Anti-PD-1 plus anti-VEGF therapy in multiple intracranial metastases of a hypermutated, IDH wild-type glioblastoma

TPS154 Background: Pts with mCRC have limited treatment options following progression on standard therapies. Current standard of care (SOC) after pts progress on trifluridine/tipiracil (TAS-102) or regorafenib is re-challenge with previous systemic treatments, enrollment in a clinical trial, or best supportive care (BSC). Fruquintinib (Elunate) is a novel, highly selective, vascular endothelial growth factor (VEGF) receptor (VEGFR)-1, -2, and -3 tyrosine kinase inhibitor (TKI) ( Cancer Biol Ther 2014;15:1635-1645). Fruquintinib is approved in China to treat pts with mCRC who received or are intolerant to fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, anti-VEGF therapy, and, if RAS wild type, anti-epidermal growth factor receptor (EGFR) therapy. Approval was based on results of the phase 3 FRESCO study (2013-013-00CH1; NCT02314819; JAMA 2018;319:2486-2496), in which fruquintinib 5 mg daily (QD), 3 weeks on, 1 week off (3 on/1 off), significantly improved overall survival (OS) in pts with mCRC in the 3rd-line+ setting when compared to placebo (median OS 9.3 months [mo] versus 6.6 mo; hazard ratio [HR] 0.65; p < .001). Progression-free survival (PFS) was also superior (median PFS 3.7 mo versus 1.8 mo; HR 0.26; p < .001). The toxicities of fruquintinib were consistent with those of other VEGF TKIs and were manageable. At the time FRESCO was conducted in China, SOC for pts with mCRC differed from that in the US, EU, and Japan. We describe here a global phase 3 study (FRESCO-2; 2019-013-GLOB1; NCT04322539) being conducted to investigate fruquintinib’s efficacy and safety in pts with refractory mCRC and a treatment profile representative of the global SOC. Methods: FRESCO-2 is a randomized, double-blind, placebo-controlled study to compare fruquintinib + BSC to placebo + BSC. Key inclusion criteria are progression on or intolerance to treatment with TAS-102 and/or regorafenib; previous treatment with standard approved therapies including chemotherapy, anti-VEGF therapy, and, if RAS wild type, anti-EGFR therapy. Prior therapy with immune checkpoint or BRAF inhibitors is required for pts with corresponding tumor alterations. Pts (~522) will be randomized 2:1 to receive either fruquintinib 5 mg orally (PO) QD + BSC or placebo 5 mg PO QD + BSC, with a 3 on/1 off schedule. Randomization will be stratified by prior therapy, RAS status, and duration of metastatic disease. The primary endpoint is OS; secondary endpoints include PFS, disease control rate, objective response rate, duration of response, and safety. Final OS analyses will be performed when 364 OS events are observed; futility analysis will be conducted with 1/3 (121) OS events. If enrichment of post-regorafenib pts occurs, enrollment to that strata will be capped at approximately 262. FRESCO-2 will be activated in the US, EU, and Japan; global enrollment is anticipated over 13 mo. Clinical trial information: NCT04322539.

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Phase III randomized trial of cetuximab (CET) plus either brivanib alaninate (BRIV) or placebo in patients (pts) with metastatic (MET) chemotherapy refractory K-RAS wild-type (WT) colorectal carcinoma (CRC): The NCIC Clinical Trials Group and AGITG CO.20 trial.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.386 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 386-386 ◽

Cited By ~ 8

Author(s):

Lillian L. Siu ◽

Jeremy D. Shapiro ◽

Derek J. Jonker ◽

Christos Stelios Karapetis ◽

John Raymond Zalcberg ◽

...

Keyword(s):

Kinase Inhibitor ◽

Objective Response ◽

Dose Intensity ◽

Phase Iii ◽

Wild Type ◽

Fibroblast Growth Factor Receptors ◽

Positive Effects ◽

Anti Vegf ◽

Global Quality Of Life ◽

Grade 3

386 Background: The anti-EGFR monoclonal antibody CET has improved survival in pts with MET, chemotherapy refractory, K-RAS wild type (WT) CRC. The addition of BRIV, a tyrosine kinase inhibitor targeting vascular endothelial and fibroblast growth factor receptors (VEGFR/FGFR), to CET has shown encouraging activity in an early phase clinical trial. Methods: Pts with MET CRC previously treated with combination chemotherapy were randomized 1:1 to receive CET 400 mg/m2 IV loading dose followed by weekly maintenance of 250 mg/m2 plus either BRIV 800 mg PO daily (Arm A) or placebo (Arm B). Pts may have had 1 prior anti-VEGF, but no prior anti-EGFR therapy. The trial was amended shortly after opening to enrol K-RAS WT pts. Primary endpoint was overall survival (OS). Results: From 02/2008 to 02/2011, 750 pts were randomized (376 in Arm A and 374 in Arm B). Demographics: median age=64 (range 27-88); male=64%; ECOG 0:1:2 (%)=32:58:10; >3 prior chemotherapy regimens=92%; prior anti-VEGF therapy=41%; K-RAS WT=97%. Median OS in the intent-to-treat population was 8.8 months in Arm A and 8.1 months in Arm B, hazard ratio (HR)=0.88; 95% CI=0.74 to 1.03; p=0.12. Median progression-free survival (PFS) was 5.0 months in Arm A and 3.4 months in Arm B, HR=0.72; 95% CI=0.62 to 0.84; p<0.0001. Both partial responses (13.6% vs 7.2%, p=0.004) and stable disease (50% vs 44%) were higher in Arm A. Incidence of any ≥grade 3 adverse event (AE) was 78% in Arm A and 53% in Arm B. Most frequent ≥grade 3 AEs were fatigue (25%), hypertension (11%) and rash (10%) in Arm A, vs fatigue (11%), rash (5%) and dyspnea (5%) in Arm B. Time to deterioration of physical function was shorter and global quality of life scores were lower in Arm A vs Arm B. Pts received ≥90% dose intensity of CET=57% in Arm A vs 83% in Arm B; of BRIV/placebo=48% in Arm A vs 87% in Arm B. Conclusions: Despite positive effects on PFS and objective response, the combination of CET+BRIV did not significantly improve OS in pts with MET, chemotherapy refractory, K-RAS WT CRC. AEs were consistent with those reported for each drug given as monotherapy.

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Withholding anti-EGFR, the impact on outcome in RAS wild-type metastatic colorectal tumors (WAIT or ACT trial).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.626 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 626-626

Author(s):

Lola-Jade Palmieri ◽

Laurent Mineur ◽

David Tougeron ◽

Benoit Rousseau ◽

Victoire Granger ◽

...

Keyword(s):

Growth Factor ◽

Propensity Score ◽

Cohort Analysis ◽

Wild Type ◽

First Line ◽

Anti Vegf ◽

Ras Status ◽

Metastatic Sites ◽

The Impact ◽

Doublet Chemotherapy

626 Background: First line of RAS wild-type (WT) unresectable metastatic colorectal cancer (mCRC) can be doublet chemotherapy with an anti-VEGF (Vascular Endothelial Growth Factor), or an anti-EGFR (Epidermal Growth Factor Receptor). Waiting for RAS status, many oncologists initiate chemotherapy and add the anti-EGFR secondly. The objective was to compare the delayed introduction of the anti-EGFR to the immediate introduction of the anti-VEGF in first-line treatment of RAS WT mCRC. Methods: This was a retrospective cohort analysis from 2013 to 2016, multicentric with 28 health care centers. We included patients with RAS WT unresectable mCRC treated between 2013 and 2016 by a doublet chemotherapy with the anti-VEGF introduced immediately or with the anti-EGFR introduced at C2 or C3. Progression free survival (PFS), overall survival (OS) and response rate (RR) for the two cohorts were compared. Hazard ratios (HR) with 95% confidence interval (95%CI) were estimated with cox regression models weighted on propensity score to deal with potential confounders. Results: A total of 262 patients were included, 129 in the immediate anti-VEGF group and 133 in the delayed anti-EGFR group. Median follow-up was 37.9 months. Ninety-two patients had the anti-EGFR introduced at C2, 40 at C3. The median delay of RAS analysis was 19 days (q1-q3: 13-26). Patients treated with anti-VEGFs were more likely men (68% versus 56%), with more metastatic sites ( > 2 sites: 15% versus 9%). A propensity score including the number of metastatic sites and a possible previous treatment was built. Delayed anti-EGFRs were associated with longer PFS compared to immediate anti-VEGFs: 13.8 versus 11.0 months, p = 0.0244. After weighting, delayed anti-EGFRs were still associated with better PFS: HR 0.74, 95%CI [0.61 – 0.90], p = 0.0024. OS was not different between the two arms (30.5 for anti-VEGF versus 29.9 months, p = 0.3934), even after weighting (HR 0.86, 95%CI [0.69 – 1.08], p = 0.2024). There was a better RR with delayed anti-EGFRs: 66.7% versus 45.6%, p = 0.0007. Conclusions: Our findings suggest that, while waiting for RAS status, the delayed introduction of the anti-EGFR is a valid option, compared to the immediate introduction of the anti-VEGF.

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Analysis of plasma biomarkers potentially associated with antiangiogenic resistance in NCIC CTG/AGITG CO.20: A phase III randomized trial of cetuximab (CET) plus either brivanib alaninate (BRIV) or placebo in patients (pts) with chemotherapy refractory, k-RAS wild-type (WT), metastatic colorectal carcinoma (mCRC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.3572 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 3572-3572

Author(s):

Jeremy David Shapiro ◽

Lillian L. Siu ◽

Christopher J O'Callaghan ◽

John Raymond Zalcberg ◽

Malcolm J. Moore ◽

...

Keyword(s):

Overall Survival ◽

Colorectal Carcinoma ◽

Randomized Trial ◽

Phase Iii ◽

Plasma Samples ◽

Wild Type ◽

Metastatic Colorectal Carcinoma ◽

Plasma Biomarkers ◽

Anti Vegf ◽

Brivanib Alaninate

3572 Notice of Retraction: "Analysis of plasma biomarkers potentially associated with antiangiogenic resistance in NCIC CTG/AGITG CO.20: A phase III randomized trial of cetuximab (CET) plus either brivanib alaninate (BRIV) or placebo in patients (pts) with chemotherapy refractory, k-RAS wild-type (WT), metastatic colorectal carcinoma (mCRC)." Abstract 3572, published in the 2012 Annual Meeting Proceedings Part I, a supplement to the Journal of Clinical Oncology, has been retracted by Jeremy Shapiro, MBBS, and Lillian Siu, MD, on behalf of the NCIC, AGITG, and all authors of the abstract. The authors have been unable to finalize their data presentation due to the complexity of the analysis, and difficulties with the statistical interpretation of the significance of several possible predictive biomarkers. Background: In the CO.20 trial, the addition of BRIV, a tyrosine kinase inhibitor targeting vascular endothelial and fibroblast growth factor receptors (VEGFR2,3 and FGFR 1,2,3), to CET, increased objective response rate and progression free survival, but did not significantly increase overall survival. Previous clinical studies demonstrated modulation of circulating angiogenic factors (CAF) in CRC which occur on therapy or upon progression (Kopetz JCO 2010). Methods: CO.20 pts were randomized 1:1 to CET plus either BRIV (Arm A) or placebo (ARM B) in a double-blind design. Pts may have had 1 prior anti-VEGF based therapy, but no prior anti-EGFR therapy. Primary endpoint was overall survival (OS). Baseline pre-treatment plasma samples were analyzed using commercial Multi-Analyte ELISAs to measure CAF, immunologic, and growth factors, with an initial discovery and subsequent validation data set. Results: 750 pts were randomized (376 in Arm A and 374 in Arm B). Median OS in the intent-to-treat population was 8.8 months in Arm A and 8.1 months in Arm B, hazard ratio (HR)=0.88; 95%CI=0.74-1.03; p=0.12. In an exploratory subgroup analysis, there is a statistically non-significant trend favoring the effect of brivanib on OS among the 41% pts who received prior anti-VEGF therapy versus those who did not.Baseline plasma samples were collected from 96% of pts, and analysis is ongoing. Results of the largest circulating biomarker analysis will be presented. CAF results will be compared with response and survival data to look for potential patient subgroups that may benefit more from the combination treatment. Conclusions: This large scale analysis will provide insights on the potential use of CAF or CAF profiles as predictive markers in CRC.

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Phase III randomized sequential open-label study to evaluate the efficacy of FOLFOX + panitumumab followed by FOLFIRI + bevacizumab (Sequence 1) versus FOLFOX+ bevacizumab followed by FOLFIRI + panitumumab (Sequence 2) in untreated patients with wild-type RAS metastatic, primary left (L)-sided, unresectable colorectal cancer (CRC): The CR-SEQUENCE.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.tps3618 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. TPS3618-TPS3618

Author(s):

Ramon Salazar ◽

Alfredo Carrato ◽

Teresa Garcia Garcia ◽

Javier Gallego Plazas ◽

Auxiliadora Gómez-España ◽

...

Keyword(s):

Colorectal Cancer ◽

Clinical Trial ◽

Objective Response ◽

Primary Objective ◽

Phase Iii ◽

Second Line ◽

Wild Type ◽

First Line ◽

Open Label ◽

Anti Vegf

TPS3618 Background: Both anti-EGFR and anti-VEGF therapies have shown clinical benefit when they are added in first and second-line in L-sided CRC. The conflicting results in anti-VEGF vs. anti-EGFR studies (FIRE-3, PEAK and CALGB/SWOG 80405 studies) suggest that the sequence of targeted therapies added to FOLFOX or FOLFIRI regimens in first- and second-line treatment could be an important factor in the overall survival (OS) of mCRC patients. Currently, there are no randomized data on the sequential use of an anti-EGFR followed by an anti-VEGF or vice versa. Therefore, the aim of this randomized clinical trial is to compare the efficacy of two treatment sequences, panitumumab followed by bevacizumab versus bevacizumab followed by panitumumab in combination with FOLFOX chemotherapy in first-line and with FOLFIRI in second-line in patients with wild-type RAS, primary L-sided, metastatic colorectal cancer (mCRC). Methods: A phase III, multicentre, open-label and randomized two-arm clinical trial. Untreated patients with wild-type RAS mCRC (determined locally), primary L-sided and unresectable will be screened for this trial. Eligible patients will be randomized 1:1 to receive first-line (1L) panitumumab plus FOLFOX and then bevacizumab plus FOLFIRI as second-line (2L) treatment (Seq. 1) or bevacizumab plus FOLFOX as 1L and then panitumumab plus FOLFIRI as 2L treatment (Seq. 2). Randomization will be stratified by number of metastatic organs involved (1 vs > 1). Primary objective is the comparison of the progression free survival (PFS) rate at 35 months (m) of Seq 1 vs Seq. 2. Secondary objectives: PFS from randomization to 2nd progression or death, OS rate at 35 months and OS of Seq. 1 vs Seq. 2; PFS, objective response rate, disease control rate, early tumour shrinkage, Depth of Response, duration and time to response and safety in 1L treatment and in 2L treatment in each Sequence arm. Exploratory objectives: impact of baseline biomarkers predictive of the efficacy in each Sequence arm and the clinical impact of clonal dynamics by longitudinal analysis of circulating tumour deoxyribonucleic acid (ctDNA) in plasma. The trial is in progress; 28 of up to 370 planned patients have been recruited at the end of January 2019 (first patient in 31 October 2018). Clinical trial information: NCT03635021.

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The Best. First. Anti-EGFR before anti-VEGF, in the first-line treatment of RAS wild-type metastatic colorectal cancer: from bench to bedside

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-016-3032-8 ◽

2016 ◽

Vol 78 (2) ◽

pp. 233-244 ◽

Cited By ~ 18

Author(s):

A. Zaniboni ◽

V. Formica

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Line Treatment ◽

Wild Type ◽

First Line ◽

Anti Vegf ◽

First Line Treatment

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Size does matter: Comparison of activity between anti-EGFR and anti-VEGF based-treatments in RAS wild type colorectal cancer patients, stratified by sizes of metastatic involvement

Annals of Oncology ◽

10.1093/annonc/mdx261.323 ◽

2017 ◽

Vol 28 ◽

pp. iii115-iii116

Author(s):

Michela Del Prete ◽

Riccardo Giampieri ◽

Luca Cantini ◽

Elena Maccaroni ◽

Alessandro Bittoni ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Patients ◽

Wild Type ◽

Anti Vegf ◽

Metastatic Involvement ◽

Colorectal Cancer Patients

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Κλινικοπαθολογοανατομικές διαφορές και συσχετίσεις μεταξύ καρκίνου του δεξιού και αριστερού τμήματος του παχέος εντέρου

10.12681/eadd/47890 ◽

2020 ◽

Author(s):

Ιωάννης Καλαντζής

Keyword(s):

Wild Type ◽

Anti Vegf ◽

Braf Mutant

Υπάρχουσα γνώση: Οι διαφορές σε ιστοπαθολογικό και μοριακό επίπεδο μεταξύ καρκίνου του δεξιού και του αριστερού τμήματος του παχέος εντέρου αναφέρθηκαν πρώτη φορά στη βιβλιογραφία από τον Bufill το 1990. Έκτοτε μεγάλος αριθμός μελετών έχει επιβεβαιώσει τις διαφορές μεταξύ τους σε επιδημιολογικό επίπεδο, σε επίπεδο κλινικής εμφάνισης, συννοσηροτήτων και βιολογικής συμπεριφοράς, τα οποία θα μπορούσαν να σχετίζονται με τις διαφορές στην πρόγνωση και την ολική επιβίωση μεταξύ τους. Στόχος: Σκοπός της παρούσης εργασίας είναι να διερευνήσει στατιστικά σημαντικές διαφορές μεταξύ Ελλήνων ασθενών με καρκίνο του δεξιού και αριστερού τμήματος του παχέος εντέρου αναφορικά με επιδημιολογικά, κλινικά, ιστοπαθολογικά και μοριακά δεδομένα, λαμβάνοντας υπόψη την ανταπόκριση των ασθενών σε στοχευμένες θεραπείες και υπολογίζοντας τυχόν διαφορές σε περιόδους προόδου νόσου ελεύθερης επιβίωσης στην πρώτη και δεύτερη γραμμή θεραπείας αλλά και στην ολική επιβίωση μεταξύ τους. Υλικό και μέθοδος: Η παρούσα μελέτη παρατήρησης περιέλαβε 144 ασθενείς με ιστολογικά επιβεβαιωμένο καρκίνο παχέος εντέρου ανεξαρτήτως σταδίου που έλαβαν χημειοθεραπευτική αγωγή σε ελληνικό ογκολογικό νοσοκομείο για χρονικό διάστημα 2.5 ετών. Οι κλινικές πληροφορίες, οι συννοσηρότητες, τα ιστολογικά και μοριακά χαρακτηριστικά συλλέχτηκαν αναδρομικά από τους φακέλους των ασθενών, ενώ τα χορηγηθέντα χημειοθεραπευτικά σχήματα, οι στοχευτικοί παράγοντες, οι χρονικές περίοδοι προόδου νόσου ελεύθερης επιβίωσης στην πρώτη και δεύτερη γραμμή θεραπείας και η ολική επιβίωση καταγράφηκαν αναδρομικά και προοπτικά. Η στατιστική ανάλυση έγινε με το στατιστικό πακέτο SPSS. Αποτελέσματα: 86 άνδρες και 58 γυναίκες συμμετείχαν στην μελέτη. 100 (69.4%) ασθενείς με εντόπιση της πρωτοπαθούς εστίας στο αριστερό κόλον και 44 (30.6%) στο δεξιό κόλον. Ασθενείς με δεξιά εντόπιση εμφάνισαν σε μεγαλύτερο ποσοστό αναιμία (OR=3.09), ενώ οι ασθενείς με αριστερή εντόπιση εμφάνισαν σε μεγαλύτερο ποσοστό αίμα στις κενώσεις (OR=3.37) και αίσθημα ατελούς κένωσης (OR=2.78). Αναφορικά με τα συνοδά νοσήματα οι ασθενείς με καρκίνο του δεξιού κόλου είχαν μεγαλύτερη πιθανότητα να πάσχουν από σακχαρώδη διαβήτη (OR=3.31) και στεφανιαία νόσο (p=0.056). Η βλεννώδης διαφοροποίηση ήταν πιο συχνή στην δεξιά υποομάδα (OR=4,49), όπως και ο αριθμός των διηθημένων λεμφαδένων (p = 0.039), ενώ η υψηλή διαφοροποίηση ήταν πιο συχνή στην αριστερή υποομάδα (OR=2,78). Οι RAS wild type ασθενείς που έλαβαν anti-EGFR αγωγή εμφάνισαν μεγαλύτερο όφελος (PFS: 16.5 μήνες) συγκριτικά με όσους έλαβαν anti-VEGF αγωγή (PFS: 13.7 μήνες) (p=0,05), ενώ μεταξύ RAS wild-type ασθενών που έλαβαν anti-EGFR αγωγή, οι ασθενείς με αριστερή εντόπιση εμφάνισαν μεγαλύτερο όφελος (PFS: 15.8 μήνες) από τους ασθενείς με δεξιά εντόπιση (PFS: 5.5 μήνες) στην πρώτη γραμμή χημειοθεραπείας (p=0.034). Oι BRAF mutant ασθενείς εμφάνισαν συντομότερη χρονική περίοδο ελεύθερη επιβίωσης (9.3 μήνες) συγκριτικά με τους BRAF wild type ασθενείς (14.5 μήνες) (p=0,033) στην πρώτη γραμμή χημειοθεραπείας. Οι ασθενείς με καρκίνο του δεξιού κόλου παρουσίασαν υποτροπή σε μικρότερο χρονικό διάστημα (7.7 μήνες) συγκριτικά με τους ασθενείς με αριστερή εντόπιση (14.5 μήνες) (p<0,001) καθώς και συντομότερη ολική επιβίωση (δεξιό κόλον: 58.4 μήνες, αριστερό κόλον: 82.4 μήνες, p=0.018). Συμπέρασμα: Οι ασθενείς με καρκίνο του δεξιού τμήματος του παχέος εντέρου εμφανίζουν περισσότερα συνοδά νοσήματα, χειρότερα ιστολογικά και μοριακά χαρακτηριστικά και συνεπώς υψηλότερη πιθανότητα υποτροπής, πτωχής ανταπόκρισης στη στοχευμένη θεραπεία και συντομότερη ολική επιβίωση από τους ασθενείς με καρκίνο του αριστερού τμήματος του παχέος εντέρου.

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