bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolomic correlates of response in nivolumab-treated renal cell carcinoma and melanoma patients.
Authors: Giannakis Marios , Li Haoxin , Jin Chelsea , Gopal Shuba , Desai Kaushal , Horak Christine , Wind-Rotolo Megan , Van Allen Eliezer Mendel , Clish Clary , Hodi F. Stephen , Garraway Levi A. , Choueiri Toni K.
Published: September 2018

3036

Background: Immune-checkpoint inhibition has been shown to be effective in a variety of cancers, including renal cell carcinoma (RCC) and melanoma. However, only a subset of patients with RCC and melanoma respond to anti-PD1 therapy. Given the importance of metabolism in the tumor immune microenvironment, we performed serum metabolomics in nivolumab-treated patients towards identifying novel non-invasive correlates of response and progression-free survival in immunotherapy-treated patients. Methods: We performed liquid chromatography-mass spectrometry on pre- and on-treatment serum samples from 79 patients with advanced melanoma (CA209-038 study) and 82 patients with metastatic RCC (CA209-009 study) receiving nivolumab. We precisely measured more than one-hundred named metabolites at baseline (prior to starting nivolumab), at 4 weeks and at 6 (melanoma) or 9 weeks (RCC) after initiation of treatment and correlated these with best overall response as well as progression-free survival (PFS). Results: In melanoma patients treated with nivolumab, the difference in mean levels of kynurenine (the product of IDO / TDO activity in tryptophan catabolism) between weeks 4 and 6 compared to baseline was significantly different between responders and non-responders (t-test with unequal variance p-value = 0.043 and p-value = 0.044 respectively). In RCC patients, we observed that patients with no response to nivolumab had significantly higher adenosine levels, than those who responded, at baseline and at 4 weeks after initiation of treatment (158% and 138% higher, t-test p-value = 0.0019 and p-value = 0.0011 respectively). RCC nivolumab-treated patients with higher (top quartile) baseline adenosine levels also had a significantly worse PFS (log rank test p-value = 0.004). Conclusions: In this first-of-its kind metabolomic analysis of peripheral blood from nivolumab-treated patients, we find that the change in kynurenine levels in melanoma patients correlates to response. In addition, higher baseline levels of adenosine in RCC patients are associated with worse PFS and lack of response to nivolumab. These results suggest a possible role for serum metabolites as biomarkers of benefit to PD1 inhibition.
CD133-redirected chimeric antigen receptor engineered autologous T-cell treatment in patients with advanced and metastatic malignancies.
Authors: Wang Yao , Chen Meixia , Wu Zhiqiang , Tong Chuan , Huang Jianhua , Lv Haiyan , Dai Hanren , Feng Kaichao , Guo Yelei , Liu Yang , Yang Qingming , Han WeiDong
Published: September 2018

3042

Background: Expressed by cancer stem cells of various epithelial cell origins, CD133 is an attractive therapeutic target for cancers. Autologous chimeric antigen receptor-modified T cells directed CD133 (CART-133) were firstly tested in this clinical trial. We aimed to determine the safety dosage, toxicity and biological activity of CART-133 in epithelium-derived solid tumors. Methods: The initially enrolled 8 patients with sorafenib-refractory hepatocellular carcinoma (HCC), treated by CART-133 monotherapy, were assigned into 3 dose cohorts (1, 0.5-1.5×105/kg; 2, 5-10×105/kg; 3, 1-2×106/kg). For the additional 16 patients (6 HCCs, 7 pancreatic carcinomas, 2 colorectal carcinomas, and 1 cholangiocarcinoma), all non-HCCs were conditioned by regimen (Nab-pacitaxel/cyclophosphamide or anti-PD1 antibody) before cell infusions. Results: For the initial 8 HCCs, 1 from cohort 2 occurred hemoglobin/platelet decline and direct hyperbilirubinemia (Grade 3), 4 from cohort 2/3 reported delayed low fever, nausea accompanied with elevation of CRP and serum cytokines. The 4-6 week persistence of relatively higher CAR copy numbers and its reverse relationship with the count of CD133+ cells harboring pro-metastatic epithelial progenitor cells in peripheral blood led to the determination of acceptable cell infusion dose from 0.5 to 2×106/kg and reinfusion cycle in 24 patients. Similar toxicities ( ≤ Grade 3) were observed in 15 cases. The cholangiocarcinoma patient who uniquely received 1 cycle of CART-133 infusion after anti-PD1, developed Grade 3 skin/mucosal vasculature damage, blood three-lineage decline and cytokine release syndrome, whereas, obtained a 4.5 month-lasting partial remission. Although no marked reduction of tumor volume was observed in most patients, 21 out of 23 patients had an 8-22 week progression-free survival, 2 patients without bulky tumor burden attained 8/10-month ongoing stable disease by the cut-off data (Jan 1, 2017). Conclusions: This trial showed the feasibility, controllable toxicities and effective biological activity of CART-133 transfer for the treatment of late-stage tumor patients. Clinical trial information: NCT02541370.
Efficacy of single administration of tumor-infiltrating lymphocytes (TIL) in heavily pretreated patients with metastatic melanoma following checkpoint therapy.
Authors: Sarnaik Amod , Kluger Harriet M. , Chesney Jason Alan , Sethuraman Jyothi , Veerapathran Anandharamen , Simpson-Abelson Michelle , Lotze Michael T. , Larsen Bente , Fischkoff Steven A. , Suzuki Sam , Wang Lei , Mirgoli Mariam , Fardis Maria , Curti Brendan D.
Published: September 2018

3045

Background: Adoptive cell therapy with TIL involves collection of autologous lymphocytes from the tumor via surgical resection, ex vivo expansion of TIL, lymphodepletion of the patient prior to infusion of TIL using Fludarabine and Cyclophosphamide, followed by infusion of TIL. Up to 6 doses of IL-2 (600,000 IU/kg) is administered to support multiplication of TIL and engraftment. Here, we present the preliminary results from an ongoing, multi-site Phase 2 study of TIL for advanced metastatic melanoma. Methods: Patients with advanced metastatic melanoma who have failed at least one prior systemic therapy were enrolled. Primary objective of the study was to characterize safety profile of LN-144. At baseline, patients had a median age of 56 (41-72) years; 44% were ≥ 60 years old. Median sum of tumor diameters for the target lesions was 10.4 cm, and median of 3 prior therapies. All enlisted patients had prior anti-PD1 as well as anti-CTLA4 and 67% had received ≥ 3 prior therapies. Responses were assessed by RECIST 1.1. TIL products were centrally manufactured. No complications arose from shipment of tumors or TIL. Results: Results are presented through 31 Jan 2017 for the first 9 infused patients evaluable by two assessments. Eight of 9 patients received all 6 doses of IL-2 per protocol. The most common (≥3 patients) non-hematologic grade 3-4 TEAE was hypophosphatemia. No neurotoxicity of grade ≥ 3 was reported. There were no deaths or discontinuations due to SAEs related to study treatment. ORR was 33% (CR = 11%, PR = 22%, SD = 22%, PD = 33%, NE = 11%). Mean time to best response was 3.0 months and median duration of follow up was 3.6 months (1.1+, 12.1). Responses were observed in patients with tumors carrying wild type or BRAF mutations. All patients demonstrated persistence of TIL on day 14 post-infusion. Conclusions: Cell therapy with TIL is an effective treatment with acceptable safety profile for advanced metastatic melanoma patients who are refractory to anti-PD1. TIL products can be centrally manufactured for broad clinical application. This study will be expanded to enroll patients with a shorter manufacturing process as well as offering retreatment for study patients. Clinical trial information: NCT02360579.
Atezolizumab (A) + cobimetinib (C) + vemurafenib (V) in BRAFV600-mutant metastatic melanoma (mel): Updated safety and clinical activity.
Authors: Sullivan Ryan J. , Gonzalez Rene , Lewis Karl D. , Hamid Omid , Infante Jeffrey R. , Patel Manish R. , Hodi F. Stephen , Wallin Jeffrey , Pitcher Bethany , Cha Edward , Roberts Louise , Ballinger Marcus , Hwu Patrick
Published: September 2018

3063

Background: Targeted inhibition of MEK with C and BRAF with V in BRAFV600-mutant mel can lead to both anticancer immune activation and direct tumor cell death. A, an anti–PD-L1 monoclonal antibody, inhibits PD-L1/PD-1 signaling. Combining C + V with A may enhance antitumor activity, potentially leading to improved clinical responses and durability. Preliminary data from this phase Ib study (NCT01656642) showed that A + C + V had a manageable safety profile and promising antitumor activity in patients (pts) with untreated BRAFV600-mutant unresectable/metastatic mel, with increases in CD8-positive T-cell infiltration observed after C + V (Sullivan et al SMR 2016). We present updated safety and efficacy data. Methods: Pts received A + C + V after a 28-day run-in with C + V. A was given at 800 mg q2w, C at 60 mg qd for the first 21 days of each 28-day cycle, and V at 960 mg bid during day 1–21 of run-in and 720 mg thereafter. Safety was evaluated in pts who had ≥1 dose of A; efficacy, in pts who had ≥1 dose of A by the data cutoff date and received ≥1 dose of A, C, or V by the dosed-by date. Results: Thirty-four patients were treated and evaluated for both safety and efficacy. Median survival follow-up was 7.1 months (range 2.5–19.9). Elevated AST/ALT, diarrhea, arthralgia, fatigue, photosensitivity, pyrexia, nausea, flu-like symptoms, maculopapular rash, and pruritus were reported as A- and/or C- and/or V-related in > 20% of pts at any grade (G). A/C/V-related G3–4 adverse events (AEs) were seen in 15 pts (44.1%) with the triple combination (none G5). Three serious AEs were A-related. All AEs were manageable and reversible. Elevated ALT/AST (three pts each) and rash (one pt) led to discontinuation of any drug. Unconfirmed RECIST V1.1 responses were observed in 29 pts (85.3%; six complete, 23 partial). Three pts with confirmed partial responses had resolution of target lesions. Twenty of the 29 responding patients continue to respond at the time of the data cutoff. Conclusions: Updated results confirm preliminary findings that A + C + V has a manageable safety profile and promising antitumor activity in pts with BRAFV600-mutant metastatic mel. Continued exploration of A + C + V is warranted. Clinical trial information: NCT01656642.
Final DFS results of the SCOT study: An international phase III randomised (1:1) non-inferiority trial comparing 3 versus 6 months of oxaliplatin based adjuvant chemotherapy for colorectal cancer.
Authors: Iveson Timothy , Kerr Rachel , Saunders Mark P. , Hollander Niels Henrik , Tabernero Josep , Haydon Andrew Mark , Glimelius Bengt , Harkin Andrea , Scudder Claire , Boyd Kathleen , Waterston Ashita Marie , Medley Louise C. , Wilson Charles , Ellis Richard , Essapen Sharadah , Dhadda Amandeep Singh , Harrison Mark , Falk Stephen , Raouf Sherif , Paul James
Published: September 2018

3502

Background: Six months of oxaliplatin-based treatment has been the mainstay of adjuvant chemotherapy for colorectal cancer for the last 13 years. Neurotoxicity from oxaliplatin is cumulative, dose limiting, and potentially irreversible. A shorter duration of treatment would save patients significant toxicity/time and substantially reduce the costs of the drug, its administration, and treatment of adverse effects. Methods: SCOT is a non-inferiority randomised study designed to determine whether 3 months of adjuvant chemotherapy with OxMdG or Xelox (physician/patient choice) in Stage III/high risk Stage II colorectal cancer is as effective as 6 months treatment. Non-inferiority was determined to be a maximum 2.5% fall in 3-year disease-free survival (DFS) on the 3 month arm (from 78% on the 6 month arm) corresponding to a hazard ratio upper limit of 1.13. The study was designed with 90% power at the 2.5% 1-sided level of statistical significance and aimed to recruit 9500 patients to observe 2,750 DFS events (relapses/deaths/new colorectal cancers). Analysis used a Cox model adjusted for study minimisation factors. Results: 6088 patients (60% male, median age 65) with Stage III/high risk Stage II cancers of the colon or rectum were randomised between 27th March 2008 and 29th November 2013. The arms were balanced for clinical and pathological factors. Intended treatment was OxMdG for 1981 and Xelox for 4107 patients. There were 1469 DFS events (734 in 3 month arm and 735 in 6 month arm) giving the study 66% power. 3 year DFS was 76.8% (se = .8%) for the 3 month arm and 77.4% (se = .8%) for the 6 month arm (HR 1.008, 95% CI 0.910-1.117, test for non-inferiority p = 0.014). Non-inferiority appeared stronger for Xelox than OxMdG (test for heterogeneity, p = .059). Results will be shown broken down by stage, site, age, gender and achieved duration of treatment. Conclusions: The SCOT study has shown that 3 months adjuvant treatment is not inferior to 6 months treatment. However the SCOT study is part of the IDEA consortium and the results from the 6 studies in the IDEA consortium addressing the same duration question will also be presented at ASCO 2017. Clinical trial information: ISRCTN59757862.
Clinical utility of colon cancer molecular subtypes: Validation of two main colorectal molecular classifications on the PETACC-8 phase III trial cohort.
Authors: Marisa Laetitia , Ayadi Mira , Balogoun Ralyath , Pilati Camilla , Le Malicot Karine , Lepage Come , Emile Jean-François , Salazar Ramon , Aust Daniela Ellen , Duval Alex , Selves Janick , Guenot Dominique Esperance , Milano Gerard A. , Seitz Jean-François , Taieb Julien , Boige Valerie , De Reynies Aurelien , Laurent-Puig Pierre
Published: September 2018

3509

Background: The molecular subtyping of colon cancers (CC) has been the subject of several recent publications, leading to an international consensus. The clinical relevance of these molecular classifications remains to be evaluated on large prospective patient cohorts using a tool that can be widely used on formalin-fixed paraffin-embedded (FFPE) samples. Methods: We aimed to evaluate the clinical relevance of two molecular subtyping systems, CMS (Guinney et al. 2015) and CCMST (Marisa et al. 2013), on the PETACC-8 cohort, a randomized phase III trial comparing adjuvant FOLFOX with or without cetuximab in patients with stage III CC. For each of these two classification systems, a predictor tool was developed and adapted to FFPE samples. The NanoString nCounter platform was used to screen 196 genes. Predictors were built from 249 frozen tumor samples previously used to build our classification system and 61 new paired FFPE/frozen samples. Both predictors were then applied to 1781 PETACC-8 FFPE samples. Subtypes associations to clinical and molecular features were analyzed. Results: The CMS predictor assigned 297 samples to CMS1 (17%), 585 to CMS2 (34%), 68 to CMS3 (4%) and 770 to CMS4 (45%). CMS were significantly associated with several molecular and clinical features, including MSI status (49% in CMS1, p < 0.001), CIMP status (47% in CMS1, p < 0.001), KRAS mutation (75% in CMS3, p < 0.001), BRAF mutation (34% in CMS1, p < 0.001), tumor location (less proximal tumors in CMS2, p < 0.001), validating the predictor tool developed. The classification was significantly associated to prognosis in multivariate analysis, CMS4 subtype having a shorter overall survival (hazard ratio = 1.7, p= 0.021). A deleterious effect of cetuximab was observed in CMS1 (p < 0.05). Similar results were obtained with the CCMST classification. Conclusions: We validated molecular CC subtyping predictors for both CMS and CCMST classifications on PETACC-8 FFPE samples. The prognostic value of CMS and CCMST classifications was confirmed, stem-like tumors being associated with a poor prognosis. These results pave the avenue for widely use of the CC molecular classification in clinical routine.
Analysis of serum vitamin D levels and prognosis in stage III colon carcinoma patients treated with adjuvant FOLFOX+/- cetuximab chemotherapy: NCCTG N0147 (Alliance).
Authors: Sinicrope Frank A. , Shi Qian , Smyrk Thomas C. , Goldberg Richard M. , Heying Erica N , Cohen Steven J. , Gill Sharlene , Kahlenberg Morton S. , Nair Suresh , Shields Anthony Frank , Sargent Daniel J. , Jahagirdar Balkrishna N. , Pollak Michael N. , Alberts Steven R.
Published: September 2018

3516

Background: Epidemiological data suggest a protective effect of vitamin D on CC risk. However, association of serum vitamin D level with clinical outcome in pts with surgically resected CC remains unknown. We analyzed total circulating 25-hydroxyvitamin D [25(OH)D)] with clinical outcome in pts with resected stage III CC treated with FOLFOX +/- cetuximab in a phase III trial. Methods: Association of pre-treatment level of plasma 25(OH)D with disease-free survival (DFS) and time-to-recurrence (TTR) was analyzed with 25(OH)D as a continuous variable by a relative risk model with splines and as a binary variable (vitamin D deficient [<30 ng/mL]) using multivariable Cox regression. Results: Overall, 49% (291/600) of pts were vitamin D deficient. Prevalence of vitamin D deficiency was significantly higher in women vs men (52% vs. 48%, p=0.030) and in blacks vs whites (74% vs. 45%, p=0.0003). The continuous 25(OH)D level and pt sex were associated by the interaction test (pinteraction=0.044). There were no statistically significant associations with DFS/TTR for either continuous 25(OH)D level (DFS, p=0.22; TTR, p=0.26) nor for vitamin D deficiency (DFS, adjusted hazard ratio [HRadj]=1.01, 95% CI, 0.74-1.38; padj=0.94; TTR, HRadj=1.00; CI, 0.72-1.38; padj=0.99. A comparison of the highest vs lowest tertile showed a significant association between the highest 25(OH)D level and better outcomes in men (DFS, HRadj.=0.18, CI, 0.04-0.76, padj=0.020; TTR, HRadj.=0.12, CI, 0.02-0.64, padj=0.014), but not in women (DFS, pinteraction=0.039; TTR, pinteraction=0.033). Conclusions: Nearly one-half of pts in the clinical trial cohort were vitamin D deficient with lowest 25(OH)D levels found in women and blacks. While vitamin D deficiency was not associated with adverse outcome, high levels of vitamin D in men, but not women, were associated with longer survival. Support: U10CA180821, U10CA180882, U10CA180820, U10CA180863, U10CA180888, U10CA077202, CCSRI 021039. ClinicalTrials.gov Identifier: NCT00079274.
Nut consumption and survival in stage III colon cancer patients: Results from CALGB 89803 (Alliance).
Authors: Fadelu Temidayo , Niedzwiecki Donna , Zhang Sui , Ye Xing , Saltz Leonard , Mayer Robert J. , Mowat Rex B. , Whittom Renaud , Hantel Alexander , Benson Al Bowen , Atienza Daniel M. , Messino Michael J. , Kindler Hedy L. , Venook Alan P. , Ogino Shuji , Ng Kimmie , Giovannucci Edward L. , Meyerhardt Jeffrey A. , Bao Ying , Fuchs Charles S.
Published: September 2018

3517

Background: Recent prospective cohort studies suggest states of energy excess and hyperinsulinemia, including type 2 diabetes (T2D), obesity, sedentary lifestyle, Western pattern diet, increased dietary glycemic load, high intake of sugar-sweetened beverages, and elevated plasma C-peptide are each associated with an increased risk of colon cancer (CC) recurrence and mortality. Conversely, observational studies indicate that increasing nut intake is associated with lower risk of T2D, metabolic syndrome and insulin resistance. However, the effect of nut intake on CC recurrence and survival is unknown. Methods: We conducted a prospective, observational study of 826 patients with stage III CC who reported dietary intake with food frequency questionnaires while enrolled in a randomized adjuvant chemotherapy trial. Using Cox proportional hazards regression, we assessed associations of nut intake with cancer recurrence and mortality. The primary endpoint was disease-free survival (DFS) defined as time from completion of dietary questionnaire following adjuvant therapy to cancer recurrence, death or last follow-up. Results: Compared to patients who abstained from nuts, those who consumed ≥ 2 servings of nuts per week had an adjusted hazard ratio (HR) of 0.58 (95% CI, 0.37 to 0.92; Ptrend = 0.03) for DFS and 0.43 (95% CI, 0.25 to 0.74; Ptrend = 0.01) for overall survival (OS). On subgroup analysis, the significant association was confined to tree-nut intake: HR = 0.54 (95% CI, 0.34 to 0.85; Ptrend = 0.04) for DFS and HR = 0.47 (95% CI, 0.27 to 0.82; Ptrend= 0.04) for OS. There was no significant association between intake of peanut or peanut butter and patient outcome. Association of total nut intake with improved outcomes was maintained across other known or suspected predictors of recurrence and mortality, including across common genomic alterations (microsatellite instability, KRAS mutation, BRAF mutation, and PIK3CA mutation). Conclusions: Higher consumption of nuts may be associated with significantly reduced cancer recurrence and death in patients with stage III CC. Support: U10CA180821, U10CA180882, Pfizer. Clinical trial information: NCT00003835.
Profiling circulating tumor (ct)DNA mutations after panitumumab treatment in patients with refractory metastatic colorectal cancer (mCRC) from the phase III ASPECCT study.
Authors: Boedigheimer Michael , Ang Agnes , Price Timothy Jay , Peeters Marc , Kim Tae Won , Gibbs Peter , Thomas Anne L. , Hool Kristina , Bach Bruce A.
Published: September 2018

3523

Background: ASPECCT was a clinical trial performed in the chemotherapy-refractory third-line mCRC setting (N = 1010). This biomarker analysis explores the mutational landscape in panitumumab monotherapy subjects. Analysis of plasma ctDNA at baseline and post-treatment (PT) by next-generation sequencing provides a snapshot of the main changes in key genes before and after therapy. Methods: CtDNA collected at baseline and PT was analyzed for mutations using the Plasma Select-R™ 63-gene panel (0.1% limit of detection). Gain or loss of mutation was defined at the amino acid level. Net change is the sum of mutations gained minus the sum of mutations lost. A single individual could have both net gain and/or net loss of mutations within a single gene. Results: Significant tumor clonal diversification was observed during therapy. In 238 subjects with paired plasma samples,29% of subjects had multiple mutations in the same gene at baseline and 41% of subjects had multiple mutations in the same gene PT. At least 10% of subjects demonstrated an on-therapy acquired mutation in at least one of the following genes: APC, EGFR, ALK, HER4, TP53, AR, KRAS, BRAF, PDGFRA, STK11, ESR1, FBXWT, and KIT (ordered by frequency). New mutations were noted both inside and outside the EGFR pathway. Unexpectedly, patients with a large decrease in mutant DNA burden after anti-EGFR treatment were also seen. EGFR pathway genes with significant net gain were: KRAS, EGFR, NRAS, BRAF, MAP2K1, PIK3CA, and AKT1. Non-EGFR pathway mutations gained included: APC, CDK6, SMARCB1, FBXW7, TERT, RB1, CTNNB1, and IDH1. Conclusions: This 63-gene plasma analysis suggests that there are significant dynamic changes in clonal mutational fraction under anti-EGFR selection. Our analysis reveals that increasing global tumor heterogeneity is associated with poorer overall survival. A subset of patients demonstrated an overall decrease in tumor heterogeneity on panitumumab therapy (28%), indicating that under anti-EGFR selective pressure mutational heterogeneity can also decrease. Clinical trial information: NCT01001377.
Phase 1b/II study of cancer stemness inhibitor napabucasin (BBI-608) in combination with FOLFIRI +/- bevacizumab (bev) in metastatic colorectal cancer (mCRC) patients (pts).
Authors: Bendell Johanna C. , Hubbard Joleen Marie , O'Neil Bert H. , Jonker Derek J. , Starodub Alexander , Peyton James D. , Pitot Henry C. , Halfdanarson Thorvardur Ragnar , Nadeau Benjamin Rolland , Zubkus John D. , Adesunloye Bamidele , Edenfield William Jeffery , Li Youzhi , Li Wei , Grothey Axel , Borodyansky Laura , Li Chiang
Published: September 2018

3529

Background: Cancer stem cells are considered to be fundamentally important for resistance, recurrence and metastasis. Napabucasin is a first-in-class cancer stemness inhibitor in development identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al, PNAS 112(6):1839, 2015). Preclinically, napabucasin sensitizes cancer cells to chemotherapy and targeted agents. Methods: A phase Ib/II multi-center study in mCRC pts was done to confirm the RP2D and signs of anti-cancer activity of napabucasin in combination with FOLFIRI +/- Bev. Pts received napabucasin 240 mg PO BID with bi-weekly FOLFIRI IV +/- Bev 5 mg/kg until disease progression or other discontinuation criterion. Results: 82 pretreated mCRC pts were enrolled (ITT); including 32 (39%) previously treated with FOLFIRI +/- bev. Of the 82 pts, 48 received FOLFIRI and 34 FOLFIRI plus bev in combination with napabucasin. There was no dose-limiting or unexpected toxicity or significant PK interactions. Most common adverse events (AEs) included grade 1/2 diarrhea, cramping, nausea, vomiting, fatigue and anorexia with grade 4 diarrhea in 1 pt and 27 pts with grade 3 AEs including: diarrhea (15), fatigue (5), dehydration (1), electrolyte imbalance (4), abdominal pain (1), vomiting (1) and weight loss (1), which resolved with dose reduction and supportive care. Disease control (CR+PR+SD) was observed in 55 of 66 pts who received RECIST evaluation (83%), with 1 CR (1.5%), 13 PR (20%) (33-100% regression) and 27 SD with tumor regression (41%). Conclusions: This phase Ib/II study confirmed that napabucasin can be safely combined with FOLFIRI +/- bev, and shows encouraging signs of efficacy in pretreated mCRC pts, including pts previously treated with FOLFIRI +/- bev. Clinical trial information: NCT02024607. [Table: see text]
A phase II study of pembrolizumab in combination with mFOLFOX6 for patients with advanced colorectal cancer.
Authors: Shahda Safi , Noonan Anne M. , Bekaii-Saab Tanios S. , O'Neil Bert H. , Sehdev Amikar , Shaib Walid Labib , Helft Paul R. , Loehrer Patrick J. , Tong Yan , Liu Ziyue , El-Rayes Bassel F.
Published: September 2018

3541

Background: Pembrolizumab (PEM) has activity in patients with deficient mismatch repair (dMMR) colorectal cancer (CRC). Oxaliplatin (OX) and 5FU lead to immunogenic cell death and increased antigen presentation. We hypothesized that combining mFOLFOX6 and PEM may enhance immunogenic cell death and improve outcome in patients with CRC irrespective of MMR status. Methods: Subjects ≥18 years old with untreated, unresectable CRC were assigned to a single arm study. The study had a safety run in cohort of six patients (OX 85 mg/m2, leucovorin 400 mg/m2, 5FU 400 mg/m2, 5FU infusion 2400 mg/m2over 46 hours) and PEM 200 mg Q 3 weeks, followed by a phase II cohort. The primary objective was median progression free survival (mPFS), with secondary objectives: safety and toxicity per CTCAE V4.03, median overall survival, response rate, immune related response, disease control rate, and molecular correlates. Results: Between 4/2015 and 9/2016, 30 subjects were enrolled with following characteristics: 11 female, 26 Caucasian, median age: 45 years (25-75), 3 with dMMR, 22 MMR-proficient, and 5 with no available data. During the safety run in, 2 patients had G3 febrile neutropenia (FN) and 1 G4 neutropenia. The data safety monitoring committee recommended dose reduction of mFOLFOX6 to OX 68 mg/m2, leucovorin 400 mg/m2, 5FU of 320 mg/m2, 5FU infusion of 1920 mg/m2over 46 hours and PEM 200 mg Q 3 weeks. At the data cut off (12/29/16), median follow up was 24 weeks (10-66) and 27 patients remained on study. Rate of G3/4 toxicity associated with FOLFOX/PEM and PEM alone was 36.7% and 13.2%, respectively. No further FN was observed. No grade 5 toxicity was seen on study. Best response was recorded as: 1 complete response, 15 partial response (CR +PR = 53%), and 14 stable disease, with 100% DCR at 8 weeks. One patient with dMMR had resection after 2 months of therapy with complete pathologic response. MPFS has not been reached (95% CI: 5.5 months, NR). Conclusions: Based on these preliminary results, PEM/mFOLFOX6 has acceptable toxicity though demonstrated a suggestion of increased neutropenia in the initial cohort. Clinical activity was seen in patients with untreated advanced CRC including those with proficient MMR. Clinical trial information: NCT02375672.
Bevacizumab combined with first-line chemotherapy in elderly patients (≥75 years old) with metastatic colorectal cancer: Final results of the noninterventional CASSIOPEE study.
Authors: Francois Eric , Smith Denis Michel , Gourgou Sophie , Gandon Sophie , Rollot Florence , Mineur Laurent
Published: September 2018

3547

Background: Approximately half of the patients (pts) with metastatic colorectal cancer (mCRC) are elderly (≥65 years). Although few elderly pts are included in clinical studies, results in mCRC have shown similar treatment benefits in terms of progression-free survival and overall survival in young and elderly pts. This study was conducted in pts ≥75 years-old with mCRC treated in real life 1st line bevacizumab + chemotherapy in order to improve the knowledge on this population and to contribute in optimizing treatment strategy. Methods: CASSIOPEE is a prospective, multicenter, non-interventional study evaluating 1st line combination of bev + chemotherapy over 24 months in pts aged ≥75 years with mCRC. The primary endpoint was to describe progression-free survival (PFS). Secondary endpoints included the description of pts characteristics, overall survival, bev and chemotherapy regimen, safety and autonomy criteria (Lawton Instrumental Activities of Daily Living Scale; Balducci score). Results: A total of 402 pts were included between March 2012 and July 2016. In the efficacy population (n = 358), 52% were men, mean age 81 (±4); 54% were≥ 80 years old and 19% were ECOG ≥2; 80% had primary tumor located in the colon; main metastatic sites: liver (66%) and lung (30%). Bev was mainly combined with Folfox (36%) and Folfiri (29%). Median PFS was 9.1 months [8.3;10.2] in the efficacy population and 9.3 months for pts aged < 80, 9.5 months for pts aged ≥ 80 or ≤ 85 and 8.3 months for pts aged > 85. The PFS rate at 24 months was 11.8%. Median OS was 19.0 months [16.5;21.5] in the efficacy population and 20.6 months for pts aged < 80, 17.8 months for pts aged ≥ 80 or ≤ 85 and 13.0 months for pts aged > 85. The OS rate at 24 months was 42.0%. Autonomy and ECOG status remained stable from baseline to 24 months. In the safety population (n = 383), grade ≥ 3 adverse events occurred in 40% pts including 10% pts with bev related AEs. Overall, 4% pts died of an AE and 0.5% were bev related. Conclusions: These results suggest that mCRC patients aged ≥75 years-old, can benefit from 1st line bev plus chemotherapy in daily practice in this population. The safety profile is acceptable. Clinical trial information: NCT01555762.
An open-label expanded-access study of trifluridine/tipiracil for metastatic colorectal cancer.
Authors: Mayer Robert J. , Grothey Axel , Hochster Howard S. , Cohen Steven J. , Vukovic Vojislav M. , Makris Lukas
Published: September 2018

3559

Background: A Phase 3 clinical trial (RECOURSE) showed that trifluridine/tipiracil (FTD/TPI) was effective in the treatment of refractory metastatic colorectal cancer (mCRC) treated with standard chemotherapy and targeted-therapy drugs (Mayer et al. N Engl J Med 2015;372:1909-19). An expanded-access program (EAP) was started to provide access to FTD/TPI for patients with mCRC with similar eligibility and to further assess the safety of FTD/TPI in a “real-world” setting in US patients. Methods: Patients aged ≥18 years with refractory mCRC resistant to ≥2 regimens of standard chemotherapy with appropriate biologics and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled to this open-label EAP. Patients received FTD/TPI 35 mg/m2twice daily for 5 days followed by 2 days’ rest repeated twice followed by 14 days’ rest over a 28-day treatment cycle until drug discontinuation. Sites reported duration of therapy, discontinuation due to disease progression, and adverse events (AEs) for each patient. Results: 549 patients were enrolled; 53.2% were male. Median duration of FTD/TPI therapy was 9.7 weeks, which was similar to US patients from RECOURSE (8.9). 10.2% of patients died during the study period, 9.7% due to disease progression. 76.1% of patients discontinued treatment due to disease progression and 4% discontinued due to AEs. Drug-related clinically significant AEs (all grades) are summarized in the table. Conclusions: Patients with refractory mCRC in this EAP had a similar exposure duration to that reported in US patients from RECOURSE, with no unexpected safety concerns. While gastrointestinal toxicity was lower in this population, this may be due to reporting of “significant” events. The clinical profile of FTD/TPI is confirmed in this larger, non-randomized “real-world” experience. Sponsorship: Taiho Oncology, Inc. Editorial Assistance: Complete HealthVizion. Clinical trial information: NCT02286492. [Table: see text]
The outcome of patients (pts) with metastatic colorectal cancer (mCRC) based on site of metastases (mets) and the impact of molecular markers and site of primary cancer on metastatic pattern.
Authors: Prasanna Thiruvarudsothy , Craft Paul Stanley , Chua Yu Jo , Karapetis Christos Stelios , Gibbs Peter , Wong Rachel , Tie Jeanne , Roder David , Price Timothy Jay , Padbury Rob , Piantadosi Cynthia , Yip Desmond
Published: September 2018

3560

Background: Although liver is the commonest site of mets in pts with CRC, pattern of spread is variable and may reflect different biology in different subsets of pts. Methods: This is a retrospective analysis to explore the outcome of pts with mCRC based on their site of mets at diagnosis and to identify tumor characteristics which could predict the site of mets. Pts from 2 Australian databases, BioGrid (BG) and South Australian Cancer Registry (SA), from 01/2006 to 12/2015 were grouped into 5 cohorts; lung only, liver only or any pts with brain, bone or peritoneal mets. Overall survival (OS) for each group was compared with the rest of the sample using Kaplan Meier analysis and the log rank test separately in each dataset. Mantel-Haenszel Chi-squared test was performed in pooled data to assess the association between KRAS, BRAF, Micro satellite instability (MSI), site of primary and site of mets. Results: 5967 pts were included. In both datasets median OS was significantly higher when mets were limited to lung or liver and shorter for those with brain, bone or peritoneal mets. BRAF, KRAS and MSI data were available for 20%, 37% and 21% of the sample. In the pooled analysis BRAF mutation was associated with brain (Relative Risk=5.2) and peritoneal mets (RR=1.8) with lower incidence of lung (RR=0.3) and liver (RR=0.7) limited mets. KRAS mutation was associated with lung only mets(RR=1.4). Left colon tumors were associated with bone (RR=1.6) and lung only mets (RR=2.3) while peritoneal spread was less frequent compared with right colon tumors(RR=0.6). Rectal cancer was strongly associated with brain, bone and lung mets (RR=1.7, 1.7, 2.0). MSI status was not associated with site of mets though liver only mets was less frequent in MSI high tumors. Conclusions: Survival duration with mCRC is related to the site of mets. OS was significantly better when mets were confined to either lung or liver. BRAF mutation and primary rectal cancer were associated with poor prognostic metastatic sites like brain and bone. [Table: see text]
Rapid in vitro evaluation of immune responses to tumor-derived organoids as an adjunct to immunotherapy trials.
Authors: Ramsay Robert George
Published: September 2018

3573

Background: Cancer immunotherapy has made rapid advances with the development of agents that subvert the negative arm of the immune system. This has been important because patients can mount anti-tumor immune responses. In the case of colorectal cancer (CRC), the presence of tumour infiltrating lymphocytes (TILs) appears to have predictive power regarding outcome. Nevertheless, assays that directly evaluate the quality, phenotype and anti-tumor activity of TILs are lacking. Here a novel immune assay platform is presented that measures the kinetics of TIL killing which correlates with pathological tumour response after treatment. Methods: Treatment naïve fresh cancer biopsies were processed to generate organoids and TILs from patients (n = 12) with pathological complete response (pCR) verses non-responding tumours (NRT). These were co-cultured with TILs to organoid ratios of 1:1, 5:1 and 10:1 for 48 hs and TILs function were measured by cytokine release and mean fluorescence intensity (MFI) based upon activated caspase activity. Additionally, TILs from patients with metastatic CRC (n = 20) have also been evaluated. Results: Ten thousand+ organoids are routinely cultured while millions of TILs are retrieved and expanded from biopsies. TIL-mediated killing of patient-matched tumor organoid confirm CD8+ve specific killing. At 24hrs MFI was significantly higher in pCR organoid indicative of immune-mediated cell death compared to NRT organoids at a ratio of 1:1. The efficiency of TIL killing was further enhanced as the ratio increased to 5:1 and 10:1. Gamma interferon production by cytotoxic (CD8+) T-cell is a robust measure of TIL activation state and was also significantly higher by pCR TILs compared to NRT TILs. Substantive differences in TIL subsets were also found in mCRC-derived samples compared to primary CRC. Conclusions: This is a novel functional immune assay and the first of its kind that successfully demonstrated the differences in patient-matched TIL killing between non-responding and responding CRC. This assay can be performed within in two weeks and thus it has translational potential that may change clinical management in the future and immunotherapy strategy design.
Extraordinary survivorship after colorectal liver metastasis resection to identify a distinct molecular profile associated with survival in an independent cohort of 965 patients.
Authors: Smith Jesse Joshua , Kandoth Cyriac , McAuliffe John Christopher , Vakiani Efsevia , Frankel Timothy , Wasserman Isaac , Chatila Walid , Lipsyc Marla , Balachandran Vinod P. , Allen Peter J. , DeMatteo Ronald P. , Kingham T. Peter , Jarnagin William R. , Schultz Nikolaus , Kemeny Nancy E. , Garcia-Aguilar Julio , Taylor Barry S. , Solit David B. , Yaeger Rona , D'Angelica Michael Ian ,   MSK Collaborators: Agnes Viale, PhD, Karuna Ganesh MD, PhD, Garrett M. Nash MD, MPH, Jose G. Guillem MD, Philip B. Paty MD, Martin R. Weiser MD, Leonard Saltz MD, Michael Berger PhD and Charles L. Sawyers MD
Published: September 2018

3581

Background: Half of patients diagnosed with colorectal cancer (CRC) develop metastases and most are CRC liver metastasis (CRLM). A mere 20% of these patients undergo complete resection of their liver disease and 5-year overall survival (OS) is only 50%. We hypothesized that we could identify a specific molecular profile associated with extraordinary survivorship in CRLM patients that would more precisely inform underlying tumor biology beyond standard clinical and pathologic features. Methods: Tumor samples were identified from patients who underwent curative resection. Patients with disease-specific survival (DSS) ≥10 years following resection were compared to those with ≤2-year survival (10yr vs. 2yr). Evaluable DNA was obtained from 36 cases (2yr, n = 17; 10yr, n = 19) then sequenced and analyzed with MSK-IMPACT (MSK-I), a hybridization capture, next generation sequencing platform. Differentially altered genes in 10yr vs. 2yr cohorts were identified (Fisher’s exact). Findings in the extraordinary survivors group were validated using MSK-I in an independent cohort of 965 metastatic CRCs (metCRCs). Kaplan-Meier estimates and log-rank test were used. Results: In the 2yr group, we noted higher clinical risk scores and more complex chemotherapy regimens vs. the 10yr group. Molecularly, mutually exclusive KRAS and TP53 mutations were noted in the 10yr group, whereas significant co-occurrence of KRAS and TP53 mutations was seen in the 2yr group. Further, we noted significant enrichment of VEGF copy number gains in the 2yr group vs. the 10yr group. APC mutation was equally common. In the validation cohort, KRASmut/TP53wt and TP53mut/KRASwt patients (median OS of 10 and 15 years respectively) had significantly better OS than the co-occurring KRASmut / TP53mutpatients (median OS of 4.9 years; (P = 0.0001)). Conclusions: Single mutation of either KRAS or TP53 is associated with better outcomes than co-occurring KRAS/TP53 mutations in metCRC. These data demonstrate use of an extraordinary survivor cohort to identify a molecular profile associated with significant survival differences in an independent cohort of metCRC patients.
Factors contributing to the black/white colorectal cancer survival disparity in nonelderly patients.
Authors: Sineshaw Helmneh M. , Ng Kimmie , Flanders W. Dana , Brawley Otis W. , Jemal Ahmedin
Published: September 2018

3587

Background: Previous studies reported that black/white survival disparities among elderly colorectal cancer (CRC) patients largely reflect differences in tumor presentation rather than differences in treatment. We sought to determine the contribution of differences in tumor presentation and receipt of treatment to the black/white survival disparity among nonelderly CRC patients. Methods: We selected non-Hispanic black (black) and Non-Hispanic white (white) patients aged 18-64 years, and diagnosed between 2004-2012 with single or first primary invasive stage I-IV CRC in the National Cancer Data Base. Blacks were sequentially matched with three white comparison cohorts, using propensity score and greedy matching algorithm, by demographics (age, sex, diagnosis year, region), tumor presentation (stage, grade, margin, tumor location, node status, comorbidity score), and treatment (surgery, chemotherapy, radiotherapy, metastatectomy) characteristics. We used Kaplan-Meier method to estimate 5-year survival for blacks compared with whites in the entire cohort and in the three sequentially matched cohorts. Results: In the entire cohort, 5-year survival was 9.2% lower in nonelderly blacks than whites (57.3% vs 66.5%). The survival difference remained unchanged after demographic matching, but it decreased to 3.3% (5.9% absolute and 64% relative reductions) after tumor presentation matching, and to 2.6% (0.7% absolute and 7.6% relative reductions) after treatment matching. By anatomic subsite, treatment matching reduced the black/white 5-year survival difference by 26% (3%/11.5%) for rectal cancer, only by 5.6% (0.5%/9%) for left colon cancer, and no change for right colon cancer. Conclusions: Differences in tumor presentation characteristics explained about two-thirds of the black/white survival disparity in nonelderly CRC patients, while treatment explained less than ten percent of the disparity. Future research should explore the biological mechanisms underlying these observed differences in tumor presentation and implications for treatment.
Genetic polymorphisms of CCL5 and CCR5 to predict efficacy of cetuximab-based treatment in metastatic colorectal cancer patients depending on primary tumor location.
Authors: Suenaga Mitsukuni , Cao Shu , Stintzing Sebastian , Zhang Wu , Yang Dongyun , Ning Yan , Okazaki Satoshi , Berger Martin D. , Miyamoto Yuji , Schirripa Marta , Gopez Roel , Melendez Elizabeth , Soni Shivani , Barzi Afsaneh , Yamaguchi Toshiharu , Heinemann Volker , Lenz Heinz-Josef
Published: September 2018

3594

Background: EGFR signaling blockade increases CCL5 expression, which attracts with tumor-infiltrating leukocytes regulating either the host-derived anti-tumor immunity or tumor progression. We tested whether genetic polymorphisms in the CCL5/CCR5 axis could predict efficacy of cetuximab (CET)-based first-line treatment in metastatic colorectal cancer (mCRC) patients (pts). Methods: Genomic DNA was extracted from 491 samples of two different cohorts with KRAS wild-type mCRC in the FIRE-3 study: an evaluation cohort of 244 pts receiving CET plus FOLFIRI (median age 64 yrs; median follow-up 34.1 mos); and a control cohort of 247 pts receiving bevacizumab plus FOLFIRI (median age 65 yrs; median follow-up 39.4 mos); Single nucleotide polymorphisms (SNPs) of CCL5 and CCR5 genes were analyzed by PCR-based direct sequencing. Results: Pts in the evaluation cohort with any CCL5 rs2280789 G allele had shorter OS compared to those with the A/A variant (19.9 vs. 33.4 mos, HR 1.56, 95%CI: 1.05–2.30, P= 0.024), which was confirmed in multivariable analysis (HR 1.64, P= 0.015). Pts carrying any CCR5 rs1799988 T allele had a trend lower response rate than those with the C/C variant (68 vs. 81%, P= 0.078). Statistically significant differences in efficacy were shown between the groups consisting SNPs and tumor location (Table). The findings were not confirmed in the control cohort. Conclusions: Genetic variants of CCL5 and CCR5 SNPs may predict outcomes in mCRC pts receiving CET-based first-line treatment depending on tumor location. [Table: see text]
Survival prediction in patients treated by FOLFIRI and bevacizumab for metastatic colorectal cancer (PRODIGE 9) using contrast-enhanced CT texture analysis (SPECTRA).
Authors: Dohan Anthony , Gallix Benoit , Guiu Boris , Le Malicot Karine , Reinhold Caroline , Soyer Philippe , Bennouna Jaafar , Ghiringhelli Francois , Boige Valerie , Taieb Julien , Bouche Olivier , Francois Eric , Phelip Jean Marc , Borel Christian , Faroux Roger , Seitz Jean-François , Jacquot Stephane , Lepage Come , Aparicio Thomas , Hoeffel Christine
Published: September 2018

3601

Background: Quantitative assessment of tumor architecture changes may help to early identify non-responder patients and propose a tailored treatment strategy. Our objective was to build and validate a radiomics signature able to predict early the lack of response to chemotherapy including FOLFIFRI and bevacizumab using baseline and first evaluation CT and to compare it to the RECIST and morphological criteria. Methods: For 230 patients of PRODIGE 9 study and treated by FOLFIRI and bevacizumab, a computed analysis (CA) was performed on the dominant liver lesion (DLL) at baseline and 2 months post-chemotherapy. RECIST evaluation was performed at 2 and 6 months. The sum of the target liver lesions (STL), the density of the DLL, CA parameters and their changes rates were correlated with the 2-year survival status. A radiomics signature combining 3 parameters was built in one arm and validated in the second arm. Survival was estimated with the Kaplan-Meier method and compared with log-rank test. Results: The strongest predictive factors for 2-year survival status were decrease in STL(AUC = .69±.05[95%CI:.60-.77]), change rate in kurtosis(ssf = 0) (AUC = .66±.05[95%CI:.57-.74]), and the baseline density of the DLL (AUC = .68±.05[95%CI:.59-.77]). Using multivariate analysis, predictive factors of 2-year survival status were the decrease in STL > 15%(HR = 1.92, P= .002), the increase in kurtosis value(ssf = 0) > 93% (HR = 2.16, P= .001), and baseline DLL > 64.3UH (HR = 1.70, P= .02). Then, the SPECTRA-score was built by according 1 point for each of the 3 criteria. Patients with a SPECTRA-score > 1 had a lower overall survival in the training ( P= .001) and in the validation cohort ( P= .002). Non-response according to RECIST at 6 months had the same prognostic value as SPECTRA-score>1 at 2 months. Conclusions: A radiomics signature combining STL, density and CA on baseline and first evaluation CT is be able to predict which patient will have a poor outcome with same performances than standard evaluation with RECIST1.1 at 6 months in mCRC patients. Clinical trial information: NCT00952029.