bluuebunny/crossref_metadata_2025 huggingface dataset:
Targetable immune checkpoint molecules may be significantly differentially expressed in minority ethnicities.
Authors: Adashek Jacob J. , Szeto Christopher , Sanborn J. Zack , Reddy Sandeep K. , Toor Amir A. , Danielides Stamatina , Smith Steven , Grossman Steven R. , Clevenger Charles V , Faber Anthony , Ferreira-Gonzalez Andrea , Boikos Sosipatros Alexandros
Published: May 2020

3576

Background: Studies of immune checkpoint blockade therapy (ICT) outcomes have been largely performed in melanoma and lung cancer patients, both of which are enriched for White patients. For example, a National Cancer Database study found that 97% of first-line ICT treatments in melanoma have been administered to White recipients (Patel, ASCO-SITC 2020). Given expanding indication in tumor types affecting more diverse populations, we sought to study whether minority populations might be projected to have differing checkpoint blockade response rates. Methods: Ethnicity information and RNAseq expression profiles and primary site information were obtained for 7087 patients from TCGA. Ethnicity was tested for association with RNA expression of targetable checkpoint genes ( PD1, PDL1, PDL2, CTLA4, IDO1, LAG3, TIM3, TIGIT, OX40, VISTA, and GITR) in 5 tumor histology types by Wilcoxon methods with Benjamini-Hochberg correction for multiple hypothesis testing. A dataset of > 2700 cases was obtained from NantHealth, with paired whole exome/RNAseq data. Ethnicity for 579 patients was assigned using allele-fraction from ~250 single nucleotide polymorphic sites found exclusively in 6 populations within the 1000 Genomes project. Ethnicity/checkpoint associations found in TCGA were tested within this dataset. Results: Within the TCGA cohort, ethnicity was not a factor in differential expression of checkpoint molecules in lung cancer. Within melanomas, in Asian patients PDL1, CTLA4, and IDO1 were expressed at lower levels than in White patients (each p = 0.04). These associations did not remain significant after correction for multiple hypothesis testing. Breast cancers in Black patients had significantly higher PD1, CTLA4, IDO1, LAG3, GITR, and OX40 expression compared to White patients, all remaining significant after correction (adj. p 3.7e-5 to 6.4e-3). Among White patients, colon cancers showed higher expression of PDL1/2, IDO1, LAG3, TIM3, and GITR (p 0.04 to 0.0017). IDO1 was significantly higher in White patients even after correction (adj. p = 0.03), and lower in Black patients (adj. p = 0.03). Conclusions: Ethnicity may represent a significant factor for efficacy checkpoint blockade therapies. White breast cancer patients might be anticipated to exhibit reduced sensitivity to PD1/CTLA4 blockade, while Black colon cancer patients may exhibit reduced sensitivity to IDO1 therapies such as epacadostat. A biomarker-driven approach to patient selection may ameliorate ethnic disparities in ICT outcomes.
Phase I study of IM156, a novel potent biguanide oxidative phosphorylation (OXPHOS) inhibitor, in patients with advanced solid tumors.
Authors: Rha Sun Young , Beom Seung-Hoon , Shin Young Geun , Yim Dong-Seok , Moon Yong Wha , Kim Tae Won , Kim Sun Young , Kim Gun Min , Kim Hyo Song , Cheong Jae-Ho , Lee Young Woo , Geiger Barbara Jean , Yoo Sanghee , Rudoltz Marc S. , Janku Filip
Published: May 2020

3590

Background: IM156, a novel oral potent biguanide OXPHOS inhibitor of Protein Complex 1 (PC1) of the mitochondrial electron transport chain, causes AMPK phosphorylation, the downstream effects of which are detrimental to OXPHOS-dependent cancer cells prone to energy stress. Preclinical experiments with IM156 demonstrated activity in solid tumor and hematologic malignancy models as a single-agent and in combinations. Methods: This was an open label, first-in-human, multi-center, dose-escalation study ( NCT03272256 ) using a 3+3 design. The primary endpoint was to determine the maximum tolerated dose and/or recommended Phase 2 dose (RP2D) based on dose limiting toxicities (DLT), safety and tolerability. Secondary endpoints included pharmacokinetics (PK), pharmacodynamics (PD) and preliminary signals of efficacy. Eligible patients were adults with advanced solid tumors refractory to standard therapies with ECOG Performance Status <2, adequate organ function, and measurable disease (RECIST 1.1 or RANO [gliomas]). IM156 was administered orally every other day (QOD) or daily (QD) in 28-day cycles. Results: 22 patients (gastric cancer: N = 8; ovarian cancer: N = 3; colorectal cancer: N = 3; endometrial cancer: N = 2; sarcoma: N = 2; other: N = 4) were enrolled in 7 dose cohorts (100, 200, 400, 800, and 1,200 mg QOD; 800 and 1,200 mg QD). The most frequent treatment-related adverse events (TRAEs) were gastrointestinal (nausea [N = 16, 73%], diarrhea [N = 12, 55%], and vomiting N = 11, 50%]). Nausea, reported in 3 (14%) patients, was the only Grade 3 TRAE. No DLTs were reported; the RP2D declared was 800 mg as 1,200 mg QD was associated with Grade 2/3 nausea requiring dose modifications. PK demonstrated dose-proportional increases in Cmax and AUC0-last reaching the expected efficacious range. PD demonstrated a decrease in tumor growth rate in 3 patients (1,200 mg QOD: N = 2; 800 mg QD: N = 1), and a decrease in VEGF and tumor markers in a patient with gastric cancer with neuroendocrine differentiation treated at 800 mg QD who remains on study in Cycle 11. Best response was stable disease in 7 (32%) patients. Conclusions: IM156 is the first PC1 OXPHOS inhibitor to have been successfully tested in patients with cancer with the identification of a RP2D. It was well tolerated at dose levels active in preclinical models, and demonstrated modest clinical activity in an unselected population of patients. Subsequent development will focus on OXPHOS-dependent tumors and in combinations with agents in which OXPHOS metabolism is a mechanism of resistance. Clinical trial information: NCT03272256 .
IGM-8444 as a potent agonistic Death Receptor 5 (DR5) IgM antibody: Induction of tumor cytotoxicity, combination with chemotherapy and in vitro safety profile.
Authors: Wang Beatrice , Wang Ling , Kothambawala Tasnim , Calhoun Susan , Matthew Thomas , Hernandez Genevive , Peterson Marvin , Sinclair Angus , Humke Eric William , Keyt Bruce
Published: May 2020

3595

Background: Death receptor 5 (DR5) is a member of the tumor necrosis factor (TNF) receptor superfamily that multimerizes when bound to its ligand, TNF-related apoptosis inducing ligand (TRAIL), to activate the extrinsic apoptotic pathway. DR5 is broadly expressed on solid and hematologic cancers and has been targeted with both recombinant TRAIL and agonistic antibodies in the clinic. However, these therapeutics have generally been unsuccessful due to toxicity or lack of efficacy. We have developed a multivalent IgM DR5 agonist, IGM-8444, that multimerizes DR5 to selectively and potently induce tumor cell apoptosis while maintaining tolerability. Methods: IGM-8444 is an engineered, pentameric IgM antibody with 10 binding sites specific for DR5. Human tumor cell lines or hepatocytes were evaluated in vitro for dose dependent IGM-8444 induced cytotoxicity. The efficacy of IGM-8444 was evaluated with or without chemotherapy, in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse tumor models, with IGM-8444 administered at various dose levels and schedules when tumors reached approximately 100 mm3. Sera and tumors were analyzed for biomarkers of tumor apoptosis. Results: In vitro cytotoxicity assays identified IGM-8444 activity across cell lines from 18 solid and hematologic malignancies. In IGM-8444 partially resistant cell lines, combination with chemotherapy or a Bcl2 inhibitor enhanced in vitro cytotoxicity. IGM-8444 was efficacious as a monotherapy in CDX and PDX tumor models including colorectal, lung, and gastric indications. In a gastric PDX model, IGM-8444 induced complete and durable dose-dependent tumor regressions. In vivo, combination of IGM-8444 with standard-of-care chemotherapies, such as irinotecan, led to enhanced efficacy. IGM-8444 administration increased markers of tumor apoptosis, identifying potential clinical pharmacodynamic biomarkers. At doses several log-fold higher than efficacious doses, IGM-8444 demonstrated a favorable single agent in vitro safety profile, with little to no in vitro cytotoxicity observed using primary human hepatocytes from multiple donors. Conclusions: These data support the clinical development of IGM-8444 in both solid and hematological malignancies as a single agent and in combination with standard of care therapy. IGM-8444 is projected for IND filing in 2020.
Preliminary clinical pharmacokinetics and dose-response to support a phase II dose selection for CX-2009: A masked probody drug conjugate to CD166.
Authors: Stroh Mark , Li Rachel , Lu Hong , Wada Russ , Richardson Jennifer Hope , Frye John W. , Peterson Amy C.
Published: May 2020

3599

Background: PROBODY therapeutics are antibody prodrugs with cleavable peptide masks designed to reduce off-tumor, on-target toxicities. The mask blocks binding in the periphery and is removed by tumor-associated proteases resulting in intratumoral binding. CX-2009 is a PROBODY drug conjugate directed against CD166/ALCAM, which is a target overexpressed in carcinomas but not suitable for traditional ADC targeting because it is expressed in normal epithelium. CX-2009 is conjugated to DM4, a potent microtubule inhibitor. Here we report preliminary clinical pharmacokinetic (PK) and exploratory dose-response (DR) analyses for CX-2009 from the ongoing phase 1/2 PROCLAIM-CX-2009 study (NCT03149549). Methods: Human PK and anti-drug antibody (ADA) data were obtained at selected times post-dose following IV 0.25–10 mpk CX-2009 Q3W and of 6 mpk Q2W. Covariates were selected for population PK (POPPK) based on multivariate screening at P< 0.01. Preliminary exploratory DR analyses were conducted for selected endpoints including adverse events of special interest and response data (CR, PR, SD, and PD). Results: Preliminary CX-2009 PK data from 92 subjects were available as of October 2019. Median free DM4 levels circulated at ≤0.3% of Total CX-2009 (masked + activated CX-2009) levels across the 1–10 mpk dose levels. A two-compartment POPPK model with linear elimination was fit to the Intact (masked form) CX-2009 data. The preliminary CX-2009 POPPK model estimates for Intact CX-2009 clearance (CL), volume of distribution, and half-life were 0.47 L/day, 4.51 L, and 7.14 days, respectively, with 91% of CX-2009 circulating as Intact CX-2009. ADA was not a statistically significant covariate on Intact CX-2009 CL. Evidence of clinical activity was observed at doses of 4 mpk Q3W or higher. DR analysis suggested that the frequency of grade ≥3 ocular toxicity events increased significantly at dose equivalents ≥8 mpk Q3W. POPPK simulations suggested that the targeted 90 nM trough concentration (based on nonclinical data) would be contained within the 90% prediction interval of predicted Intact CX-2009 levels following CX-2009 7 mpk. Conclusions: Preliminary CX-2009 PK data following CX-2009 0.25-10 mpk suggest that CX-2009 circulates predominantly as Intact CX-2009, and that Intact CX-2009 PK is not strongly influenced by target-mediated drug disposition or ADA. Preliminary DR and POPPK simulations support further evaluation of 7 mpk CX-2009 Q3W in selected cohort expansions. Clinical trial information: NCT03149549 .
Efficacy and safety of entrectinib in patients (pts) with NTRK-fusion positive (NTRK-fp) solid tumors: An updated integrated analysis.
Authors: Rolfo Christian Diego , De Braud Filippo G. , Doebele Robert Charles , Drilon Alexander E. , Siena Salvatore , Patel Manish , Cho Byoung Chul , Liu Stephen V. , Ahn Myung-Ju , Chiu Chao-Hua , Farago Anna F. , Goto Koichi , Lee Jeeyun , Bazhenova Lyudmila , John Tom , Fakih Marwan , Simmons Brian P. , Pitcher Bethany , Huang Xinhui , Demetri George D.
Published: May 2020

3605

Background: NTRK gene fusions lead to transcription of chimeric TRK proteins with overexpressed kinase function. Entrectinib is a potent inhibitor of TRKA/B/C. In phase 1/2 studies (ALKA, STARTRK-1, STARTRK-2; EudraCT 2012-000148-88; NCT02097810; NCT02568267), entrectinib was effective in pts with NTRK-fp solid tumors. We present updated data in a larger population with longer follow-up. Methods: In this integrated analysis of adult pts from 3 phase 1/2 trials (data cut-off 31 Oct 2018), tumors were assessed by blinded independent central review (BICR) with RECIST v1.1 (end of cycle 1; then every 8 wks). Primary endpoints were overall response rate (ORR) and duration of response (DOR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), efficacy in pts with/without baseline CNS disease, and safety. Results: There were 74 evaluable pts with advanced/metastatic NTRK-fp solid tumors (Table). Median duration of survival follow-up in all pts was 14.2 mo (range 0.1–29.7). BICR ORR was 63.5% (95% CI 51.5–74.4), with 5 complete responses (6.8%). Median BICR DOR was 12.9 mo (95% CI 9.3–NE); median BICR PFS was 11.2 mo (95% CI 8.0–15.7); median OS was 23.9 mo (16.0–NE). In pts with no baseline CNS disease (investigator-assessed; n=55), BICR ORR was 65.5% (95% CI 51.4–77.8) and median BICR DOR in responders was 12.9 mo (95% CI 9.3–NE). In pts with baseline CNS disease (investigator-assessed; n=19), BICR ORR was 57.9% (95% CI 33.5–79.8) and median BICR DOR in responders was 6.0 mo (95% CI 4.2–NE). Safety was in line with that previously reported; the most common ≥grade 3 treatment-related AEs were weight gain (8, 7.1%), anemia (8, 7.1%), and fatigue (7, 6.2%). Conclusions: In this updated analysis, including more pts and longer follow-up, entrectinib continued to demonstrate clinically meaningful responses in pts with NTRK-fp solid tumors, with and without baseline CNS disease. Clinical trial information: NCT02097810, NCT02568267 . [Table: see text]
CTEP 9557: A dose-escalation trial of combination dabrafenib, trametinib, and AT13387 in patients with BRAF mutant solid tumors.
Authors: Mooradian Meghan , Cleary James M. , Cohen Justine Vanessa , Lawrence Donald P. , Buchbinder Elizabeth Iannotti , Giobbie-Hurder Anita , Parikh Aparna Raj , Shapiro Geoffrey , Darville Lancia , Smalley Keiran , Koomen John M , Newton Amber , Keer Harold N. , Ivy S. Percy , Chen Helen X. , Sullivan Ryan J.
Published: May 2020

3609

Background: Combination BRAF and MEK inhibitor therapy is associated with response in patients (pts) with BRAF mutant (mut) solid tumors; however critical limitations for the durable activity of these agents remains. Preclinically, the addition of heat shock protein 90 (HSP90) inhibitors improves the efficacy of BRAF inhibitor (BRAFi) therapy in both BRAFi -sensitive and resistant mutant cell lines. Methods: CTEP study 9557 (NCT02097225) is a phase I study designed to determine the safety and efficacy of the small molecule HSP90inhibitor, AT13387, in combination with dabrafenib (dab) and trametinib (tram) in patients with BRAF V600E/K mut solid tumors. Prior chemotherapy, immunotherapy, BRAF and/or MEK exposure was permitted. The primary objective was to determine the maximum tolerated dose (MTD). Results: From July 2015 to June 2018, 22 patients with previously treated, metastatic BRAF V600E/K mut solid tumors were enrolled using a 3 + 3 design at four dose levels (DL) (Table). Pts were predominantly female (59%) with a median age of 57.5yrs (37 -75). The most common tumor type was BRAF V600Emut colon cancer (N=12). Dose limiting toxicities (DLTs) occurred in one patient in DL3 and one in DL4, specifically grade 3 myelosuppression and fatigue, respectively. The MTD was Dab 150mg [BID/PO], Tram 2mg [QD/PO] and AT1187 260mg/m2 [D1,8,15/IV]. Twenty-one of 22 pts were eligible for efficacy assessment. Best response, per RECIST 1.1, was partial response (PR) in 2 pts – one with colon ca (TKI-naïve), one with melanoma (TKI-resistant) - stable disease (SD) in 8 pts, and disease progression (PD) in 11 with a disease control rate (PR + SD) of 47.6% (90% CI: 29% - 67%). Median time to progression was significantly longer in DL3 (3.9 mths; 1.8-9.2) compared to DL1 (1.6mths; 0.9-1.7) or DL2 (1.5; 0.6-3.6). Median PFS and OS were 1.8mths (90% CI: 1.6 – 3.7mths) and 5.1 mths (90% CI: 2.5 -10.6mths), respectively. Median OS was not reached in DL3/4. Correlative data on the expression of the key signaling proteins relating to response will be presented at the meeting. Conclusions: HSP90 inhibition combined with BRAF/MEK inhibition was determined to be safe with evidence of disease control in a heavily pre-treated population of pts with BRAF V600E/K mut solid tumors. Clinical trial information: NCT02097225 . [Table: see text]
Evaluation of a computational decision support system for molecularly targeted treatment planning by the clinical outcome data of the randomized trial SHIVA01.
Authors: Dirner Anna , Doczi Robert , Filotas Peter , Vodicska Barbara , Varkondi Edit , Tihanyi Dora , Dupain Célia , Servant Nicolas , Kamal Maud , Hegedűs Csilla , Schwab Richárd , Le Tourneau Christophe , Valyi-Nagy Istvan T. , Peták István
Published: May 2020

3642

Background: Precision oncology requires the identification of individual molecular pathomechanisms to find optimal personalized treatment strategies for every cancer patient. Incorporation of complex molecular information into routine clinical practice remains a significant challenge due to the lack of a reproducible, standardized process of clinical decision making. Methods: To provide a standardized process for molecular interpretation, we develop a precision oncology decision support system, the Realtime Oncology Molecular Treatment Calculator (MTC). MTC is a rule-based medical knowledge engine that dynamically aggregates and ranks relevant scientific and clinical evidence using currently 26,000 evidence-based associations and reproducible algorithm scoring of drivers, molecular targets to match molecular alterations to efficient therapies. To validate this novel method and system, we used data of the SHIVA01 trial of molecularly targeted therapy (Lancet Oncol 2015 16:1324-34). Molecular profiles of participants were uploaded to MTC and aggregated evidence level (AEL) values of associated targeted treatments were calculated, including those used in the SHIVA01 trial. Results: The MTC output provided a prioritized list of drugs associated with the driver alterations in the patient molecular profile, where ranking is based on AEL values. Of 113 patients who received targeted therapy with available clinical best response data, disease control was experienced in 63 cases (PR: 5, SD: 58), while disease progression occurred in 50 cases. The average AEL score for the therapies applied was significantly higher in the responsive group than in the non-responsive group (1512 and 614, respectively (p = 0.049)). In 94 cases, drugs other than those used for therapy were ranked higher by the MTC. The average AEL difference between the top-ranked and the used drugs was in an inverse correlation with clinical response, i.e. smaller differences associated with a better outcome. Conclusions: Results indicate that the aggregation of evidence-based tumor-driver-target-drug associations using standardized mathematical algorithms of this computational tool is a promising novel approach to improve clinical decisions in precision oncology. Further validation based on the results of other targeted clinical trials and real-life data using more detailed molecular profiles is warranted to explore the full clinical potential of this novel medical solution.
Encorafenib plus cetuximab with or without binimetinib for BRAF V600E metastatic colorectal cancer: Updated survival results from a randomized, three-arm, phase III study versus choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC).
Authors: Kopetz Scott , Grothey Axel , Van Cutsem Eric , Yaeger Rona , Wasan Harpreet Singh , Yoshino Takayuki , Desai Jayesh , Ciardiello Fortunato , Loupakis Fotios , Hong Yong Sang , Steeghs Neeltje , Guren Tormod Kyrre , Arkenau Hendrik-Tobias , Garcia-Alfonso Pilar , Gollerkeri Ashwin , Maharry Kati , Christy-Bittel Janna , Tabernero Josep
Published: May 2020

4001

Background: BEACON CRC is a randomized, phase 3 study which evaluated the triplet of encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) and the doublet of ENCO + CETUX vs. investigator’s choice of irinotecan + CETUX or FOLFIRI + CETUX in patients (pts) with BRAFV600E metastatic colorectal cancer (mCRC) whose disease had progressed after 1-2 prior regimens in the metastatic setting. Primary endpoints were overall survival (OS) and objective response rate (ORR; by blinded central review) for triplet vs control. In a previous interim analysis, triplet and doublet improved OS and ORR versus standard of care. Here we report on an updated analysis. Methods: Updated analysis includes 6 months of additional follow-up and response data for all randomized pts. The study is ongoing. Results: Pts received triplet (n=224), doublet (n=220), or control (n=221). Median OS was 9.3 months (95% confidence interval [CI]:8.2, 10.8) for triplet and 5.9 months (95% CI:5.1-7.1) for control (hazard ratio [HR] (95% CI): 0.60 (0.47-0.75)). Median OS for doublet was 9.3 months (95% CI: 8.0-11.3) (HR vs. control: 0.61 (0.48-0.77). Confirmed ORR was 26.8% (95% CI: 21.1%-33.1%) for triplet, 19.5% (95% CI: 14.5%-25.4%) for doublet, and 1.8% (95% CI: 0.5%-4.6%) for control. Retrospective subgroup analyses suggested some pts may benefit more from triplet than doublet therapy (Table). Both triplet and doublet showed improved OS compared to control in all subgroups. Adverse events were consistent with prior analysis, with grade ≥3 adverse events in 65.8%, 57.4%, and 64.2% for triplet, doublet and control, respectively. Conclusions: The updated analysis of the BEACON CRC study confirmed that encorafenib + cetuximab with or without binimetinib improved OS and ORR in previously treated pts with BRAF V600E mCRC compared with standard chemotherapy. Clinical trial information: NCT02928224 . [Table: see text]
Preliminary results of the organ preservation of rectal adenocarcinoma (OPRA) trial.
Authors: Garcia-Aguilar Julio , Patil Sujata , Kim Jin K. , Yuval Jonathan B. , Thompson Hannah , Verheij Floris , Lee Meghan , Saltz Leonard B. ,   on behalf of the OPRA Consortium
Published: May 2020

4008

Background: Organ preservation (OP) with a watch and wait strategy (WW) and total neoadjuvant therapy (TNT) are new treatment paradigms for patients with locally advanced rectal cancer. The safety and efficacy of WW and of TNT have not been studied prospectively. Methods: Patients with MRI stage II and III rectal adenocarcinoma were randomized to 4 months of FOLFOX or CAPEOX before (Induction) or after (Consolidation) fluorouracil or capecitabine based chemoradiotherapy (CRT). Patients were re-staged 8-12 weeks after finishing TNT with digital rectal exam, flexible sigmoidoscopy and MRI. Patients with complete or near-complete clinical response were offered WW. Those with incomplete response had total mesorectal excision. The trial was designed so that each arm served as its own single-stage study that discriminates between 3-year disease-free survival (DFS) rates of 75% (historical null) and 85%, with 86% power, and a two-sided type I error of 5%. Secondary objectives included comparing DFS, OP, and distant metastasis-free survival (DMFS) rates between the two arms using the log-rank test. Results: Of 324 patients enrolled, 307 (152 I, 155 C) are currently evaluable for the time-to-event analysis as of 2/1/2020. Median follow-up is 2.1 years; 52 DFS events were observed. Patient demographics and tumor characteristics were generally balanced across the two arms. Full compliance with systemic chemotherapy was 82% and 81% for the I- and C-arms, respectively. The median radiation dose was 5400 cGy for both arms. Table shows 3-y DFS, DMFS, and OP rates. Conclusions: A WW strategy for patients with locally advanced rectal cancer that achieve a clinical complete response to TNT results in organ preservation for a high proportion of patients without compromising survival. Up-front CRT followed by consolidation chemotherapy resulted in a numerically higher WW rate compared to induction chemotherapy followed by CRT. Clinical trial information: NCT02008656 . [Table: see text]
A new prognostic and predictive tool to enhance shared decision making in stage III colon cancer.
Authors: Sobrero Alberto F. , Puccini Alberto , Shi Qian , Grothey Axel , Andre Thierry , Shields Anthony Frank , Ceppi Marcello , Bruzzi Paolo
Published: May 2020

4010

Background: Survival outcomes in patients with stage III colon cancer varies widely according to T-N sub-stages. The ability to estimate the benefit of each therapeutic option (surgery alone, fluoropyrimidines alone, oxaliplatin-based doublet for either 3 or 6 months) in each T-N subgroup within stage III, may provide more accurate information helping doctors and patients in the complex shared decision-making process surrounding adjuvant therapy. Methods: Theoutcomedata of 12,834 patients with stage III colon cancer enrolled in the IDEA trial served as our database. Patients were categorized in 16 sub-stages, based on the T-N categories. We created a meta-regression model to predict the expected 3-year DFS within each T-N sub-stage and hence the 5-year DFS rates were projected. We then evaluated the efficacy of each therapeutic option in every sub-stage, working backward by subtraction, using an average of the HRs reported in the pertinent trials publication as conversion factor. Results: Large differences in 3-year DFS rate were observed among the subgroups, ranging from 95% (T1N1a) to 29% (T4N2b) in the overall population. The contribution to outcome of each therapeutic option in this setting varied widely across sub-stages. According to our model, patients with T1N1a cancers have a projected 5-year DFS of 85% with surgery alone. Adjuvant fluoropyrimidine alone results in 4.2% absolute DFS gain; an additional 1.7% and 0.6% gain is seen with oxaliplatin for 3 and 6 months, respectively. Patients with T4N2b cancers show a 4.7% 5-year DFS with surgery alone, and a 7.1%, 5.0%, 2.1% increase with the aforementioned adjuvant options, respectively. Conclusions: The resulting overlay bar graph gives patients and doctors the projected relative benefit of each treatment option and may substantially help the shared decision-making process.
Impact of empirically eliminating 5-fluorouracil (5-FU) bolus and leucovorin (LV) in patients with metastatic colorectal cancer (mCRC) receiving first-line treatment with mFOLFOX6.
Authors: Basilio Alexa , Shah Anand , Sommerer Katelyn , Chehab Sarah , Bottiglieri Salvatore Michael , Imanirad Iman
Published: May 2020

4022

Background: Systemic chemotherapy with a 5-FU-based regimen, such as mFOLFOX6, is the preferred first line treatment option for mCRC. Due to hematologic toxicities associated with the 5-FU bolus component, providers may choose to eliminate it empirically in patients receiving palliative therapy. This study aimed to assess the impact of empirically eliminating the 5-FU bolus and LV from first line treatment with mFOLFOX6 in mCRC. Methods: This was a retrospective chart review of patients ≥ 18 years old with mCRC receiving palliative first line mFOLFOX6 chemotherapy with (bolus) or without (non-bolus) the 5-FU bolus and LV components from January 1, 2015 through August 31, 2019 at Moffitt Cancer Center. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), disease control rate (DCR) defined as partial response and stable disease at first scan, utilization of growth factor support and safety. Results: Data analysis cutoff was December 31, 2019, with 61 patients included in the bolus arm and 72 in the non-bolus arm. Median follow-up time was 21.8 months. No difference was found in median PFS (8.12 vs. 6.64 months, p=0.787) or OS (29.36 vs. 21.6 months, p=0.395) between the bolus and non-bolus arms, respectively. Observed DCR at first scan was similar between both arms (47.3% vs. 52.7%, p=0.44). Utilization of growth factor support was significantly higher in the bolus arm (73.7% vs. 26.3%, p=0.012). Fewer grade ≥ 3 treatment-related hematologic adverse events (AE) were seen in the non-bolus arm (37.7% vs. 22.2%, p=0.058) (table). Conclusions: This is the only study to date that analyzed the impact of empirically eliminating 5-FU bolus and LV from first line palliative therapy with mFOLFOX6 in mCRC. Results showed no significant difference in median PFS or OS. Despite reduced growth factor utilization, the non-bolus arm demonstrated a favorable safety profile with less treatment-related hematologic grade ≥ 3 AE. The results of this study warrant consideration of empirically eliminating 5-FU bolus and LV from the mFOLFOX6 regimen to avoid additive toxicities without negatively impacting efficacy. [Table: see text]
Differential association of proton pump inhibitors with efficacy of capecitabine and 5-fluorouracil in metastatic colorectal cancer: A post-hoc analysis from AXEPT phase III trial.
Authors: Kim Sun Young , Lee Ji Sung , Kang Junho , Morita Satoshi , Park Young Suk , Sakamoto Junichi , Muro Kei , Xu Rui-hua , Kim Tae Won
Published: May 2020

4023

Background: Proton pump inhibitors (PPIs) reportedly can impair the absorption of oral anticancer agents by potent acid suppression. Concomitant use of a PPI with capecitabine (Cap) was suggested to be associated with poor outcome in gastrointestinal cancers, however, the potential interaction has not been studied yet in a prospective randomized clinical trial comparing Cap with 5-fluorouracil (FU). We analyzed the differential impact of PPI use on Cap and FU using dataset from AXEPT trial, a phase III randomized trial that demonstrated non-inferiority of a modified XELIRI (mXELIRI; Cap plus irinotecan) with FOLFIRI (FU, leucovorin and irinotecan), both either with or without bevacizumab in patients (pts) with metastatic colorectal cancer (mCRC). Methods: From the per-protocol set (n = 620), pts with available information on concomitant medications (n = 482) were eligible for this sub-study. PPI use was defined as concomitant exposure of Cap and any PPI for 20% or more of the study period. The treatment-by-PPI-use interaction was examined adjusting to stratification factors including age, sex, country, performance status, number of metastatic sites, previous use of oxaliplatin, and concurrent bevacizumab treatment. Results: 49 (10.1%) pts were PPI users. Clinical characteristics were well balanced between the two groups differing in PPI use. In PPI users, the mXELIRI group tended to have poorer OS (hazard ratio [HR], 1.83; 95% confidence interval [CI], 0.96–3.48; p = 0.0644) compared with the FOLFIRI group. In contrast, within PPI non-users, OS of mXELIRI was better than that of FOLFIRI (HR, 0.76; 95% CI, 0.61- 0.95; p = 0.0162). Similarly, a trend of worse PFS with mXELIRI than with FOLFIRI was observed in PPI users (HR, 1.73; 95% CI, 0.94-3.21; p = 0.0798), but not in PPI non-users (HR, 0.90; 95%CI, 0.73 – 1.10; p = 0.2871). Treatment-by-PPI-use interaction was significant for OS (p = 0.0116) and PFS (p = 0.0415). No significant interactions were found between treatment and PPI use in terms of treatment failure, overall response, disease control, and grade 3–4 toxicities. Conclusions: There was a significant interaction between PPI use and treatment (Cap vs FU) in terms of OS and PFS in AXEPT dataset. This suggests that PPI use could impair the efficacy of Cap, but not that of FU. PPIs should be used with caution in pts with mCRC taking Cap. Clinical trial information: NCT01996306 .
Skeletal muscle loss under chemotherapy and its association with survival and systemic treatment toxicity in metastatic colorectal cancer: An AGEO prospective multicenter study.
Authors: Gallois Claire , Bourillon Camille , Auclin Edouard , Artru Pascal , Lievre Astrid , Lecomte Thierry , Locher Christophe , Marthey Lysiane , Faroux Roger , Pernot Simon , Barret Maximilien , Taieb Julien
Published: May 2020

4025

Background: We showed in a previous work that “Patient Generated-Subjective Global Assessment” (PG-SGA) was independently associated with survival and treatment toxicities in non-pretreated metastatic colorectal cancer (mCRC) patients. We have evaluated here if muscle mass in these patients can provide useful additional information for clinical practice. The objective of the present work was to evaluate the association between baseline sarcopenia, and the variation of the Skeletal Muscle Index (SMI) under treatment with survival and chemotherapy-related toxicities in our population of non-pretreated mCRC patients. Methods: This prospective multicenter observational study enrolled non-pretreated mCRC patients. Measurement of SMI was performed on routine CT scan at day 0 (D0) and day 60 (D60). PG-SGA score and other nutritional factors were collected at D0. Progression-free survival (PFS) and overall survival (OS) were calculated from treatment start. Treatment related toxicities were registered according to the NCI CTCAE v4.0. Results: 149 patients were included in eight French centers from 7/2013 to 11/2016. Sarcopenia at baseline was not significantly associated with survival outcomes or chemotherapy-related toxicities. The best cut-point value of SMI variation (between D0 and D60) for OS prediction obtained with a log-rank maximisation method was -14%. The decrease in SMI > 14%, with a median follow-up of 23 months, was significantly associated with shorter PFS (6 vs 9 mo; HR 1.8, 95%CI 1.1-3.1, p = 0.02) and OS (8.5 vs 26 mo; HR 2.4, 95%CI 1.3-4.4, p = 0.004), independently of hypoalbuminemia and malnutrition defined by PG-SGA, in multivariate analysis. 40% of patients with a SMI decrease > 14%, and 22% of patients with a SMI increase or stable or decrease < 14% developed grade ≥ 2 clinical toxicities (OR 3.0, 95%CI 1.2-7.7, p = 0.02), but the difference was not statistically significant in multivariate analysis (OR 2.3. 95%CI 0.8-6.7, p = 0.1). Conclusions: To our knowledge, this study is the first study assessing the association of skeletal muscle loss with survival and treatment toxicities in patients with mCRC prospectively. In our population of non pre-treated mCRC patients, baseline sarcopenia was not associated with poor survival outcomes, but the decrease in SMI > 14% during the first two months of treatment was significantly associated with decreased PFS and OS, independently of other prognostic and nutritional factors.
Prognostic characteristics of patients with benign mesenteric lymph node enlargement after surgical resection for colorectal cancer.
Authors: Tian Fei , Chen Gong
Published: May 2020

4027

Background: Patients with lymph node metastasis of colorectal cancer (CRC) have a greater risk of recurrence. However, the characteristics of benign mesenteric lymph node enlargement (BLNE) are not well documented. The aim of this study is to assess clinical and prognostic significance of BLNE in patients with CRC. Methods: 601 patients who underwent surgery for stage 0, I, II CRC from January 2010 to April 2014 were included and separated into two groups by presence of BLNE. Univariate and multivariate analyses were constructed to demonstrate prognostic factors between BLNE group (n = 275) and control group (n = 326). Results: The risk of recurrence in BLNE group after curative resection was significantly lower than control group, with the 1-, 3-, and 5-year disease-free survival rates being 98.2, 91.6, and 86.9 %, in BLNE group and 95.7, 86.2, and 78.2 %, in control group respectively (p = 0.004). The mortality in BLNE group was lower compared with non BLNE group (mean overall survival: 95.7±1.2 vs. 89.5±1.4 months, p = 0.001). Patients of BLNE group also had a higher percentage of younger age, family tumor history, left sided tumors and tumor size ≥4cm. Adjusted Cox regression showed BLNE was an independent prognostic factor for both disease free survival and overall survival ( P= 0.003 and 0.001). Conclusions: The study indicates that BLNE can be a useful positive factor in predicting recurrence and long-term survival concerning CRC patients. This conclusion offers a new viewpoint about CRC genesis and progression.
Outcomes and prognostic factors of patients (pts) with metastatic colorectal cancer (mCRC) who underwent pulmonary metastasectomy (PM) with curative intent.
Authors: Gössling Gustavo Cartaxo de Lima , Pereira Fernando de Souza , Silva Rafaela Kathrine da , Andrade Leonardo de Brittes , Peruzzo Nicolas , Saueressig Maurício Guidi , Chedid Márcio Fernandes , Schwartsmann Gilberto , Parikh Aparna Raj
Published: May 2020

4034

Background: Indications for PM in pts with mCRC are often based on the presence of favorable prognostic factors. We aimed to analyze the prognostic factors and outcomes of pts treated with PM for mCRC. Methods: We retrospectively identified pts with mCRC who underwent PM with curative intent between Jan 1985 and Dec 2019 at Hospital de Clínicas de Porto Alegre. Demographics, clinicopathological features and previously described prognostic factors were collected. Univariate Cox regression was performed and followed by Kaplan-Meier (KM) curves with log-rank test when significant. Results: Fifty-eight pts underwent PM. Demographics are described in Table. Wedge resection was performed in 87.9% and margins were negative in 89.1%. Mean number of lesions was 2.4 ± 1.7, with the largest measuring 1.7 ± 0.9 cm. Two or more resections were performed in 36.2%, nodal sampling in 27.3%, and nodal disease was found in 5.2%.Thirty-day readmission rate was 5.2%. One pt had a Clavien-Dindo grade IIIb complication. RAS/RAF/MMR and CK20/CDX2 were available for 13.8% and 58.6% of the sample. Median PFS 14 months (m) (95% CI 10.4 - 17.5), median OS 58 m (95% CI 33.5 - 82.4) and 5-year survival 49.8%. Unfavorable prognostic factors for OS included disease-free interval (DFI) < 24 m (40 m, 95% CI 31.8 - 48.1 vs 85 m, 95% CI 75.7 -96.2; P < 0.005), synchronous presentation (33 m, 95% CI 23.9 - 42.0 vs 77 m, 95% CI 50.7 - 103.2; P < 0.001), largest lesion size ≥ 2cm (37 m, 95% CI 22.9 - 51.0 m vs 81 m, 95% CI - 33.7 - 128.2, P = 0.019) and lack of CK20 expression (19 m, 95% CI 12.1 - 27.2 vs. 83 m, 95% CI 46.9 - 119.0; P < 0.001). More than one lesion at presentation was prognostic for PFS (11 m, 95% CI 7.6 - 14.3 vs 23 m, 95% CI 0.1 - 59.2; P = 0.003) but not OS (P = 0.11). Grade was significant at Cox regression but showed no effect in further analysis. Neither CEA at baseline or relapse, resection margins, Charlson comorbidity index (CCI) or adjuvant chemotherapy were prognostic. Conclusions: Our results suggest a benefit for select pts and PM. Lack of CK20 expression may be associated with more aggressive disease and shorter OS. Additional molecular prognostic factors after PM should be further explored. [Table: see text]
FOLFIRI versus irinotecan monodrug as second-line treatment in metastatic colorectal cancer patients: An open, multicenter, prospective, randomized controlled phase III clinical study.
Authors: Guo Weijian , Zhang Xiaowei , Wang Yusheng , Zhang Wen , Liu Xin , Shen Wei , He Yifu , Zhu Xiaodong , Chen Zhiyu , Wang Hong Qiang , Huang Mingzhu , Zhang Zhe , Zhao Xiaoying , Qiu Lixin , Wang Chenchen , Sheng Xuedan
Published: May 2020

4038

Background: The most commonly used treatment methods for metastatic colorectal cancer (mCRC)are systemic chemotherapy, molecular targeted therapy and local treatment. The main chemotherapy drugs for mCRC include Irinotecan, Oxaliplatin and 5-Fu. V308 Research shows that FOLFOX and FOLFIRI can be standard first or second-line of each other in the treatment of metastatic colorectal cancer. However if the first-line treatment regimen containing 5-FU fails, whether it is necessary to re-challenge 5-FU when Irinotecan is applied in the second line is unknown. There is no head-to-head comparative study to answer whether the FOLFIRI regimen is better than the Irinotecan monodrug. Therefore, it is necessary to carry out a comparative study of FOLFIRI Versus Irinotecan monodrug to observe whether adding 5-Fu on the basis of Irinotecan can improve the therapeutic effect. Methods: This was a randomized phase III trial. Patients from 5 centers in China with metastatic colorectal adenocarcinoma, for whom first-line of chemotherapy including oxaliplatin combined with fluorouracil drugs (combined or not combined with targeted therapy) had failed, were enrolled. 172 patients with mCRC were randomly treated with FOLFIRI or Irinotecan monodrug were included in this study. FOLFIRI group: Irinotecan 180mg/m2; Lecovorin 400mg/m2; 5-Fu 400mg/m2; 5-Fu 2400mg/m2 CIV 46h. Irinotecan monodrug group 180mg/m2, The regimen was repeated every 2 weeks. The primary endpoint is PFS, and this clinical trail is a superiority trial. Results: ITT (Intention-To-Treat) analysis: Among 172 patients, 10 had PR, 93 had SD, and 63 had PD, 6 patients have not received efficacy evaluation yet. The ORR was 5.68% VS. 5.95%, and the DCR was 61.36% and 54.76% in FOLFIRI group and Irinotecan monodrug group, respectively. Adverse reactions included neutropenia, stomatitis, diarrhea, fatigue, abnormal liver enzymes, pyrexia, arrhythmia, nausea and most of these were grade 1-2. The dose reduction rate induced by drug tocixity of was 13.64% and 7.14% in FOLFIRI group and Irinotecan monodrug group, respectively. Conclusions: These data show that Irinotecan monodrug has the similar ORR and DCR with FOLFIRI regimen in second-line treatment of mCRC. Irinotecan monodrug has lower adverse effect. Clinical trial information: NCT02935764 .
Encorafenib plus cetuximab with or without binimetinib for BRAF V600E-mutant metastatic colorectal cancer: Quality-of-life results from a randomized, three-arm, phase III study versus the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC).
Authors: Kopetz Scott , Grothey Axel , Van Cutsem Eric , Yaeger Rona , Wasan Harpreet Singh , Yoshino Takayuki , Desai Jayesh , Ciardiello Fortunato , Loupakis Fotios , Hong Yong Sang , Steeghs Neeltje , Guren Tormod Kyrre , Arkenau Hendrik-Tobias , Garcia-Alfonso Pilar , Gollerkeri Ashwin , Maharry Kati , Christy-Bittel Janna , Keir Christopher Hunt , Pickard Michael D , Tabernero Josep
Published: May 2020

4039

Background: In the BEACON CRC study, the triplet regimen of encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) significantly improved overall survival (OS, HR:0.52, P < 0.0001) and objective response rates (ORR, 26% vs 2%, P < 0.0001) in patients (pts) with BRAFV600E metastatic colorectal cancer (mCRC) compared with current standard of care. This analysis focuses on the patient-reported quality of life (QOL) assessments from this study. Methods: The BEACON CRC study was a randomized, open-label, 3-arm, phase 3 global study which evaluated triplet (ENCO+BINI+CETUX) or doublet (ENCO+CETUX) vs. investigator’s choice of irinotecan + CETUX or FOLFIRI + CETUX in pts with BRAFV600E mCRC. QOL assessments (secondary endpoints in the trial) included the EORTC QOL Questionnaire (QLQ C30), Functional Assessment of Cancer Therapy Colon Cancer (FACT C), EuroQol 5D 5L, and Patient Global Impression of Change (PGIC). The primary assessment for the QOL variables was the time to definitive 10% deterioration. The study is ongoing. Results: 665 pts were randomly assigned to receive either triplet (n = 224), doublet (n = 220), or control (n = 221). Reduction in the risk of QOL deterioration was an estimated 45% (HR 0.55, 95% CI: 0.43, 0.70) and 52% (HR 0., 9485% CI: 0.38, 0.62) in EORTC QLQ C30 and FACT C assessments, respectively, in favor of the triplet regimen over control. For the doublet vs. control, reduction in risk of QOL deterioration was an estimated 46% (HR 0.54, 95% CI: 0.43, 0.69) and 54% (HR 0.46, 95% CI: 0.36, 0.59) in EORTC QLQ C30 and FACT C, respectively in favor of the doublet. Similar results were observed in EuroQol 5D 5L and PGIC assessments. There were no overall differences in QOL between triplet and doublet across the 4 instruments. Conclusions: In BEACON CRC, triplet and doublet demonstrated substantial improvement in patient-reported QOL assessments over the current standard of care in pts with BRAFV600E-mutant metastatic CRC whose disease had progressed after 1 or 2 prior regimens. Clinical trial information: NCT02928224 .
Nivolumab (NIVO) + low-dose ipilimumab (IPI) as first-line (1L) therapy in microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Two-year clinical update.
Authors: Lenz Heinz-Josef , Lonardi Sara , Zagonel Vittorina , Van Cutsem Eric , Limon M. Luisa , Wong Mark , Hendlisz Alain , Aglietta Massimo , Garcia-Alfonso Pilar , Neyns Bart , Gelsomino Fabio , Cardin Dana Backlund , Dragovich Tomislav , Shah Usman , Yang Jing , Ledeine Jean-Marie , Overman Michael J.
Published: May 2020

4040

Background: In the phase 2 CheckMate 142 trial, NIVO + low-dose IPI had robust, durable clinical benefit and was well tolerated as 1L therapy for MSI-H/dMMR mCRC (median follow-up 13.8 months [mo; range, 9–19]; Lenz et al. Ann Oncol 2018;29:LBA18). Longer follow-up is presented here. Methods: Patients (pts) with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received NIVO 3 mg/kg Q2W + low-dose IPI 1 mg/kg Q6W until disease progression or discontinuation. The primary endpoint was investigator-assessed (INV) objective response rate (ORR) per RECIST v1.1. Results: In 45 pts with median follow-up of 29.0 mo, ORR (95% CI) increased to 69% (53–82) (Table) from 60% (44.3–74.3); complete response (CR) rate increased to 13% from 7%. The concordance rate of INV and blinded independent central review was 89%. Median duration of response (DOR) was not reached (Table). Median progression-free survival (PFS) and overall survival (OS) were not reached, and 24-mo rates were 74% and 79%, respectively (Table). Nineteen pts discontinued study treatment without subsequent therapy. An analysis of tumor response post discontinuation will be presented. Ten (22%) pts had grade 3–4 treatment-related adverse events (TRAEs); 3 (7%) had grade 3–4 TRAEs leading to discontinuation. Conclusions: NIVO + low-dose IPI continued to show robust, durable clinical benefit with a deepening of response, and was well tolerated with no new safety signals identified with longer follow-up. NIVO + low-dose IPI may represent a new 1L therapy option for pts with MSI-H/dMMR mCRC. Clinical trial information: NTC02060188 . [Table: see text]