

Background: The PD-1 blockers Nivo and Pembro are widely used to treat patients (pts) with various types of cancer, but their PK and immunogenicity have not been adequately characterized in clinical practice. Here we report the first long-term follow-up of PK and anti-drug antibodies (ADAs) of Nivo and Pembro, correlated with efficacy and safety. Methods: We included 147 pts receiving Nivo (n = 98) or Pembro (n = 49) between May 2016 and Jan 2019. Plasma samples were longitudinally collected before each infusion and after discontinuation for as long as samples were obtainable. Drug concentrations were measured by ELISA (LLOQ: 0.0125 µg/mL), and ADAs were evaluated by bridging ELISA. Results: Median (range) follow-up was 6.0 (0.1-38.7) mo, and 1718 samples were analyzed. ADAs were confirmed at baseline or at last sample for both Nivo (2 [2.2%] and 4 [4.5%] pts, respectively) and Pembro (2 [4.2%] and 3 [6.7%] pts). Of the 4 baseline ADA-positive pts, 3 experienced drug-induced fever after initial infusion. Pts developing ADAs at last sample had earlier progression than ADA-negative pts (median PFS: 46 vs. 119 days, log-rank P = 0.0827). Persistent drug exposure until ~1 y beyond discontinuation was observed for both drugs. In 1 Nivo-treated pt with delayed adrenal insufficiency 8.6 mo after discontinuation, Nivo was still detectable (0.2 µg/mL). In 71 and 41 efficacy-evaluable pts receiving Nivo and Pembro, respectively, mean trough levels in the early period (~cycle 6) were significantly higher in pts achieving response than in pts with progressive disease at first assessment (Nivo: 43.5 vs. 31.0 µg/mL, P = 0.0107; Pembro: 30.6 vs. 22.1 µg/mL, P = 0.0174). Conclusions: Our findings provide insight into the etiological mechanism of late-onset adverse events associated with PD-1 blockers. Moreover, ADA may potentially influence clinical outcomes, and it may be possible to optimize dose in certain pts with lower drug exposure for improved efficacy, warranting further investigation. Clinical trial information: UMIN000033036. [Table: see text]
A phase I study of a novel IAP inhibitor APG-1387 as a monotherapy or in combination with pembrolizumab in treatments of patients with advanced solid tumors.
Authors: Rasco Drew W. , Li Yufeng , Tang Yuefen , Men Lichuang , Wang Hengbang , Ji Jiao , Liang Zhiyan , Sun Joan , Amaya Alex , Huang Yingjie , Yang Dajun , Zhai Yifan
Published: May 2019

3125

Background: APG-1387 is a novel, bivalent small molecule IAP (inhibitor of apoptosis proteins) inhibitor. It has shown strong antitumor activities in multiple human xenograft cancer models. APG-1387 also acts as host immune modulator, supporting the notion that APG-1387 in combination with anti-PD1 antibody for cancer therapy. Methods: This study consists of two parts (NCT03386526). Part 1 is the dose escalation study of APG-1387 including a mPC (metastatic pancreatic cancer) cohort expansion. Part 2 is the dose escalation and cohort expansion study of APG-1387 in combination with pembrolizumab. APG-1387 is administrated IV for 30 minutes once weekly in a 21-day-cycle. Pembrolizumab is administrated at 200mg IV on day1 of a 21-day-cycle. The study objectives are to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy (assessed per RECIST v1.1 every 6 weeks). Results: Through Jan 4, 2019, total 23 patients had been treated in 4 cohorts of APG-1387 (20mg, 30mg, 45mg, 60mg). Two DLTs were observed at 60mg including lipase increase and Bell’s palsy, MTD was determined as 45mg. Nineteen of 23 patients experienced at least 1 TEAE. The most common TEAEs were nausea (21.7%), fatigue (17.4%), decreased appetite (13.0%), and abdominal pain (13.0%). Three grade 3 TEAEs including elevated bilirubin, lipase increase, and shortness of breath were documented at 45mg and 60mg. Three out of six mPC patients (one at 60mg, two at 45mg) achieved SD, one of them at 45mg has been treated > 5 cycles with confirmed SD (-18%). Two patients, who were treated with APG-1387 at 20mg in combination with pembrolizumab, had no DLT observed during the first cycle. Preliminary PK data of APG-1387 showed a dose proportionality in exposure (Cmax and AUC) over the dose range of 20-60 mg. Conclusions: APG-1387 was well tolerated and had manageable adverse events. The potential effects of APG-1387 alone or in combination with pembrolizumab deserve further exploration in patients with advanced solid tumors, especially in the mPC patients. Clinical trial information: NCT03386526.
A phase I study of a novel MDM2 antagonist APG-115 in patients with advanced solid tumors.
Authors: Rasco Drew W. , Lakhani Nehal J. , Li Yufeng , Men Lichuang , Wang Hengbang , Ji Jiao , Tang Yuefen , Liang Zhiyan , Amaya Alex , Estkowski Kathy , Sun Joan , Huang Yingjie , Yang Dajun , Zhai Yifan
Published: May 2019

3126

Background: APG-115 is a potent and orally active small-molecule MDM2 protein inhibitor. Binding to MDM2 protein, APG-115 restores p53 tumor suppressive function via induction of apoptosis in tumor cells retaining wild-type p53. In addition, enhanced antitumor activity was demonstrated in the syngeneic tumor models after APG-115 combined with PD-1 blockade. Methods: This Phase I study (APG-115-US-001) was designed to enroll the patients with advanced solid tumors in US (NCT02935907). Study objectives included to assess safety, dose limited toxicity (DLT), pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity (assessed every 8 weeks per RECIST v1.1). The patients received APG-115 orally every other day (QOD) at the designated dose (ranging from 10 to 300 mg) for first 21 days of a 28-day cycle, until disease progression. Results: Up until Jan 4 2019, total 28 patients were treated with APG-115 at various doses (one patient at 10mg, 20mg and 50mg, respectively; 14 patients at 100mg, 6 patients at 200mg, and 5 patients at 300mg). The median number of prior systemic anticancer therapies was 4 (range 0-15). The DLTs were observed during cycle 1, including one grade 2 thrombocytopenia at 200mg, one grade 3 thrombocytopenia at 300mg, and one grade 3 fatigue at 100mg and 300mg respectively. The most common AEs (reported in ≥10% of pts) included: fatigue, nausea, vomiting, diarrhea, decreased appetite, dehydration, neutrophil count decreased, white blood cell count decreased, pain in extremity, thrombocytopenia. The most common Grade 3 or 4 treatment related AEs were fatigue (10.7%), and thrombocytopenia (10.7%). Six patients had stable disease (SD) after two cycle treatments, two of them are continuing in this study. PK analyses indicated that exposure (Cmax and AUC) generally increases with the increase of dose level from 20 mg to 300 mg. Conclusions: APG-115 was well tolerated and had manageable adverse events. The MTD/RP2D of APG-115 monotherapy with oral administration, QOD for 21 days of a 28-day cycle for treatment of patients with advanced solid tumors was determined as 100 mg. Further evaluation of APG-115 in combination with pembrolizumab in patients with advanced solid tumors is ongoing. Clinical trial information: NCT02935907.
Molecular differences between lymph nodes (LNs) and distant metastases (mets) in colorectal cancer (CRC).
Authors: Puccini Alberto , Xiu Joanne , Goldberg Richard M. , Grothey Axel , Shields Anthony Frank , Salem Mohamed E. , Seeber Andreas , Battaglin Francesca , Berger Martin D. , El-Deiry Wafik S. , Tokunaga Ryuma , Naseem Madiha , Zhang Wu , Arora Sukeshi Patel , Khushman Moh'd M. , Hall Michael J. , Philip Philip Agop , Marshall John , Korn Wolfgang Michael , Lenz Heinz-Josef
Published: May 2019

3130

Background: LNs mets are thought to occur before distant mets. However, lymphatic and distant mets arise from independent subclones of the primary tumor, suggesting that LNs are not essential intermediaries for distant mets. We aimed to comprehensively characterize the molecular profile of LN mets and to explore the differences between LN vs distant mets and primary tumors. Methods: Tumor samples from primary CRCs, LNs, and distant mets were analyzed using NGS (MiSeq on 47 genes, NextSeq on 592 genes), immunohistochemistry. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. Results: In total, 11871 tumors samples were examined, comprising primaries (N = 5862), distant (N = 5605) and LNs mets (N = 404). The most frequently mutated genes in LNs were TP53 (72%), APC (61%), KRAS (39%), ARID1A (20%), and PIK3CA (12%). LNs showed a higher mean TMB (13 mut/MB) vs distant mets (9, P < .0001). TMB-high (17mut/MB) was more frequent in primaries and LNs vs distant mets (9.5% and 8.8% vs 4.2%, P < .001 and P = .001, respectively), as well as MSI-H (8.8% and 6.9% vs 3.7%, P < .001 and P = .017, respectively). TMB-high is significantly higher in LNs vs distant mets and primaries (P < .0001), independent of MSI-H status. Analyzing distant mets by location, LNs showed higher TMB compared to lung, liver and peritoneum mets (P < .0001). Overall, LNs showed significantly different rates of mutations in APC, KRAS, PI3KCA, KDM6A, and BRIP1 (P < .01 for all comparisons) vs primaries; while presenting a distinct molecular profile compared to distant mets ( TP53 72 vs 67%; KRAS 39 vs 50%; RNF43 7 vs 4%; ATM 5 vs 3%; KDM6A 4 vs 1%; BRCA2 4 vs 2%; MSH6 3 vs 2%; PTCH1 4 vs 1%; BRCA1 2 vs 1%; GNAS 2 vs 5%; P < .05 for all comparisons). Our cohort of 30 paired samples confirmed the molecular heterogeneity between primaries, LNs, and distant mets. Conclusions: This is the largest study to investigate the molecular differences between LNs mets, distant mets and primary tumors in CRC patients. Our data support the hypothesis that lymphatic and distants mets harbor different mutation profiles which suggests that they may arise from distinct subclones.
HER family protein expression and activation predicts response to combination T-DM1/pertuzumab in HER2+ patients in the I-SPY 2 TRIAL.
Authors: Wulfkuhle Julia Dianne , Wolf Denise M. , Yau Christina , Gallagher Rosa Isela , Brown Swigart Lamorna , Hirst Gillian L. , Yee Douglas , Pohlmann Paula Raffin , Elias Anthony D. , Moulder Stacy L. , Tripathy Debu , DeMichele Angela , Esserman Laura , Berry Donald A. , van 't Veer Laura , Petricoin Emanuel ,   I-SPY 2 Investigators
Published: May 2019

3133

Background: T-DM1 (T), a conjugate of the anti-HER2 therapeutic antibody trastuzumab and the microtubule assembly inhibitor emtansine, was administered in combination with pertuzumab (P), an anti-HER2 therapeutic antibody, to HER2+ breast cancer patients in the I-SPY 2 TRIAL, and graduated in all HER2+ subtypes. Pre-specified biomarker analysis was performed to identify candidate biomarkers associated with pCR within the HER family and cell proliferation pathways in patients treated with T+P. We hypothesized that quantitative measurement and activation of HER2 and activation of its major dimerization partner, EGFR would predict response to T+P. Methods: In the T+P treatment arm, 49 had RPPA and pCR data. 40 RPPA endpoints including 14 total/phospho-proteins in the HER family were assessed for association with pCR using logistic regression (likelihood ratio test; p < 0.05). Analysis was also performed adjusting for HR status and within HR subsets. Markers were analyzed individually; multiple comparison correction (Benjamini-Hochberg) was applied to all p-values. Our statistics are descriptive and do not adjust for multiplicities of other biomarkers outside this study. Results: Of the endpoints tested, only quantitative total HER2 expression, phospho-HER2 (Y1248 and Y877), phospho-EGFR (Y1173 and Y1068), and phospho-SHC Y317 had a positive association with response in the population as a whole, and in a model adjusting for HR status (BH p < 0.05). In HR subset analysis, these 5 analytes had uncorrected p < 0.05 regardless of HR subtype but only survived p-value correction in HR+ tumors. Conclusions: Quantitative measurement of HER2 protein positively associates with response to T+P in patients already identified as HER2+ by central IHC and FISH testing. Activation of HER2 and its dimerization partner, EGFR, also associate with response to T+P in HR+ patients. While our results need to be validated in larger prospective trials, they indicate that new approaches to measure more quantitatively the amount and activation state of HER2 and activated EGFR may more effectively identify patients that respond to HER2 targeted therapies than HER2 IHC and FISH alone.
A prognostic 10-miRNA risk score (10-miRNA RS) in predicting neoadjuvant chemotherapy sensitivity of luminal breast cancer.
Authors: Gong Chang , Tan Luyuan , You Na , Chen Kai , Tan Weige , Tian Zhenluan , Zhong Wenjing , Lin Wanyi , Yu Zhigang , Li Zhihua , Zheng Wenbo , Liu Qiang , Song Erwei
Published: May 2019

3139

Background: The 10-miRNA risk score is a prognostic 10-gene expression signature specifically developed in luminal breast cancer associated with relapse-free survival. Since high-risk patients identified by10-miRNA RS had worse prognosis but better outcome with chemotherapy than low-risk patients (Gong C et al, EBioMedicine. 2016), this model may facilitate personalized therapy-decision making for luminal breast cancer patients. Therefore, we seek to validate whether high-risk group are more sensitive to chemotherapy than low-risk group by assessing the predictive value of 10-miRNA RS for pathological complete response (pCR) in patients receiving neoadjuvant chemotherapy (NAC). Methods: The 10-miRNA gene expression and clinicopathological data were prospectively gathered from 251 pretreated biopsy-diagnosed luminal breast cancer patients from 4 breast cancer centers. Formalin-fixed paraffin-embedded tissues from basal line biopsy were used for the detection of 10-miRNA expression to calculate the RS. The correlation between pCR and the 10-miRNA RS classification were identified. Results: In this prospective, multicenter study, the overall pCR rate was 13.6% (34/251). The 10-miRNA RS of the pCR group was significantly higher than the non-pCR group ( P = 0.015). Fifty-one percent of patients were classified as low-risk according to the 10-miRNA RS classification and 49% as high-risk with a RS cut-off point of 2.144. The 10-miRNA RS classification was associated with a pCR rate of 9.4% in the low-risk group and 17.8% in the high-risk group ( P = 0.041). The correlation between the pCR and the 10-miRNA RS classification was significant in subgroup analysis stratified by molecular subtypes (8% vs. 13.2% in luminal B1; 14.7% vs. 30.1% in luminal B2; no pCR was observed in all 13 luminal A subtype). In multivariate analysis, the 10-miRNA RS remained significantly associated with pCR and independent from subtype, ki67 and other clinicopathological characteristics. Conclusions: 10-miRNA RS clearly defined that high-risk patients are more sensitive to chemotherapy which leads to a higher pCR rate in NAC patients. Thus, 10-miRNA RS is not only a prognostic factor but an effective method in determining whether a patient would undergo surgery or receive NAC prior to surgery. Clinical trial information: ChiCTR-DDD-17013651.
Vascular endothelial growth factor A (VEGF-A) amplification and long-term response to ramucirumab (ram) in metastatic gastric cancer (mGC): The VERA study.
Authors: Raimondi Alessandra , Gasparini Patrizia , Lonardi Sara , Corallo Salvatore , Fornaro Lorenzo , Laterza Maria Maddalena , Di Salvatore Mariantonietta , Giommoni Elisa , Lotesoriere Claudio , Murgioni Sabina , Saggio Serena , Martinetti Antonia , Niger Monica , Antista Maria , Pupa Serenella , De Braud Filippo G. , Di Bartolomeo Maria , Sozzi Gabriella , Morano Federica , Pietrantonio Filippo
Published: May 2019

3143

Background: The anti-VEGFR-2 monoclonal antibody ram, alone or with paclitaxel, is a cornerstone of second-line treatment of mGC. Even if about half patients do not benefit from ram, no predictive biomarkers have been identified so far. In TCGA, VEGF-A amplification was found in 7% of cases, almost exclusively in chromosomal instability subtype. We hypothesize that VEGF-A amplification in tumor cells could lead to autocrine/paracrine stimulation of tumor growth beside angiogenesis, potentially identifying a patients’ subgroup with exceptional responses to ram. Methods: VERA was a multicentric, prospective study based on a translational hypothesis. mGC patients were included according to the following criteria: 1) complete (CR) or partial response (PR) to single-agent ram; 2) >6 months PFS to single-agent ram; 3) >10 months PFS to paclitaxel+ram. According to a Fleming single-stage design, hypothesizing a prevalence of VEGF-A amplification of 1% and 15% among all-comers and exceptional responders, 20 exceptional responders were required to reject the null hypothesis of low prevalence of VEGF-A amplification, with alpha- and beta- errors of 0.05 and 0.10, respectively. VEGF-A amplification (defined as >10% tumor cells with ≥10 VEGF-A copies, variably sized signal clusters or a ratio of VEGF-A gene to centromere of ≥2) was centrally assessed through fluorescent in situ hybridization on pre-treatment FFPE tumor tissue. Results: At 7 Italian Centers, we included 20 patients satisfying the 1st (n=1), 2nd (n=2), or 3rd (n=17) criterion. Clinical-pathological features were: M/F, 11/9; median age 63 years; gastric/GEJ, 17/3; intestinal/diffuse, 14/6, HER2+/HER2-, 4/16. Median PFS and overall survival to ram-based treatment were 15.6 and 25.7 months, with best response: CR/PR/SD, 0/10/10. VERA met its primary endpoint, revealing 3/20 (15%) tumors with VEGF-A amplification (1 case presenting big clusters, 1 small clusters and 1 with >10% tumor cells with ≥10 VEGF-A copies). Conclusions: Validation analyses of first- and second-line randomized trials could confirm VEGF-A amplification as a biomarker of long-term response to ram-based treatment in mGC patients, advancing treatment personalization.
Prospective pooled analysis of four randomized trials investigating duration of adjuvant (adj) oxaliplatin-based therapy (3 vs 6 months {m}) for patients (pts) with high-risk stage II colorectal cancer (CC).
Authors: Iveson Timothy , Sobrero Alberto F. , Yoshino Takayuki , Sougklakos Ioannis , Ou Fang-Shu , Meyers Jeffery P. , Shi Qian , Saunders Mark P. , Labianca Roberto , Yamanaka Takeharu , Boukovinas Ioannis , Hollander Niels Henrik , Torri Valter , Yamazaki Kentaro , Georgoulias Vassilis , Lonardi Sara , Harkin Andrea , Rosati Gerardo , Paul James ,   on behalf of the IDEA Collaboration
Published: May 2019

3501

Background: 6m of oxaliplatin-based treatment is an option as adj chemotherapy for patients with high risk stage II CC (T4, inadequate nodal harvest, poorly differentiated, obstruction, perforation or vascular/perineural invasion). The IDEA collaboration showed shorter treatment duration to be appropriate for most pts with stage III colon cancer. The results of the 4 IDEA studies with stage II pts are presented here. Methods: A prospective, pre-planned pooled analysis of high-risk stage II patients from 4 concurrently conducted randomized phase III trials (SCOT, TOSCA, ACHIEVE-2, HORG) was performed to evaluate non-inferiority (NI) of 3m compared with 6m (ref) of adj FOLFOX/CAPOX (regimen preselected, not randomized). The primary endpoint was disease-free survival (DFS), NI was to be declared if the 2-sided 80% confidence interval (CI) for DFS hazard ratio (HR 3m v 6m) estimated by a stratified Cox model was below 1.2. 542 DFS events were required to provide 80% power to declare NI. NI was also examined within regimen, T4 (Yes v No) and inadequate nodal harvest (Yes v No) as pre-planned subgroups. Results: The primary analysis included 3273 randomised pts of which 1254 had FOLFOX and 2019 had CAPOX. There were 552 events and the median follow-up was 60.2 m. There was significantly less grade 3-5 toxicity with 3m treatment (p < .0001). The 5-year DFS rate was 80.7% and 84.0% for 3m and 6m treatment with an estimated DFS HR of 1.18 (80% CI:1.05-1.31, p for NI = 0.404). For CAPOX the estimated HR was 1.02 (80% CI: 0.88-1.17, p for NI = 0.087) and for FOLFOX the estimated HR was 1.42 (80% CI: 1.19-1.70, p for NI = 0.894). The test for interaction between duration and regimen was not statistically significant (p = .174 adjusted for multiple testing) but was stronger than that for the other subgroups examined. Conclusions: In the overall population non-inferiority for 3m adj treatment in pts with high-risk stage II CC was not shown. As with the stage III population the choice of adj regimen appears important (although this did not reach statistical significance) with a small difference in DFS between 3 and 6 m treatment if CAPOX is used. Clinical trial information: ISRCTN59757862.
Re-evaluating disease-free survival (DFS) as an endpoint versus overall survival (OS) in adjuvant colon cancer (CC) trials with chemotherapy +/- biologics: An updated surrogacy analysis based on 18,886 patients (pts) from the Accent database.
Authors: Shi Qian , De Gramont Aimery , Dixon Jesse G. , Yin Jun , Van Cutsem Eric , Taieb Julien , Alberts Steven R , Wolmark Norman , Schmoll Hans-Joachim hans-joachim , Saltz Leonard B. , Goldberg Richard M. , Kerr Rachel , Lonardi Sara , Yoshino Takayuki , Yothers Greg , Grothey Axel , Andre Thierry , Salem Mohamed E. ,   Adjuvant Colon Cancer ENd PoinTs (ACCENT) Group
Published: May 2019

3502

Background: DFS with 3 years median follow-up (3yDFS) was validated as a surrogate for OS with 5 years median follow-up (5yOS) in adjuvant chemotherapy CC trials prior. Recent data showed improved survival after recurrence and OS, over time, in pts who received adjuvant FOLFOX. Hence, re-evaluation of the association between DFS and OS, as well as the optimal follow-up of OS to aid its utility in future adjuvant trials is needed. Methods: Individual patient data from 8 randomized adjuvant studies conducted from 1998-2009 were included; 3 trials tested anti-VEGF or anti-EGFR agents. Trial-level surrogacy examining the correlation of treatment effect estimates (i.e. hazard ratios) of 3yDFS and 5y to 8yOS was evaluated using both linear regression (R2WLS) and Copula bivariate (R2Copula) models. For the R2, a value closer to 1 indicates a stronger correlation. Prespecified criteria for surrogacy required either R2WLS or R2Copula ≥ 0.80 and neither < 0.7, with lower-bound 95% Confidence Interval (CI) > 0.60. The rank correlation coefficient (ρ) quantified the individual-level surrogacy. Results: Total of 18,886 pts were analyzed, with median age 60, 54% male, 83% stage III, 59% > 12 nodes examined. Median follow-up for survival ranged from 5 to 10 years across trials. Trial level correlation between 3yDFS and OS remained strong (R2WLS ≥0.74; R2Copula ≥ 0.89) and increased as the median follow-up of OS extended longer (see table). Analyses limited to stage III pts and/or trials tested biologics showed consistent results. Conclusions: 3yDFS remains a validated surrogate endpoint for 5yOS in adjuvant trials in CC pts per prespecified criteria. The correlation was strengthened with more than 6 years of follow-up for OS. [Table: see text]
FOxTROT: an international randomised controlled trial in 1052 patients (pts) evaluating neoadjuvant chemotherapy (NAC) for colon cancer.
Authors: Seymour Matthew T. , Morton Dion ,   on behalf of the International FOxTROT Trial Investigators
Published: May 2019

3504

Background: NAC is well established in many solid tumours but has not undergone large-scale evaluation in colon cancer. Methods: Pts had operable, non-obstructed colon cancer; CT-predicted stage T3-4, N0-2, M0, and were fit for FOLFOX and surgery. They were randomised 2:1 to the novel sequence (6 wk FOLFOX NAC, then surgery, then 18 wk FOLFOX) or control (surgery then 24 wk FOLFOX). RAS-wt pts allocated to the novel arm could optionally be sub-randomized 1:1 to ± panitumumab (pan) during the NAC phase. Two "dealer’s choices" allowed total chemo duration 12 wk instead of 24 (in older/low-risk pts) and OxCap in place of FOLFOX (except in pts randomized ± pan). Primary endpoint is freedom from recurrent or persistent disease after 2 yrs, by ITT. Secondary endpoints include safety, histological stage, completeness of resection, OS. Results: 1052 pts were randomised, Jun 2008-Dec 2016, at 85 centres in UK, Denmark and Sweden. Conclusions: NAC was well tolerated and safe, with no increase in perioperative morbidity and a trend toward fewer serious postoperative complications. Evidence of histological regression was seen in 59% pts after NAC, including some pCRs. This resulted in marked histological downstaging and a halving of the rate of incomplete resections. We observed an improvement in 2-yr failure rate (HR=0.77), but this fell short of statistical significance (p=0.11). NAC for colon cancer improves surgical outcomes and can now be considered as a treatment option; longer follow-up and further trials are required to confirm the long-term benefits, refine its use and optimise case selection. Clinical trial information: 87163246. [Table: see text]
NRG-GI002: A phase II clinical trial platform using total neoadjuvant therapy (TNT) in locally advanced rectal cancer (LARC)—First experimental arm (EA) initial results.
Authors: George Thomas J. , Yothers Greg , Hong Theodore S. , Russell Marcia McGory , You Y. Nancy , Parker William , Jacobs Samuel A. , Lucas Peter C. , Gollub Marc Jeffrey , Hall William Adrian , Kachnic Lisa A. , Vijayvergia Namrata , Wolmark Norman
Published: May 2019

3505

Background: This NCTN multi-arm randomized phase II modular clinical trial platform utilizes TNT with parallel EAs in LARC. EAs are not intended for direct comparison, but rather to test a variety of hypotheses in a consistent high-risk pt population with correlative biomarkers. Primary endpoint (EP) and available secondary EPs from the first EA using veliparib (a PARPi) are reported. NCT02921256. Methods: Stage II/III pts with LARC (with any ONE of the following: distal location [cT3-4 ≤5cm from anal verge, any N]; bulky [any cT4 or tumor within 3mm of mesorectal fascia]; high risk for metastatic disease [cN2]; or not a sphincter-sparing surgery [SSS] candidate) were randomized to neoadjuvant FOLFOX (x 4mo) → chemoRT (cape with 50.4Gy +/- veliparib 400mg PO BID) → surgery 8-12 wks later. Primary EP: 4 point reduction in Neoadjuvant Rectal Cancer (NAR) score with a one-sided α = 0.10 and 80% power. NAR compared by linear model controlling for stratification and possibly other factors. Secondary EPs: OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, and SSS. Binary EPs compared by Fisher’s exact test. Reported p-values are two-sided. Results: From 10/2016 - 2/2018, 178 pts were randomized (88 control, 90 veliparib). Baseline characteristics were balanced except for candidate for SSS at entry (39% control, 61% veliparib). 140 pts were evaluable for NAR (72 control, 68 veliparib). Mean NAR was 12.6 control (95% CI: 9.8–15.3) vs 13.7 for veliparib (CI: 10.2–17.2). Controlling for stratification (p = 0.69) or stratification and candidate for SSS (p = 0.78), NAR difference was not significant. pCR = 21.6% vs 33.8% (p = 0.14); cCR = 28.2% vs 33.3% (p = 0.60); and SSS = 52.5% vs 59.3% (p = 0.43). Most common grade 3/4 AEs were diarrhea and cytopenias. The EA had two deaths (cardiac arrest [FOLFOX]; enterocolitis [chemoRT]). Conclusions: Veliparib added to chemoRT as part of TNT was safe and without unexpected short-term toxicities but failed to improve the NAR score. Support: U10CA180868, -180822; UG1-189867; U24-196067; AbbVie. Clinical trial information: NCT02921256.
Final results and OS of the randomized phase II VOLFI trial (AIO- KRK0109): mFOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild- type metastatic colorectal cancer (mCRC).
Authors: Geissler Michael , Riera-Knorrenschild Jorge , Martens Uwe Marc , Held Swantje , Greeve Jobst , Florschütz Axel , Ettrich Thomas Jens , Kanzler Stephan , Tannapfel Andrea , Heinemann Volker , Reinacher-Schick Anke C. , Seufferlein Thomas , Wessendorf Swen , Modest Dominik Paul
Published: May 2019

3511

Background: This trial evaluated activity and safety of mFOLFOXIRI + panitumumab vs FOLFOXIRI in ECOG 0-1, primarily non-resectable mCRC patients. The final primary endpoint was presented at ASCO and ESMO 2018. Now we report for the first time the final results regarding OS and PFS. Methods: Prospective 2:1 randomized, controlled, open label multi-center, phase II trial comparing mFOLFOXIRI (Ox 85 mg/m2, Iri 150 mg/m2, 5-FU 3000mg/m2 cont. 48h, LV 200 mg/m2) + Panitumumab 6 mg/KG (arm A) with FOLFOXIRI (Ox 85 mg/m2, Iri 165 mg/m2, 5-FU 3200mg/m2 cont. 48h, LV 200 mg/m2; arm B), both arms q2w. Prospective strata were cohort 1: irresectable mCRC (n=65), and cohort 2: chance of secondary resection of metastatic lesions (n=31). Primary endpoint was ORR, secondary endpoints were secondary resection rate (cohort 2), DCR, PFS, OS, toxicity, quality of life (QLQ-C30). Financially supported by an unrestricted grant from Amgen. Results: A total of 96 patients were randomized (63 arm A, 33 arm B). ORR was 87.3% in arm A and 60.6% in arm B (p=0.0041, OR 4.47; 95%-CI 1.614-12.376). Secondary resections of metastases in the ITT population were observed in 33·3% (arm A Pmab) versus 12·1% (arm B) (OR=3.63; 95%-CI 1.13–11.67, p=0·029) and in cohort 2 in 75% (arm A Pmab) versus 36.4% (arm B) (OR=5.25; 95%-CI 1.07–25.8, p=0.05), respectively. Median PFS was similar in the study arms (9.7 mo in both arms, HR 1.071; 95%-CI 0.689-1.665, p=0.76). OS in the ITT population showed a strong trend in favour of the Pmab-containing arm A with a median OS of 35.7 mo compared to 29.8 mo in arm B (HR: 0·67; 95%-CI 0.41-1.11, P=0·12). mOS of cohort 2 was 52.0 mo in arm A versus 41.7 mo in arm B (HR 0.413; 95%-CI 0.15-1.12, p=0.07). Further results regarding to sidedness and BRAF mutational status will be presented. Conclusions: The addition of Pmab to a mFOLFOXIRI regimen in patients with RASwildtype metastatic colorectal cancer significantly improved objective response rate and the rate of secondary resection of metastases. Although PFS was comparable, there was a strong trend towards improved OS in the Pmab arm. Future studies are warranted to confirm this trend towards improved overall survival with this regimen. Clinical trial information: NCT01328171.
Relative contribution of clinical and molecular features to outcome within low and high risk T and N groups in stage III colon cancer (CC).
Authors: Sinicrope Frank A. , Huebner Lucas J. , Laurent-Puig Pierre , Smyrk Thomas C. , Tabernero Josep , Mini Enrico , Goldberg Richard M. , Folprecht Gunnar , Zaanan Aziz , Le Malicot Karine , Shi Qian , Alberts Steven R , Taieb Julien
Published: May 2019

3520

Background: Duration of adjuvant FOLFOX or CAPOX for stage III CC is being guided by pt stratification into low (T1-3N1) and high (T4 or N2) risk groups based on the IDEA study. We determined the relative contributions of clinical and molecular features for prediction of time-to-recurrence (TTR) and survival after recurrence (SAR) within each risk group. Methods: Stage III CC (N=5,430) from 2 trials of adjuvant FOLFOX ± cetuximab with similar outcome by study arm [NCCTG N0147 (Alliance), PETACC-8] were used. Tumors were analyzed for mismatch repair (dMMR vs pMMR), mutations in KRAS (exon 2) and BRAFV600E. Median pt follow-up was 83.4 months. Relative contributions to predicting outcome were assessed using χ2 (Harrell’s rms) based on multivariable (MV) Cox models. Results: N (50.8%) and T (31.8%) stage were the top two contributors to prediction of TTR which supports risk grouping. High risk (n=2566) vs low risk (n=2774) pts had poorer TTR (HR 2.7, 95% CI, 2.4-3.0) and SAR [HR 1.6 (1.4-1.9)], both p<.0001. TTR: KRAS contributed the most to predicting TTR among high (58.6%) and low (51.1%) risk pts (Table). Contribution of MMR (16%) to predicting TTR was limited to low risk pts. Contribution of BRAFV600E to TTR was nearly 3-fold increased in high vs low risk pts. SAR: BRAFV600E contributed the most to predicting SAR, especially in high vs low risk pts (2-fold increase). Tumor sidedness and performance status (PS) were key contributors to SAR, but not TTR. MV associations: TTR: low risk, KRAS [HR 1.7 (1.4-2.3], MMR [HR 0.55 (.35-.87), gender (M/F) [HR 1.3 (1.0-1.5)], all p<.04]; high risk: BRAF [HR 1.3 (1.1-1.7)], sidedness (R vs L) [HR 1.14 (1.0-1.3)], KRAS [HR 1.4 (1.2-1.6)], all p<.04]. SAR: BRAF, sidedness, PS (all p<.05). Conclusions: KRAS mutation was the strongest predictor of shorter TTR in both risk groups whereas BRAFV600E was the primary driver of SAR, especially in high risk pts. Support: U10CA180821, U10CA180882, U24CA196171; BMS, Pfizer, Sanofi. NCT00079274.[Table: see text]
Nivolumab (NIVO) + low-dose ipilimumab (IPI) as first-line (1L) therapy in microsatellite instability-high/DNA mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Clinical update.
Authors: Lenz Heinz-Josef , Lonardi Sara , Zagonel Vittorina , Van Cutsem Eric , Limon M. Luisa , Wong Ka Yeung Mark , Hendlisz Alain , Aglietta Massimo , Garcia-Alfonso Pilar , Neyns Bart , Cardin Dana Backlund , Spallanzani Andrea , Dragovich Tomislav , Shah Usman , Atasoy Ajlan , Ledeine Jean-Marie , Overman Michael J.
Published: May 2019

3521

Background: In the phase 2 CheckMate 142 trial, NIVO + low-dose IPI provided robust and durable clinical benefit and was well tolerated as 1L therapy for MSI-H/dMMR mCRC (Lenz et al. Ann Oncol 2018;29:LBA18). Longer follow-up data will be presented. Methods: Patients with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received NIVO 3 mg/kg every 2 weeks + low-dose IPI 1 mg/kg every 6 weeks until disease progression or discontinuation. The primary endpoint was investigator-assessed objective response rate (ORR). Results: For all 45 patients (median follow-up was 13.8 months), ORR was 60% (95% CI 44.3–74.3). Responses were consistent with the overall population across subgroups including age, Eastern Cooperative Oncology Group (ECOG) performance status, prior adjuvant/neoadjuvant therapy, and mutation status (Table). Seven patients (16%) had grade 3–4 treatment-related adverse events (TRAEs); 3 (7%) had any grade TRAEs leading to discontinuation. Updated response, survival, and safety data after a longer follow-up (median 19.9 months) will be presented. Conclusions: NIVO + low-dose IPI demonstrated robust and durable clinical benefit and was well tolerated. Evaluated subgroups had responses consistent with the overall population. NIVO + low-dose IPI may represent a new 1L treatment option for patients with MSI-H/dMMR mCRC. Clinical trial information: NCT02060188. [Table: see text]
Apatinib monotherapy for chemotherapy-refractory metastatic colorectal cancer: A multicenter, single-arm, prospective study.
Authors: Wang Fen , Wang Shubin , Yuan Xia , Jia Jun , Bi Xiaoxia , Zhou Zeqiang , Zhou Qiming , Luo Changguo , Deng Minghui , Yi Liangjie , Li Yong , Li Xia , Lu Jianxin , Su Wenzhi , Chen Hanbin , Zhu Yu
Published: May 2019

3527

Background: Apatinib is an oral highly-selective tyrosine kinase inhibitor (TKI) that blocks vascular endothelial growth factor receptor 2 (VEGFR-2). This exploratory study evaluated the efficacy and safety of apatinib monotherapy in patients with chemotherapy-refractory metastatic colorectal cancer. Methods: In this multicenter, single-arm, prospective study, 48 patients with metastatic colorectal cancer who had failed at least two lines standard chemotherapies including fluorouracil, oxaliplatin and irinotecan were recruited from 14 centers in Guangdong, China. Apatinib at a 500mg dose was administered daily continuously. Each cycle was 4 weeks (28 days). The primary endpoint was progression free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), disease control rate (DCR), quality of life (QoL) and toxicity. Results: A total of 48 patients was enrolled in the study from September 3, 2015 to June9, 2017. Four patients achieved a partial response, and 22 achieved stable disease, representing a response rate of 8.3% and a disease control rate of 60.4%. Median follow-up time was 10.3 months. Median progression-free survival (PFS) and overall survival (OS) of evaluable patients (n=41) were 4.7 months (95% confidence interval [CI] 3.7-5.9) and 9.7 months (95% CI 5.9-13.6). The most common grade 3 or 4 adverse events (AE) were hypertension (12.5%), hand-foot syndrome (10.4%), thrombocytopenia (10.4%), proteinuria (8.3%) and mucositis oral (6.3%). Conclusions: Apatinib monotherapy shows promising efficacy and manageable toxicities in patients with chemotherapy-refractory metastatic colorectal cancer. Further phase 3 trial is warranted. Clinical trial information: ChiCTR1900020503.
Impact of age on safety and efficacy of first-line FOLFOXIRI/bevacizumab in mCRC: A pooled analysis of TRIBE and TRIBE2 studies.
Authors: Marmorino Federica , Rossini Daniele , Aprile Giuseppe , Casagrande Mariaelena , Lonardi Sara , Murgioni Sabina , Dell'Aquila Emanuela , Tomasello Gianluca , Antoniotti Carlotta , Borelli Beatrice , Zucchelli Gemma , Urbano Federica , Ronzoni Monica , Zaniboni Alberto , Manglaviti Sara , Buonadonna Angela , Ritorto Giuliana , Allegrini Giacomo , Falcone Alfredo , Cremolini Chiara
Published: May 2019

3536

Background: FOLFOXIRI/bevacizumab is a valuable upfront option in mCRC based on results of phase III TRIBE and TRIBE2 studies: 1187 pts aged 18–70 years with ECOG performance status (PS) ≤ 2 or between 71–75 years with an ECOG PS of 0 were randomized to receive first-line FOLFOXIRI/bevacizumab or a doublet (FOLFIRI in TRIBE and mFOLFOX6 in TRIBE2)/bevacizumab. Here, we aimed at assessing the effect of the intensification of the upfront chemotherapy (triplet versus doublet) in terms of safety and efficacy in pts aged < 70 versus 70-75. Methods: Subgroup analyses for ORR, PFS, G3/4 overall adverse events (AEs), chemo-related and bevacizumab-related AEs were performed according to baseline age. Results: 182 (15%) out of 1187 pts were 70-75 years old (97 in the FOLFOXIRI/bevacizumab and 85 in the doublets/bevacizumab arms). The benefit provided by the intensification of the upfront chemotherapy was independent of the age subgroup in terms of both ORR (p for interaction = 0.684) and PFS (p for interaction = 0.634). The risk of overall and chemo-related G3/4 AEs was increased with the triplet independently of age (p for interaction = 0.736 and 0.790), while no difference in bevacizumab-related AEs was observed in both subgroups (p for interaction = 0.566). In the overall population, as compared to younger pts, those aged 70-75 were more susceptible to overall G3/4 AEs (70% vs 57%, p = 0.001). In the FOLFOXIRI/bevacizumab arm a higher incidence of G3/4 diarrhea (27% vs 17%, p = 0.016) and febrile neutropenia (16% vs 6% p = 0.001) and a lower incidence of all grade nausea (51% vs 65%, p = 0.009) and vomiting (26% vs 44% p = 0.001) were reported among elderly pts. Conclusions: The activity and efficacy of FOLFOXIRI/bevacizumab are confirmed among selected pts between 70 and 75 years old, with a relative increase in the risk of chemo-related AEs similar to that of younger pts. However, elderly pts are more susceptible to experience AEs independently of the treatment arm. Considering the increased incidence of febrile neutropenia and diarrhea with FOLFOXIRI/bevacizumab, the use of G-CSF as primary prophylaxis or an initial dose reduction of irinotecan and 5-fluorouracil might be considered in this population.
Evaluating gender as a predictive marker for response to bevacizuamb (Bev) in metastatic colorectal carcinoma (mCRC): Pooled analysis of 3369 patients (pts) in the ARCAD database.
Authors: Margalit Ofer , Harmsen William S. , shacham-Shmueli Einat , Petersen Molly , Boursi Ben , Saltz Leonard B. , Adams Richard , Maughan Tim , Douillard Jean-Yves , Van Cutsem Eric , Hurwitz Herbert , Bokemeyer Carsten , Tebbutt Niall C. , Kabbinavar Fairooz F. , De Gramont Aimery , Shi Qian , Lenz Heinz-Josef
Published: May 2019

3539

Background: Previous studies suggest a possible gender-specific response to Bev in mCRC, showing a benefit in males, while the effect in females is less significant. Therefore, we evaluated response to Bev according to gender. Methods: Data from 3369 mCRC patients enrolled on 4 first-line randomized trials testing Bev (2000-2007) were pooled. Association between gender and progression-free survival (PFS)/overall survival (OS) was evaluated by stratified Cox regression model, adjusted for potential confounders. Predictive value was evaluated by interaction (inter.) effect between gender and treatment. In a pre-planned secondary analysis, analyses were stratified using an age cut-point of 60 years (commonly used in breast cancer trials) to evaluate the possible role of menopausal-related effects. Results: OS was not statistically different between males and females (median OS [mOS], 18.8 vs. 17.6 months [mo], adjusted hazard ratio [HRadj], 0.93, 95% confidence interval [CI], 0.84-1.03, p, 0.15) in the overall population. Bev was associated with an improved mOS in males and females, with a 2.3 and 0.6 mo benefit, respectively, as well as an improved PFS. There was no statistically significant interaction effect between gender and treatment (see table). Further stratified by age (< vs. ≥ 60 years), Bev resulted in improved PFS and OS in both genders, at all ages, except for the effect in young females which did not reach statistical significance (see table). Conclusions: Our results confirmed the mOS benefit from addition of Bev to first-line chemotherapy in mCRC in both genders, although the benefit in females was < 1 month. For females under the age of 60, there are uncertainties for mOS benefit from addition of Bev and further evaluation is needed. [Table: see text]
Development and validation of a prognostic score for overall survival integrating baseline metabolically active tumor volume measured by 18F-FDG PET/CT and clinical factors for metastatic colorectal cancer patients.
Authors: Woff Erwin , Hendlisz Alain , Salvatore Lisa , Marmorino Federica , Falcone Alfredo , Genovesi Dario , Giorgetti Assuero , Critchi Gabriela , Ameye Lieveke , Paesmans Marianne , Guiot Thomas , Levillain Hugo , Flamen Patrick
Published: May 2019

3543

Background: This study aimed to develop and validate a prognostic score integrating baseline metabolically active tumor volume (MATV) and clinical factors in metastatic colorectal cancer (mCRC) patients. Methods: The development cohort included chemorefractory mCRC patients enrolled in two prospective multicenter non-randomized trials evaluating sorafenib/regorafenib as last line therapy. The validation cohort included mCRC patients from another center, treated with chemotherapy and bevacizumab as first line. Baseline MATV was defined as the sum of metabolically active volumes of all target lesions identified on the baseline 18F-FDG PET/CT. MATV optimal cutoff for OS prediction was determined from the development cohort with Contal and O’Quigley’s method. MATV, age, gender, BMI, ECOG PS, years since diagnosis, and KRAS status were included in a multivariate analysis. A prognostic score to predict OS was developed from the development cohort using Cox proportional hazards model. Results: MATV and clinical factors were evaluable respectively in 155 and 122 patients of the development and validation cohorts. In univariate analysis, MATV with cutoff set at 100 cm³ identified two risk groups with different median OS (mOS) in both the development (4.5 vs 10.9 months, HR: 2.64; p < 0.001) and validation cohorts (20.9 vs 42.9 months, HR: 2.39; p < 0.001). A multivariate analysis identified four independent negative predictors of OS (high MATV, short time since diagnosis, poor PS, BMI < 25). Combining these factors in a prognostic score for OS (best cutoff:-2) allowed to identify two risk groups with different mOS in the development (4.4 vs 13.4 months, HR: 3.67; p < 0.001) and validation cohorts (25 vs 63.8 months, HR: 2.5; p = 0.001). Conclusions: In mCRC patients, the high prognostic value of baseline MATV found in the development cohort was confirmed by external validation, independently of patients’ treatment. In both the development and validation cohorts the prognostic score for OS allowed to identify two risk groups of mCRC patients with significantly different mOS. MATV and our prognostic score for OS should provide a firm basis for risk stratification, in clinical practice and research trials.