bluuebunny/crossref_metadata_2025 huggingface dataset:
A dose-escalation study of imipridone ONC201 administered every one (QW) or three weeks (Q3W) in advanced solid tumors and multiple myeloma.
Authors: Olszanski Anthony J. , Dotan Efrat , Hall Michael J. , vonMehren Margaret , Ross Eric A. , Viereck Amanda M , Denlinger Crystal Shereen
Published: September 2018

2592

Background: ONC201 is an orally active, first-in-class small molecule activator of the integrated stress response that selectively upregulates ATF4 to trigger tumor cell death. A phase I study of ONC201 exploring different dosing regimens and drug exposure was conducted to determine the maximum tolerated dose (MTD), and recommended phase II dose (RP2D). Methods: A modified accelerated-titration dose escalation design was employed to enroll patients onto 2 sequential dose-escalation arms: ONC201 Q3W and QW. Dose escalation proceeded with the following order: 125, 250, 500, and 625mg (Q3W) and 250, 375, 500 and 625 (QW). Dose exposure ranged from 125 mg/6 wks to 1875 mg/3 wks. Key eligibility: advance/refractory solid tumor or myeloma, ECOG 0/1, and no active CNS disease. Adverse events, SAEs, laboratory values, physical exam findings, EKGs and bio-samples (for PK/PD) are collected. Pre and post ONC201 dose biopsies are being obtained from the 500mg weekly cohort and above. Results: 17 pts (12F:5M) with treatment-refractory tumors have been enrolled to date. Dose/#pts Q3W: 125/6, 250/1, 500/1, and 625/1; QW: 250/4, 375/4. Two patients have been enrolled at 500mg QW after database lock and not included in this assessment. Median (range) age: 57 yrs (27-72). ECOG 0/1: 2/15. MTD has not been reached. No DLTs observed. Tumor types: 8 CRC, 3 pancreatic, 2 sarcoma and 1 each cervical, endometrial, NSCLC (adeno) and small bowel. Of 17 pts, 10 (59%) had ≥1 tx-related adverse events (TRAEs), possibly related. Most common TRAEs (≥15% pts): fatigue (9,53%), anorexia (5,29%), nausea (4,24%), vomiting (4,24%), abdominal pain (3,18%), and arthralgias (2,12%). Grade ≥ 3 TRAEs were observed in 3 pts (18%). Pharmacokinetic and pharmacodynamic analysis is ongoing. Fresh frozen and paraffin-embedded biopsies (baseline and week 2) are being assessed for tumor markers implicated in the mechanism of action. No objective responses by RECIST have been seen. Final cohort is enrolling. Conclusions: ONC201 was well tolerated throughout the Q3W dosing and weekly dosing has been well tolerated to date without an apparent increase in AEs. Final enrollment summary, AEs and PK/PD data will be presented. Clinical trial information: NCT02609230.
Updated results from ZUMA-3, a phase 1/2 study of KTE-C19 chimeric antigen receptor (CAR) T cell therapy, in adults with high-burden relapsed/refractory acute lymphoblastic leukemia (R/R ALL).
Authors: Shah Bijal D. , Wierda William G. , Schiller Gary J. , Bishop Michael Russell , Castro Januario E. , Sabatino Marianna , Bot Adrian , Mardiros Armen , Rossi John , Jiang Yizhou , Navale Lynn , Stout Shanna , Aycock Jeff , Wiezorek Jeffrey S. , Jain Rajul K.
Published: September 2018

3024

Background: Promising results have been observed with KTE-C19, an anti-CD19 CAR T cell therapy, in refractory aggressive NHL in the ZUMA-1 trial (Blood 2016;128:LBA-6). We present here updated results from the ZUMA-3 phase 1 trial of KTE-C19 in adult patients (pts) with R/R ALL. Methods: Adult (≥18 y) pts with R/R ALL (Ph+ eligible), ≥25% bone marrow (BM) blasts, adequate organ function and ECOG status 0-1 received 1 or 2×106 CAR T cells/kg after conditioning with cyclophosphamide + fludarabine. Phase 1 primary endpoint is incidence of dose-limiting toxicity (DLT). Secondary endpoints include efficacy outcomes and biomarker associations. Results: As of Nov 1, 2016, 11 pts were enrolled; 10 received KTE-C19. One pt had a serious adverse event (SAE) prior to dosing and was not treated. KTE-C19 was successfully manufactured in all pts across a broad range of baseline absolute lymphocyte counts in 6 days in a centralized facility, with an approximate 2-week turnaround time. Pts were 60% men with 1-4 prior lines of therapy and high disease burden (median, 70% BM blasts). No pt (0/3) experienced a DLT at the 2×106 dose. Phase 1 was expanded to 6 pts at the same dose; 1 grade (Gr) 5 AE (multiorgan failure due to cytokine release syndrome [CRS]) was observed. Subsequent pts (4) received 1×106 CAR T cells/kg. Overall, the most common Gr≥3 AEs were cytopenias (80%), febrile neutropenia (50%), pyrexia (40%), and transaminitis (40%). Gr≥3 CRS and neurologic events (NEs) were reported in 20% and 40% of pts, respectively. Cerebral edema was not observed. All CRS (except Gr5) and 5 of 6 NEs (1 Gr3 ongoing at cut-off) resolved. Of the 8 efficacy evaluable pts, 6 achieved an MRD-negative (MRD–) complete response (CR, or CR + partial or incomplete hematopoietic recovery). Updated results will include additional pt follow-up and biomarker data. Conclusions: No DLTs were observed with KTE-C19 in adult pts with high BM disease burden; one pt had G5 CRS after the DLT cohort. Manufacturing was successful in all pts; most pts achieved an MRD– CR. Based on these results, ZUMA-3 continues to enroll pts with additional measures implemented to further enhance safety. Clinical trial information: NCT02614066.
Epitope mapping of PD-L1 primary antibodies (28-8, SP142, SP263, E1L3N).
Authors: Schats Kelly , Van Vre Emily A. , Schrijvers Dorien , De Meester Ingrid , Kockx Mark
Published: September 2018

3028

Background: Currently, programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) assays received approval in combination with an anti-PD-1 or anti-PD-L1 compounds. However, the FDA blueprint and other publications revealed differences in staining pattern between PD-L1 IHC assays. More precisely the SP142 assay detects less tumor cells (TC), but more immune cells (IC), while the 28-8 assay is more sensitive for TC and less appropriate for IC detection. SP263 stains TC and IC equally well. E1L3N IHC reveals IC and slightly more TC staining than SP142. This study investigates whether these staining discrepancies can be partly explained by specific epitope recognition. Methods: Linear epitope mapping was performed for PD-L1 antibody clones 28-8, E1L3N, SP142 and SP263. In brief, the PD-L1 sequence (Q9NZQ7, Uniprot) was split into 15 amino acid (AA) peptides with a peptide overlap of 14 AA . Each peptide was printed in duplicate on the PD-L1 microarray. The microarray was exposed to different concentration of the four PD-L1 antibodies. For the detection, sheep anti-rabbit IgG DyLight800 was used. Results: Epitope mapping for the E1L3N antibody revealed a linear epitope in the intracellular domain. The other clones showed weaker binding to multiple peptides. The 28.8 clone demonstrated binding to predominantly intracellular epitopes, while SP142 and SP263 clones showed binding to both intracellularly and extracellularly located epitopes. Blasting the epitope sequences of the PD-L1 antibodies did not disclose identity with another (non-PD-L1) human protein. Conclusions: Different binding characteristics were found for all four PD-L1 antibody clones in a linear epitope mapping experiment. This could lead to particular staining patterns depending on PD-L1 conformation (folding) or isoform expression. Two PD-L1 isoforms are known, with isoform 2 lacking AA 19-132 of the extracellular domain. Especially SP142 binding can be impacted in the case of dominant isoform 2 presence, since epitopes were observed in this spliced domain. Further investigation is needed into the potentially conformational epitopes of SP142, SP263 and 28.8 antibody clones as well as in the PD-L1 conformation and isoform expression in TC and IC.
Excision repair cross complementation group 1 (ERCC-1) gene polymorphisms and response to nivolumab in advanced non-small cell lung cancer (NSCLC).
Authors: Aiello Marco M. , Vigneri Paolo Giovanni , Bruzzi Paolo , Verderame Francesco , Paratore Sabrina , Restuccia Nunzio , Albanese Valeria , Soto Parra Hector J.
Published: September 2018

3032

Background: Anti PD1 antibodies showed significant clinical activity in different cancer types. Recently, it was observed that cancers with higher somatic mutation burden, as tumors with genome instability due to DNA repair defects, develop more elevated anti PD1 induced neoantigen specific T cell reactivity which results into increased susceptibility to PD1 blockade. We hypothesize that NSCLC pts with single nucleotide polymorphisms (SNPs) of the ERCC-1 gene, a key enzyme of DNA nucleotide excision repair pathway, may be more responsive to PD-1 blockade due to their genetic instability. Methods: We evaluated the rs11615 and rs3212986 ERCC1 SNPs by pyrosequencing analysis on tumor DNA of stage IIIb-IV previously treated NSCLC patients receiving Nivolumab (Nivo) 3 mg/kg q2w. To be eligible for this study, pts had to have a complete record of clinical and radiological parameters. Objective tumour response was assessed according to RECIST 1.1 criteria. Results: Between Jul 2015 and Jan 2016, 45 NSCLC pts received Nivo. Pts characteristics were as follows: M/F = 37/8; median age (range) = 64 (38-80); ECOG PS, 0/1/2 = 33/9/3; Stage IIIb/IV = 8/37; sqNSCLC/non sq NSCLC = 11/34; current-former smokers/non-smokers = 40/5; EGFR status, mutant/wildtype/unknown = 4/35/6; median cycles (range) = 12 (1-28). Only two pts presented the rs11615 SNP. 16 pts were positive for the rs3212986 SNP. ORR for all pts was 26.6% (95% CI, 10 to 47). The ORR was significantly higher in NSCLC pts positive for the rs3212986 SNP than for wild-type NSCLC patients (62.5% vs. 6.9%. p = 0.0001). For all pts median PFS was 4.3 mos (95% CI, 1.2 to 7.4)and median OS not-reached. Among pts positive for the rs3212986 SNP, median PFS and OS were 8.2 mos and not-reached respectively. In contrast wild-type patients presented a median PFS of 3.1 mos (HR = 0.21 95% CI, 0.07 to 0.57; p = 0.02) and a median OS of 6.5 mos (HR = 0,403 95% CI = 0,131-1,237 p = 0.11). Multivariate analyses confirmed the effect of rs3212986 SNP after adjustment for age, PS, sex and disease stage for PFS. Conclusions: This study suggests that genetic instability due to tumor ERCC1 SNPs in advanced NSCLC pts may be of value to predict clinical benefit from Nivo.
A phase I study of anti-GPC3 chimeric antigen receptor modified T cells (GPC3 CAR-T) in Chinese patients with refractory or relapsed GPC3+ hepatocellular carcinoma (r/r GPC3+ HCC).
Authors: Zhai Bo , Shi Donghua , Gao Huiping , Qi Xingxing , Jiang Hua , Zhang Yuan , Chi Jiachang , Ruan Huaying , Wang Huamao , Ru Qinhua Cindy , Li Zonghai
Published: September 2018

3049

Background: HCC was commonly diagnosed and identified as leading causes of cancer death in China. Using a 10% cutoff score, GPC3 was detected in 63.6% of HCCs. Safety and preliminary efficacy of a GPC3 CAR-T was evaluated in 13 Chinese patients (pts) with r/r GPC3+ HCC in a Phase I trial. Methods: Pts between 18 and 70 yrs old with histopathological confirmed r/r GPC3+ HCC, Child-Pugh score≤B7, ECOG≤1, lymphocyte ≥ □0.7 x109, post-transduction positive T cells □ ≥30%, amplification by α CD3/CD28 ≥5 □, and without ascites and HIV infection were enrolled. Eligible pts undergo leukapheresis or whole blood colletion, which further developed into GPC3 CAR-T via lentiviral transduction. Standard release tests were conducted before administering GPC3 CAR-T in pts. Adverse events were graded per NCI CTCAE v.4.03. Efficacy was evaluated per modified RECIST (mRECIST). Results: All 13 pts, who received at least one infusion of GPC3 CAR-T, tolerated the treatment well. No dose-limiting toxicity (DLT) was identified, and only one SAE of grade 3 fever was reported. Preliminary analysis compared the clinical outcomes in pts who received GPC3 CAR-T without lymphodepleting conditioning (LDC) (Group A) vs. with LDC (Group B) at baseline. In Group A (N = 5), all pts developed progressive disease (PD) shortly after received a total infusion of GPC3 CAR-T ranging from 0.92x107 to 8.72 x107 cells/kg. In Group B (N = 8), following the LDC with fludarabine and cyclophosphamide, pts received a total infusion of GPC3 CAR-T ranging from 0.013x107 to 14.68 x107 cells/kg. Except two non-evaluable pts, the best response for the rest 6 pts are 1 PR, 3 SD, 2 PD. As of Feb 1, 2017, the PR pt remains alive for 385 days; 2 SD pts remain alive for 384 and 562 days, respectively; and one SD deceased at 108 days. Also worth to mention, one pt in Group A decided to remain on the study after PD, further received a total of 6.23 x107cells/kg infusions following a LDC given around Day 150, remains stable for 571 days as of Feb 1, 2017. Conclusions: Phase I trial shows GPC3 CAR-T is feasible and safe for Chinese pts with r/r GPC3+ HCC, and holds promising antitumor potential when LDC is applied along with GPC3 CAR-T. Clinical trial information: NCT02395250.
Atezolizumab (A) + cobimetinib (C) in metastatic melanoma (mel): Updated safety and clinical activity.
Authors: Miller Wilson H. , Kim Tae Min , Lee Carrie B. , Flaherty Keith T. , Reddy Sunil , Jamal Rahima , Chow Laura Q. , Rooney Isabelle Anne , Pitcher Bethany , Cha Edward , Infante Jeffrey R.
Published: September 2018

3057

Background: A, an anti–programmed death-ligand 1 (PD-L1) monoclonal antibody, inhibits PD-L1/programmed death-1 (PD-1) and PD-L1/B7.1 binding and shows promising clinical activity in patients (pts) with cutaneous mel (objective response rate [ORR] 33%; median progression-free survival [mPFS] 5.5 months; Hodi et al SMR 2014). C promotes intratumoral T-cell infiltration, major histocompatibility complex 1 upregulation, and PD-L1 expression via targeted MEK inhibition in preclinical models (Ebert et al Immunity 2016) and tumor biopsy specimens (Bendell et al ASCO 2016). Therefore, clinical benefits may be enhanced by combining A + C vs A. This Phase Ib dose-escalation and -expansion study (NCT01988896) suggested higher ORR/disease control rate (DCR, ORR + stable disease) and longer PFS may be achieved with A + C vs A or C alone in mel. We present updated safety and efficacy data. Methods: Oral C, escalated 20 mg→40 mg→60 mg, was given qd for 21 days followed by 7 days off. Intravenous (IV) A was given at 800 mg q2w. Tumor-specific expansion cohorts were enrolled at maximum tolerated doses (C 60 mg/d 21/7; A 800 mg IV q2w). No prior anti–PD-L1 or –PD-1 therapy was allowed. Results: Data cut-off was Oct 12, 2016; 22 patients were safety-evaluable (two ocular, 20 non-ocular [ten each BRAF-mutant and -wild-type]). Median safety follow-up was 14.4 months (range 2.1–23.2). Adverse events (AEs) were experienced in all pts (diarrhea [20 pts, 90.9%] and rash [15 pts, 68.2%] were most common); related grade (G)3–4 AEs in 54.5% (diarrhea [three pts, 13.6%] and dermatitis acneiform [two pts, 9.1%] were most common; no related G5 AEs); related serious AEs in 13.6%. All were manageable. One pt discontinued A + C due to an AE. RECIST v1.1-confirmed ORR was 45.0% in pts with non-ocular mel (median duration of response was not reached); DCR was 75.0%; mPFS was 12.0 months (95% CI 2.8–not evaluable). ORR was similar for pts with BRAF-mutant and wild-type mel. Conclusions: Updated results confirm previous findings that suggest higher ORR/DCR and longer PFS may be achieved with A + C vs A or C monotherapy for mel. Together with biomarker data from other cohorts, our data suggest that the immune contexture may be altered by C, enhancing A activity. Clinical trial information: NCT01988896.
A phase I study of JS001, a humanized IgG4 mAb against programmed death-1 (PD-1) in patients with advanced solid tumors.
Authors: Chi Zhihong , Tang Bixia , Sheng Xinan , Si Lu , Cui Chuanliang , Kong Yan , Li Dan , Li Si Ming , Yan Xieqiao , Mao Li Li , Lian Bin , Bai Xue , Wang Xuan , Zhou Li , Yu Jiayi , Xu Mingli , Dong Lihou , Song Haifeng , Guo Jun ,   Shanghai Junshi Biosciences
Published: September 2018

3067

Background: JS001 blocks the interaction between PD-1 and its ligands and eradicates established tumor in human PD-1 Knock-in mouse model. Methods: A Phase I open-label study is designed to evaluate the safety and tolerability of JS001 in advanced solid tumor pts who are refractory to standard therapy. The study has a 3+3 dose escalation design with planned cohorts at 1, 3, and 10 mg/kg followed by a dose expansion. (Clinical Trial ID: NCT02836795). Results: As of January 27, 2017, pts enrollment has been completed with 36 pts from 3 indications (22 Melanoma; 9 Urothelial Carcinoma; 5 Renal Cell Carcinoma). The majority of melanomas are acral and mucosal origin. No DLT was observed and no MTD was reached in the study. The most common treatment-related AEs were grade 1/2, including hyper- or hypo-thyroidism (42%), rash (39%), fever (28%), leukopenia (22%), elevation of liver enzymes (19%), anorexia (17%), and fatigue (14%). Treatment–related grade 3 AEs include proteinuria (n = 1), and lipase increase (n = 2). The emergence of AEs is not dose related. JS001 PK shows dose-dependent exposure with the elimination half-life of 6 to 12 days. Among 32 evaluable pts, 1 pt have complete response (melanoma), 6 pts have partial response (3 melanoma, 2 RCC and 1 UC), and 10 pts achieve stable disease, for an ORR of 22% and a DCR of 53%. 6 out of 7 CR/PR pts still have ongoing response. Two groups of pts benefited most from JS001 treatment, pts with high tumor-infiltrating lymphocytes (TIL) (50% ORR) and pts with > 1% PD-L1 expression in tumor biopsy (46% ORR). Conclusions: JS001 exhibited a favorable safety profile in human. Treatment related AEs are in line with those from approved drugs in the same class. JS001 has demonstrated promising anti-tumor activity, especially in previously under-evaluated acral (20% ORR, 53% DCR) and mucosal (25% ORR, 50% DCR) melanomas. Clinical trial information: NCT02836795.
Validation of the Princess Margaret immune oncology prognostic index (PM-IPI) for patients (pts) treated in immune oncology (IO) early phase trials.
Authors: Day Daphne , Spreafico Anna , Lheureux Stephanie , Abdul Razak Albiruni Ryan , Hansen Aaron Richard , Wang Lisa , Butler Marcus O. , Siu Lillian L. , Bedard Philippe L.
Published: September 2018

3070

Background: We previously developed the PM-IPI (ECOG performance status [PS] > / = 1, albumin < lower limit of normal [LLN] and > 2 metastatic sites) from a retrospective cohort of 192 pts treated in phase I IO trials (development cohort). The PM-IPI prognosticated for overall survival (OS), 90-day mortality (90DM) and was associated with improved overall response rate (ORR) and progression free survival (PFS). Our aim was to prospectively validate the PM-IPI in an independent cohort of pts treated on IO trials. Methods: We included 152 consecutively treated advanced solid tumor pts at PM from Aug 2015 to Aug 2016 in 24 IO early phase trials, targeting immune checkpoints and/or co-stimulatory molecules. Pts from the development cohort were excluded. The ability of the PM-IPI to prognosticate OS and 90DM, and predict PFS and ORR was compared with the previously published Royal Marsden Hospital prognostic score (RMI: albumin < 35g/L, LDH > upper limit of normal and > 2 metastatic sites) using the C-index (0.5 = no discrimination, 1 = perfect discrimination) and Area Under the Curve (AUC). Results: Median age was 59y (range 20-86), 28%/72% of pts were ECOG PS 0/1, and 88% had at least 1 prior systemic therapy (range 0-7). The most common tumor sites were gastrointestinal (23%), gynecological (16%), head and neck (15%) and urological (10%). Median PFS and OS were 9.0 and 39.7 wk respectively and 90DM was 14%. ORR was 7% by RECIST 1.1, immune related RECIST or immune related response criteria. In multivariable analysis, ECOG PS > / = 1 (HR 2.7, p = 0.01), albumin < LLN (HR 2.1, p = 0.01) and > 2 metastatic sites (HR 1.8, p = 0.04) were independently prognostic for OS. Pts with a PM-IPI score of 2-3 compared to 0-1 had significantly shorter OS (HR 3.3, p < 0.0001), PFS (HR 1.7, p = 0.005) and higher 90DM (OR 12.2, p = 0.019), and a trend towards lower ORR (OR 0.4, p = 0.15). The prognostic performance of PM-IPI was superior to the RMI for OS and 90DM, but not PFS and ORR (Table). Conclusions: In this independent validation cohort, the PM-IPI prognosticated for OS and 90DM and was associated with PFS. Validation in a large external cohort is ongoing. [Table: see text]
Subgroup efficacy evaluation of the AE37 HER2 vaccine in breast cancer patients in the adjuvant setting.
Authors: Peace Kaitlin M. , Mittendorf Elizabeth Ann , Perez Sonia A. , Tzonis Panagiotis , Pistamaltzian Nikolaos Fragkiskos , Anastasopoulou Eleftheria A , Vreeland Timothy J. , Hale Diane F , Clifton Guy T , Litton Jennifer Keating , von Hofe Eric , Ardavanis Alexandros , Papamichail Michael , Peoples George Earl
Published: September 2018

3088

Background: AE37 is a Ii-Key hybrid of the HER2 peptide AE36 (HER2776-790), which stimulates peptide-specific T cells. We have completed the active phase of a prospective, randomized, multi-center, phase II trial of the AE37 vaccine in the adjuvant setting. The primary analysis, performed after a median follow up (f/u) of 25 months (mo), did not show a significant difference in disease free survival (DFS) between vaccinated and control patients (pts). However, demonstrating the efficacy of cancer vaccines may require more time than other therapies, especially in malignancies with relatively late recurrences like breast cancer. Here, we present updated efficacy data after extended f/u in subgroups of pts stratified by clinicopathologic characteristics. Methods: Clinically disease-free, node positive or high-risk node negative pts with any level of HER2 expression were randomized to receive AE37 + GM-CSF (VG) or GM-CSF alone (CG) following standard of care therapy. Pts received 6 monthly intradermal inoculations during the primary vaccine series (PVS) followed by 4 boosters administered every 6 mo. Kaplan Meier and log rank analyses were performed from the time of the first inoculation in pts who completed at least the PVS, according to stage, node status, tumor size, HER2 expression and ER/PR status. Results: There were no clinicopathologic differences between groups in the 298 enrolled pts (VG = 153, CG = 145). The vaccine is safe and well tolerated. After a median f/u of 55 mo, there was a trend toward improved DFS in the VG among stage IIB/III pts (VG, n = 73, DFS 82% vs CG, n = 61, 67%, HR = 0.48, p = 0.06) and those with low HER2 expression (HER2 LE, VG, n = 68, 89% vs CG, n = 66, 51%, HR = 0.47, p = 0.1). Improved DFS in the VG was documented in patients with both stage IIB/III disease and HER2 LE (VG, n = 39, 90% vs CG, n = 38, 32%, HR 0.3, p = 0.02) and triple negative (TNBC) pts (VG, n = 21, 89% vs CG, n = 21, 0%, HR 0.26, p = 0.05). Conclusions: The AE37 vaccine is safe and well tolerated and has statistically significant efficacy in stage IIB/III pts with HER2 LE and in TNBC pts. This justifies further evaluation in a phase III study enrolling stage IIb/III pts not eligible for trastuzumab treatment and the very high risk TNBC group. Clinical trial information: NCT00524277.
Three versus six months adjuvant oxaliplatin-based chemotherapy for patients with stage III colon cancer: The French participation to the International Duration Evaluation of Adjuvant chemotherapy (IDEA) project.
Authors: Andre Thierry , Bonnetain Franck , Mineur Laurent , Bennouna Jaafar , Desrame Jérôme , Faroux Roger , Dauba Jérôme , Vernerey Dewi , Aissat Nasredine , Louvet Christophe , Lepère Céline , Dupuis Olivier Jean Marie , Becouarn Yves , Mabro May , Egreteau Joëlle , Bouche Olivier , Deplanque Gael , Ychou Marc , De Gramont Aimery , Taieb Julien ,   GERCOR, FFCD, and UNICANCER (PRODIGE) Study Groups
Published: September 2018

3500

Background: The IDEA international collaboration was established to combine data from 6 randomized trials to assess whether a 3-month (3M) of oxaliplatin/fluoropyrimidines-based adjuvant chemotherapy (CT) is non-inferior to the 6-month (6M) for 3-year disease free survival (DFS) in stage III colon cancer (CC). Methods: French IDEA randomized patients (pts) between 3M and 6M of CT with mFOLFOX6 or XELOX (physician/pts choice). DFS was estimated using the Kaplan–Meier method and described using 3 years DFS rate. Results: Among 2022 randomized pts between May 2009 and May 2014, 2010 (99.4%) received CT and were enrolled in the mITT population: 49.9 and 50.1% in 3M and 6M, respectively. 99.5% of the mITT pts had stage III (N1: 74.9%; N2: 25.2%); median age 63.9 years; mFOLFOX6: 90% and XELOX 10% of pts. DFS median follow-up is 50.2 months. There were 578 DFS events (314 in 3M and 264 in 6M arm) leading to a 3-year DFS rate of 72.1% in the 3M vs. 75.7% in the 6M (HR=1.24; 95%CI 1.05–1.46, p=0.0112). For pts receiving mFOLFOX6, 3-year DFS rate was 72.0% in the 3M vs. 76.3% in the 6M (HR=1.27; 95%CI 1.07–1.51 p=0.0069). 94.2% and 78.0% of pts completed 3 and 6 months of CT, respectively. Median oxaliplatin doses intensity were 96.9% in 3M and 72.1% in 6M (495.0 and 735.1 mg/m2). By considering the neuropathy grade with 15375 neuropathy longitudinal measurements the overall maximal neuropathy grade 0-1/2/3-4 was 63.6/28.5/7.9% in 3M and 33.4/41.3/25.3% in 6M; p<0.0001. At last follow-up assessment, with a median of 43.1 months, final residual grade 2/3-4 neuropathy was 2.1/0.4% in 3M and 5.4/1.3% in 6M; p<0.0001. Conclusions: The IDEA France study, with 90% of patients treated with mFOLFOX6 regimen has shown that 6 months adjuvant treatment is superior to 3 months treatment. IDEA France study results should be considered in line with the international IDEA project that will also be presented at ASCO 2017. Clinical trial information: 2009-010384-16.
Primary (1°) tumor location as an independent prognostic marker from molecular features for overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB / SWOG 80405 (Alliance).
Authors: Venook Alan P. , Ou Fang-Shu , Lenz Heinz-Josef , Kabbarah Omar , Qu Xueping , Niedzwiecki Donna , Zemla Tyler , Goldberg Richard M. , Hochster Howard S. , O'Neil Bert H. , Sanoff Hanna Kelly , Mayer Robert J. , Bertagnolli Monica M. , Blanke Charles David , Innocenti Federico
Published: September 2018

3503

Background: 80405 found no OS or Progression Free Survival (PFS) difference when bevacizumab (BV) or cetuximab (Cet) was added to 1st-line FOLFOX or FOLFIRI in All RAS wild type (wt) mCRC pts. There was a significant 1° side by biologic interaction (P int: OS = 0.008, PFS = 0.001) favoring pts with left-sided (L) 1°. Analyses of 1° tumors beyond All RAS includes Consensus Molecular Subtype (CMS), BRAF and MSI. (CMS results - see Lenz et al; BRAF -see Innocenti et al) We asked whether 1° tumor location - L vs right (R) - is an independent prognostic marker when these other molecular features are considered. Methods: We used a Cox proportional hazard model stratified by prior XRT and +/- adjuvant chemo; adjusted for age, gender, synchronous vs metachronous, CMS, MSI and BRAF status. Pts with transverse (T) tumors were excluded in this analysis. Results: Sidedness was determined in 782 pts (L - 472; R - 256; T -54). Molecular data from 728 pts (with L - and R-sided 1°s) was available as follows: KRAS -- 291, NRAS -393, BRAF - 393, MSI - 378, CMS - 533. L vs R mOS: 32.9 v 19.6 months (mo) (p < 0.0001). See Table for OS results in All RAS / BRAF wt and BRAF mutant (mut) pts. Sidedness (R vs L) is an independent prognostic marker even after adjusting for all these molecular features: HR = 1.392 (1.032, 1.878), p = 0.031. Conclusions: Primary tumor location is an independent prognostic factor when adjusted for age, gender, synchronous/metachronous, CMS, MSI and BRAF status. We are exploring clinical variables such as tumor burden, metastatic sites and measurability of disease in an attempt to explain the impact of sidedness. Support: U10CA188021, U10CA180882. Eli Lilly and Co, Genentech/Roche, Pfizer, Sanofi. Clinical trial information: NCT002655850. [Table: see text]
Overall survival analysis of the FOXFIRE prospective randomized studies of first-line selective internal radiotherapy (SIRT) in patients with liver metastases from colorectal cancer.
Authors: Sharma Ricky A. , Wasan Harpreet Singh , Van Hazel Guy A. , Heinemann Volker , Sharma Navesh K. , Taieb Julien , Ricke Jens , Mills Jamie , Tait Nicholas Paul , Boardman Philip , Peeters Marc , Findlay Michael P. N. , Virdee Pradeep Singh , Moschandreas Joanna , Gebski Val , Love Sharon , Gray Alastair , Gibbs Peter
Published: September 2018

3507

Background: The FOXFIRE, SIRFLOX and FOXFIRE-Global (FF-SF-FFG) randomized studies evaluated the efficacy of combining first-line chemotherapy for metastatic colorectal cancer (mCRC) with selective internal radiotherapy (SIRT) using yttrium-90 resin microspheres in patients with liver metastases. The studies were designed for prospective, combined analysis of overall survival (OS). Methods: FF-SF-FFG randomized (1:1) chemotherapy-naïve mCRC patients (performance status 0/1) with liver metastases not suitable for curative resection/ablation. Arm A was oxaliplatin-based chemotherapy (mFOLFOX6/ OxMdG) ± investigator-chosen biologically targeted agent. Arm B was the same systemic therapy (oxaliplatin dose modification) + single treatment SIRT with cycle 1/2 of chemotherapy. Primary tumor in situ and/or limited extra-hepatic metastases were permitted. Minimum sample size was 1075 patients (HR 0.8, 80% power, two-sided 5% significance). Secondary outcomes included PFS, liver-specific PFS and response rate. Apart from safety, outcomes were analysed on intention-to-treat population using meta-analytic methods of pooled individual patient data. Results: Between 2006 and 2014, 1103 patients were randomized in 14 countries. Median age was 63 years (range 23-89); median follow-up 43.3 months. There were 844 deaths. There was no difference in OS (HR 1.04; 95% CI 0.90-1.19, p= 0.609) or PFS (HR 0.90, CI 0.79-1.02, p= 0.108) between Arms. Objective response rate ( p= 0.001) and liver-specific progression (HR 0.51, CI 0.43-0.62, p< 0.001) were significantly more favorable in Arm B. Patients in Arm B had higher risk of non-liver progression as first event (HR 1.98, CI 1.53-2.58, p< 0.001). Grade 3-5 adverse events were more common in Arm B (74.0%) than A (66.5%), p= 0.009. In health status questionnaires, EQ-5D utility scores were not significantly different between Arms at 6, 12 or 24 months. Conclusion: Despite higher response rates and improved liver-specific PFS, the addition of SIRT to first-line oxaliplatin-fluorouracil chemotherapy for patients with liver-only and liver-dominant mCRC did not improve OS or PFS. Clinical trial information: 83867919.
A randomized, double-blind, placebo-controlled, multi-centered phase 3 trial comparing fruquintinib versus placebo plus best supportive care in Chinese patients with metastatic colorectal cancer (FRESCO).
Authors: Li Jin , Qin Shukui , Bai Yuxian , Deng Yanhong , Yang Lei , Xu Rui-hua , Chen Zhendong , Zhong Haijun , Pan Hongming , Shu Yongqian , Yuan Ying , Xu Nong , Zhou Jianfeng , Liu Tianshu , MA DONG , Wu Changping , Cheng Ying , Fan Songhua , Hua Ye , Su Weiguo ,   ASCO Authors' Group
Published: September 2018

3508

Background: Treatment options for third-line metastatic colorectal cancer (mCRC) patients remain limited in China. Fruquintinib, an oral kinase inhibitor selectively targeting vascular endothelial growth factor receptors, in a phase II study was found to significantly improve progression free survival (“PFS”) in patients with mCRC as compared to placebo (ESMO abs#2111). Based on these results, a Phase III registration trial, FRESCO, was carried out to confirm fruquintinib’s efficacy and safety in third-line mCRC patients (clinicaltrials.gov # NCT02314819). Methods: This is a randomized, double-blind, placebo-controlled, multi-center phase III trial. Patients with mCRC who have failed at least 2 lines of systemic chemotherapy were enrolled from 28 centers in China. Patients were stratified based on prior anti-VEGF therapy and K-ras status and randomized to a fruquintinib or placebo arm in a 2:1 ratio. The primary endpoint was overall survival (“OS”) which was analyzed in the intent-to-treat population. Results: Between December 12, 2014 and May 13, 2016, 416 patients were randomized. Protocol predefined number of OS events for final analysis was reached on January 17, 2017. Fruquintinib significantly improved OS comparing to placebo with a hazard ratio of 0.65 (95% CI: 0.51-0.83; two sided p<0.001). Median OS was 9.30 months [95% CI 8.18-10.45] in the fruquintinib group versus 6.57 months [95% CI 5.88-8.11] in the placebo group. Statistically significant benefits were also seen with fruquintinib in all secondary endpoints, such as PFS, objective response rate and disease control rate. The most frequent fruquintinib-related ≥ Grade 3 treatment emerged adverse events included hypertension (21.6%), hand-foot skin reaction (10.8%), proteinuria (3.2%) and diarrhea (3.2%). Conclusion: In this phase III confirmatory trial, fruquintinib demonstrated a statistically significant and clinically meaningful OS benefit as compared with placebo in mCRC patients in China. Fruquintinib was well tolerated with a safety profile that is consistent with what was reported previously. Clinical trial information: NCT02314819.
Association of prognostic value of primary tumor location in stage III colon cancer with RAS and BRAF mutational status.
Authors: Taieb Julien , Kourie Hampig Raphael , Emile Jean-François , Le Malicot Karine , Balogoun Ralyath , Tabernero Josep , Mini Enrico , Folprecht Gunnar , Van Laethem Jean-Luc , Mulot Claire , Bouche Olivier , Aparicio Thomas , Michel Pierre , Thaler Josef , Bridgewater John A. , Van Cutsem Eric , Perkins Géraldine , Salazar Ramon , Lepage Come , Laurent-Puig Pierre
Published: September 2018

3515

Background: Recent data suggest that the anatomic site of colon primary tumor may be an important factor in the interpretation of molecular markers with clinical outcome in metastatic colon cancer (CC) patients (pts). We assessed here the prognostic value of primary location in fully resected stage III CC pts and its relationship to MSI, RAS and BRAF mutational status. Methods: Pts enrolled in the PETACC-8 trial were analyzed. We categorized tumor site as located proximal (left-sided) or distal (right-sided) to the splenic flexure. The association between tumor location and disease free survival (DFS), survival after relapse (SAR) and overall survival (OS) were assessed by Cox models and adjusted for clinical and pathological features, MSI, BRAF and RASmutation status. The outcome of pts receiving FOLFOX or FOLFOX and cetuximab in the adjuvant setting were also determined according to tumor site. Results: Among the 1869 pts with full molecular data available, 755 (40%) had a right-sided tumor, 164 (10%) were MSI, 942 (50%) were mutated for RAS and 212 (11%) were mutated for BRAF. Right-sided tumor was not prognostic for DFS in the whole population but was associated to a shorter SAR (HR: 1.54 [1.23 - 1.93], p = 0.001) and OS (HR: 1.25 [1.02 - 1.54], p = 0.03). Same results were observed for MSS and for MSI pts. However, when looking at pts mutated for RAS or BRAF(MUT) and those double wild type (DWT) for those mutations, we found that right-sided tumors, when compared to left-sided tumors, was associated with a worst DFS in DWT patients (HR:1.39[1.01-1.92], p = 0.04) and a better DFS in MUT patients (HR:0.77[0.63-0.95], p = 0.01). These results were found independently of the treatment received and no beneficial effect of cetuximab on DFS or OS was observed in left-sided tumors. Conclusions: In the whole study population of stage III CC pts, though right-sided tumor location influences OS as previously reported, it does not seem to influence DFS but only SAR, when disease becomes metastatic. Interestingly, sidedness seems to influence DFS when splitting the population in MUT or DWT for RAS and BRAF, with a worst DFS for right-sided tumors in DWT and a worst DFS for left-sided tumors in RAS or BRAF mutants. Clinical trial information: 2005-003463-23.
Primary tumor location and efficacy of second-line therapy after initial treatment with FOLFIRI in combination with cetuximab or bevacizumab in patients with metastatic colorectal cancer- FIRE-3 (AIOKRK0306).
Authors: Modest Dominik Paul , Stintzing Sebastian , Fischer von Weikersthal Ludwig , Decker Thomas , Kiani Alexander , Vehling-Kaiser Ursula , Al-Batran Salah-Eddin , Heintges Tobias , Kahl Christoph , Seipelt Gernot , Kullmann Frank , Stauch Martina , Scheithauer Werner , Held Swantje , Giessen-Jung Clemens , Jung Andreas , Kirchner Thomas , Heinemann Volker
Published: September 2018

3525

Background: FIRE3 compared 1st-line therapy with FOLFIRI plus either cetuximab (arm A) or bevacizumab (arm B) in 592 patients (pts) with KRAS exon 2 wild-type metastatic colorectal cancer (mCRC). Second-line therapies appeared more successful in arm A compared to arm B. The impact of primary tumor location on this observation is unclear. Methods: Pts. were stratified for primary tumor site (left- vs. right-sided). Duration of 2nd-line therapy was calculated as time from first to last application. Progression-free survival (PFS2nd) and overall survival (OS2nd) of second-line therapy) were evaluated by Kaplan-Meier method and compared by log rank test as well as Cox regression. All analyses were performed in the RAS wild-type population of the trial and reported according to drug sequences. Results: 272 of 400 pts. (68%) received 2nd-line therapy, of those 206 (109 in arm A, 97 in arm B) pts. presented left-sided, whereas 66 (26 in arm A, 40 in arm B) pts. presented right-sided primaries. PFS2nd was markedly longer in pts. with left-sided as compared to right-sided primary tumors (6.0 (95% CI: 5.5-6.7) vs. 3.4 (95% CI: 3.0-5.8) months, hazard ratio (HR): 0.64 (95% CI: 0.47-0.87), P = 0.005). Differences in PFS2nd between study-arms were evident in pts. with left-sided primaries (arm A: 7.3 (95% CI: 6.4-7.7) vs. arm B: 5.3 (95% CI: 4.3-5.9) months, HR: 0.61 (95% CI: 0.44-0.84), P = 0.002), but not in pts. with right-sided primaries (arm A: 4.0 (95% CI: 3.0-6.3) vs. arm B: 3.3 (95% CI: 2.6-5.8) months, HR: 1.09 (95% CI: 0.62-1.90). Consistent observations were also made for treatment duration and OS2nd. Conclusions: This retrospective analysis indicates that treatment duration and efficacy of second-line therapy are associated with primary tumor location. Efficacy of second-line therapy was significantly greater in pts. with left-sided tumors as compared to right sided tumors. This difference was driven by superior activity of second-line regimens of arm A compared to arm B in left-sided tumors. Our observations confirm the strong prognostic value of primary tumor location in mCRC across treatment lines. Clinical trial information: NCT00433927.
Heterogeneity in early lesion changes on treatment as a marker of poor prognosis in patients (pts) with metastatic colorectal cancer (mCRC) treated with first line systemic chemotherapy ± biologic: Findings from 9,092 pts in the ARCAD database.
Authors: Ou Fang-Shu , Hubbard Joleen Marie , Kasi Pashtoon Murtaza , Dixon Jesse , Van Cutsem Eric , Saltz Leonard , Schmoll Hans-Joachim , Punt Cornelis J. A. , Goldberg Richard M. , Hoff Paulo , Douillard Jean-Yves , Hecht J. Randolph , Hurwitz Herbert , Bokemeyer Carsten , Fuchs Charles , Diaz-Rubio Eduardo , Sargent Daniel J. , De Gramont Aimery , Shi Qian , Grothey Axel ,   ARCAD
Published: September 2018

3535

Background: CRC is known to be a heterogeneous disease. This study quantifies within pt heterogeneity in early lesion change rate (LCR) in the era of targeted agents compared to chemo alone and its potential impact on survival. Methods: Pts with 2-10 lesions measured at baseline were included. For each lesion, the early LCR was defined as the change in size (shrinking or growing) from baseline to 12 weeks on treatment. Within pt heterogeneity in early LCR among lesions was estimated by standard deviation (STD). A larger value of STD indicates larger variation of LCR per pt. Stratified multivariate Cox models were used to assess the associations between LCR STD with overall survival (OS). Adjusted hazard ratios (HRadj) and 95% confidence intervals (CIs) are reported. Results: Data were available on 9,092 mCRC pts (median age 61; 60% male, 55% ECOG PS 0; 61% 2+ metastatic sites) enrolled in 16 1st-line randomized trials, with 44%, 42%, and 10% of pts received chemo alone, + a VEGF inhibitor (VEGFi) or an EGFR inhibitor (EGFRi), respectively. LCR heterogeneity is the highest among pts received EGFRi but lowest among pts received VEGFi (Table). Overall, higher heterogeneity is associated with worst OS (HRadj1.22, 95% CI (1.16, 1.27)). The effect is most pronounced in pts received VEGFi (interaction p=0.0012). Conclusions: There was heterogeneity observed in lesion size changes within pts. Its magnitude varies across treatment approaches, and was associated with poor survival. This preliminary result reveals the great potentials to define novel response endpoint and refine treatment decision-making by incorporating heterogeneities in lesion changes. [Table: see text]
Treatments (tx) after progression to first-line FOLFOXIRI plus bevacizumab (bev) in metastatic colorectal cancer (mCRC) patients (pts): A pooled analysis of TRIBE and MOMA studies by GONO group.
Authors: Rossini Daniele , Moretto Roberto , Cremolini Chiara , Zagonel Vittorina , Tonini Giuseppe , Ricci Vincenzo , Aprile Giuseppe , Lonardi Sara , Tomasello Gianluca , Dell'Aquila Emanuela , Allegrini Giacomo , Bergamo Francesca , Mancini Marialaura , Antoniotti Carlotta , Ronzoni Monica , Zaniboni Alberto , Marmorino Federica , Bustreo Sara , Mori Elena , Falcone Alfredo
Published: September 2018

3542

Background: FOLFOXIRI plus bev is regarded by international guidelines as a valuable option in the first-line tx of mCRC pts. One of the major concerns for the adoption of this regimen is the potential limitation of subsequent therapeutic options. The aim of the present analysis was to focus on treatments received after progression in TRIBE (NCT00719797) and MOMA (NCTNCT02271464) studies. Methods: We collected data of tx received after progression and their outcome in terms of 2ndPFS (time from 2nd line tx start to disease progression or death) and OS II (time from 2nd line tx start to death). For pts in which the same drugs used in first-line were totally or partially reintroduced, the chemotherapy-free interval (CFI, time from the last administration of irinotecan or oxaliplatin during first-line to disease progression) was calculated. Results: Out of 482 pts treated with upfront FOLFOXIRI plus bev, 429 progressed. 303 (70.6%) pts received a 2nd line tx: 93 FOLFOXIRI +/- bev (Group A), 119 FOLFOX/XELOX or FOLFIRI +/- bev (Group B) and 91 other tx (Group C), including an anti-EGFR moAb in 60 cases. No difference was observed among the three groups in terms of 2ndPFS (median 2nd PFS Group A: 5.6 vs Group B: 4.4 vs Group C: 3.9 mos; p = 0.60) or OS II (median OS II Group A: 14.9 vs Group B: 13.8 vs Group C: 11.7 mos; p = 0.49). In the subgroup of pts with a CFI < 6 mos, Group A (n = 52) reported longer 2ndPFS compared to both Group B (n = 58) (median 2ndPFS 5.3 vs 3.0 mos; HR: 0.61,95%CI 0.41-0.89; p = 0.009) and Group C (n = 58) (5.3 vs 3.2 mos; HR: 0.71, 95%CI 0.48-1.05; p = 0.07). Consistent results were achieved in OS II (Group A vs Group B; median OS 13.6 vs 10.8 mos; HR: 0.65, 95%CI 0.42-1.00; p = 0.053; Group A vs Group C 13.6 vs 8.9 mos; HR: 0.60, 95%CI 0.39-0.93; p = 0.002). In the subgroup of pts with a CFI ≥ 6 mos, no significant difference was shown between Group A (n = 41) and Group B (n = 61) or C (n = 33). Conclusions: Tx after progression to first-line FOLFOXIRI plus bev are feasible and show expected efficacy results. The reintroduction of the triplet plus bev seems more effective than doublets plus bev or other tx when a more aggressive disease biology is suggested (CFI < 6 mos).
Localization of the primary tumor (LPT) and maintenance strategies after first line oxaliplatin (Ox), fluoropyrimidine (FP), and bevacizumab (Bev) in metastatic colorectal cancer (mCRC): Results from the AIO 0207 trial.
Authors: Reinacher-Schick Anke C. , Noepel-Duennebacke Stefanie , Hertel Jan , Tannapfel Andrea , Arnold Dirk , Hinke Axel , Hegewisch-Becker Susanna
Published: September 2018

3543

Background: Numerous trials have examined the prognostic and predictive value of the LPT in mCRC, but little is known about the predictive value of LPT on different maintenance strategies. We analyzed progression-free survival (PFS) and overall survival (OS) from start of maintenance according to LPT in patients (pts) from the AIO KRK 0207 trial. Methods: Following a 24-week standard induction 471 pts were randomized to FP/Bev, Bev mono or no treatment with 454 pts being evaluable for PFS. Right sided primary tumors were defined as located in the caecum, ascending colon, transverse colon up to the splenic flexure; left colon was defined as splenic flexure, descending and sigmoid colon and rectum. Results: Data on LPT was available in 414 pts. for PFS (91%). LPT was left sided (LPTl) in 291 (70%) and right-sided (LPTr) in 123 (30%) of pts, respectively (remaining pts: status was either unknown, n = 37 or LPT was located in both regions, n = 3). Median PFS1 was 3.9 months (mos.) for LPTr and 5.3 mos. for LPTl (p = 0.11; HR 1.19, 95%CI 0.96 - 1.48). Analyses on PFS did not demonstrate a major predictive impact of LPT on the efficacy of the three maintenance strategies. The pairwise comparison of treatment arms showed a better PFS for FP/Bev vs no treatment independent from LPT (left: p < 0.0001; HR = 2.39, 95%CI 1.73-3.31; right: p = 0.011; HR 1.78, 95%CI 1.14-2.80). In addition, Bev mono vs no treatment was superior in LPTl (p = 0.0032; HR 1.54, 95%CI 1.15-2.06) with less difference in LPTr (p = 0.17; HR 1.36, 95%CI 0.87-2.14). Analysis for OS (429 evaluable pts) confirmed the strong prognostic impact of LPT (left vs right: 24.0 vs 16.7 months; p < 0.0001; HR = 1.65, 95%CI 1.32 - 2.06), but without major interaction between LPT and maintenance arms. The impact related to RAS mutational status will be reported. Conclusions: The strong prognostic factor of the LPT is confirmed in pts with mCRC undergoing Ox/FP/Bev induction therapy while there seems to be no major predictive impact of LPT on different maintenance strategies. Clinical trial information: EudraCT-Nr: 2008-007974-39.