^
9d
Structure, function, signaling pathways and clinical therapeutics: The translational potential of STAT3 as a target for cancer therapy. (PubMed, Biochim Biophys Acta Rev Cancer)
Some of them such as TTI101 and BBI608 have been approved by the FDA for the treatment of certain cancers. All in all, STAT3 plays an important role in cancer progression and becomes a potential target for cancer treatment.
Review • Journal
|
STAT3 (Signal Transducer And Activator Of Transcription 3)
|
napabucasin (BBI608)
15d
Probing the Depths of Molecular Complexity: STAT3 as a Key Architect in Colorectal Cancer Pathogenesis. (PubMed, Curr Gene Ther)
For example, imatinib acts by targeting cell surface receptors, and these inhibitors have shown potential for the control and treatment of tumor growth, angiogenesis, and metastasis. Imatinib, for example acts by targeting cell surface receptors, and these inhibitors have shown the future direction toward the control and treatment of tumor growth, angiogenesis, and metastasis.
Journal
|
STAT3 (Signal Transducer And Activator Of Transcription 3)
|
imatinib • napabucasin (BBI608)
19d
Napabucasin Inhibits Proliferation and Migration of Glioblastoma Cells (U87) by Regulating JAK2/STAT3 Signaling Pathway. (PubMed, Medicina (Kaunas))
In this study, the anti-proliferative and apoptotic effects of NP and the chemotherapy agent doxorubicin (DX), a natural compound, on glioblastoma cells (U87) were investigated. Since it can suppress Jak2/Stat3, an important cancer cell proliferation pathway in glioblastoma, the combination of NP and DX can be used as an alternative treatment agent. But no synergistic effect of NP and DX on the U87 cells of the glioblastoma cell line was observed.
Journal
|
JAK2 (Janus kinase 2)
|
STAT3 expression
|
doxorubicin hydrochloride • napabucasin (BBI608)
1m
Targeted delivery of napabucasin with radiotherapy improves outcomes in diffuse midline glioma. (PubMed, Neuro Oncol)
As nearly all DMG patients will receive RT as part of their treatment course, our validation of the efficacy of radiosensitizing therapy using CED to prolong survival in DMG opens the door for exciting novel studies of alternative radiosensitization strategies in this devastating disease while overcoming limitations of the BBB.
Journal
|
NQO1 (NAD(P)H dehydrogenase, quinone 1)
|
napabucasin (BBI608)
1m
Effect of napabucasin and doxorubicin via the Jak2/Stat3 signaling pathway in suppressing the proliferation of neuroblastoma cells. (PubMed, Acta Cir Bras)
NP showed that it suppresses the proliferation of neuroblastoma cells. Due to its inhibitory effect on Jak2 and Stat3, it can be used to prevent invasion of SH-SY5Y cells. NP, which can inactivate Jak2/Stat3, can be used as a treatment agent by combining with DX in proliferation pathway in neuroblastoma.
Journal
|
IL6 (Interleukin 6)
|
STAT3 expression
|
doxorubicin hydrochloride • napabucasin (BBI608)
3ms
Napabucasin deactivates STAT3 and promotes mitoxantrone-mediated cGAS-STING activation for hepatocellular carcinoma chemo-immunotherapy. (PubMed, Biomaterials)
Consequently, the resultant co-nanoformulation can promote anti-PD-1 antibody for suppressing HCC development, generating long-term survival, and inhibiting tumor recurrence. This study reveals the potential of MIT to activate the cGAS-STING signaling pathway, and confirms the feasibility of nano co-delivery for MIT and NAP on achieving HCC chemo-immunotherapy.
Journal
|
STAT3 (Signal Transducer And Activator Of Transcription 3) • STING (stimulator of interferon response cGAMP interactor 1)
|
mitoxantrone • napabucasin (BBI608)
5ms
Design, synthesis and biological evaluation of novel naphthoquinothiazole derivatives as potent antitumor agents through inhibiting STAT3. (PubMed, Bioorg Chem)
In this study, a series of 21 derivatives of the STAT3 inhibitor napabucasin were designed and synthesized...Notably, in vivo studies revealed that SZ6 significantly inhibited tumor growth without any observed organ toxicity. Collectively, these findings identify SZ6 as a promising STAT3 inhibitor for colorectal cancer treatment.
Journal
|
STAT3 (Signal Transducer And Activator Of Transcription 3)
|
napabucasin (BBI608)
7ms
New P3 trial • Combination therapy • Metastases
|
CTNNB1 (Catenin (cadherin-associated protein), beta 1) • STAT3 (Signal Transducer And Activator Of Transcription 3)
|
5-fluorouracil • irinotecan • leucovorin calcium • napabucasin (BBI608)
8ms
In Situ Hydrogel Modulates cDC1-Based Antigen Presentation and Cancer Stemness to Enhance Cancer Vaccine Efficiency. (PubMed, Adv Sci (Weinh))
Furthermore, tumor cell stemness are inhibited by napabucasin, which can help CTLs to achieve comprehensive tumor killing. Collectively, the proposed strategy of cDC1 in situ recruitment and activation combined with stemness inhibition provides great immune response and anti-tumor potential, providing new ideas for clinical tumor vaccine design.
Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
napabucasin (BBI608)
9ms
Molecular crosstalk between MUC1 and STAT3 influences the anti-proliferative effect of Napabucasin in epithelial cancers. (PubMed, Sci Rep)
Therefore, high-MUC1 tumors may have a better outcome to Napabucasin therapy. We report how MUC1 regulates STAT3 activity and provide a new perspective on repurposing the STAT3-inhibitor Napabucasin to improve clinical outcome of epithelial cancer treatment.
Journal
|
MUC1 (Mucin 1) • STAT3 (Signal Transducer And Activator Of Transcription 3)
|
MUC1 expression
|
napabucasin (BBI608)
10ms
Gastric cancer patient-derived organoids model for the therapeutic drug screening. (PubMed, Biochim Biophys Acta Gen Subj)
PDOs maintained the histological and genetic characteristics of original cancer tissues. PDOs biobank opens up new perspectives for studying cancer cell biology and personalized medicine as a preclinical study platform.
Journal
|
HER-2 (Human epidermal growth factor receptor 2)
|
napabucasin (BBI608) • COTI-2
11ms
Inhibitory effect of napabucasin on arbidol metabolism and its mechanism research. (PubMed, Front Pharmacol)
We also found that napabucasin increased the AUC and AUC of M6-1, the main metabolite of arbidol. This study provides a reference for the combined use of napabucasin and arbidol in clinical practice.
Journal
|
CYP3A4 (Cytochrome P450, family 3, subfamily A, polypeptide 4)
|
napabucasin (BBI608)
1year
A redox-responsive nanosystem to suppress chemoresistant lung cancer through targeting STAT3. (PubMed, J Control Release)
Furthermore, the BBI608-SS-NPs preferentially accumulate in tumor sites, resulting in a superior anti-tumor efficacy in both cisplatin-resistant cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of NSCLC. Mechanistic studies demonstrate that BBI608-SS-NPs not only directly inhibit the downstream genes of the STAT3 pathway, but also indirectly inhibit the Wnt pathway. Overall, this stimuli-responsive polymeric nanoformulation of BBI608 shows great potential in the treatment of chemoresistant NSCLC by targeting CSCs.
Journal
|
STAT3 (Signal Transducer And Activator Of Transcription 3)
|
cisplatin • napabucasin (BBI608)
1year
Alcohol reshapes a liver premetastatic niche for cancer by extra- and intrahepatic crosstalk-mediated immune evasion. (PubMed, Mol Ther)
BBI608 pretreatment protects the liver and suppresses the alcohol-triggered premetastatic niche formation. In conclusion, under the extra- and intrahepatic crosstalk, the alcoholic injured liver forms a favorable niche for cancer cell metastasis, while BBI608 is a promising anti-metastatic agent targeting such microenvironment.
Journal • Metastases
|
IL6 (Interleukin 6) • LCN2 (Lipocalin-2)
|
IL6 expression
|
napabucasin (BBI608)
over1year
A Phase I Study to Investigate the Safety, Tolerability and Pharmacokinetics of Napabucasin Combined with Sorafenib in Japanese Patients with Unresectable Hepatocellular Carcinoma. (PubMed, Drugs R D)
These findings confirm the viability of napabucasin plus sorafenib treatment, and there were no safety or tolerability concerns in Japanese patients with unresectable HCC.
P1 data • PK/PD data • Journal
|
sorafenib • napabucasin (BBI608)
over1year
Interactions between driver genes shape the signaling pathway landscape and direct hepatocellular carcinoma therapy. (PubMed, Cancer Sci)
The sgTrp53 + sgPten tumor upregulated mTOR and noncanonical nuclear factor-κB signaling, which was shown to be strongly inhibited by rapamycin (an mTOR inhibitor) in vitro and in vivo...We found that JAK-STAT, MAPK, and cytoskeleton signaling were activated in sgTrp53 + Kras tumor and the combination of sorafenib and napabucasin led to the complete inhibition of tumor growth in vivo. In patients with HCC, who had the same molecular classification as our mouse models, the downstream signaling pathway landscapes associated with genomic alterations were identical. Our research provides novel targeted therapeutic options for the clinical treatment of HCC, based on the presence of specific genetic alterations within the tumor.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • PTEN (Phosphatase and tensin homolog)
|
PTEN mutation
|
sorafenib • sirolimus • napabucasin (BBI608)
over1year
Quassinoid analogs exert potent antitumor activity via reversible protein biosynthesis inhibition in human colorectal cancer. (PubMed, Biochem Pharmacol)
BOL-resistant (BR) cell lines, HCT116 and HCA7, were equally sensitive to standard CRC therapeutic agents and known STAT3 inhibitors but resistant to homoharringtonine (HHT), a known protein synthesis inhibitor...Of note, BOL did not inhibit protein synthesis in normal human colon epithelial cells whereas HHT and napabucasin remained effective in these normal cells...Treatment with the most potent analog, 5c, resulted in significant inhibition of cell proliferation and protein synthesis at nanomolar concentrations. These quassinoid analogs may represent a novel class of protein synthesis inhibitors for the treatment of human CRC.
Journal
|
Synribo (omacetaxine mepesuccinate) • napabucasin (BBI608)
over1year
P3 data • Journal • Head-to-Head • Metastases
|
NQO1 (NAD(P)H dehydrogenase, quinone 1)
|
gemcitabine • albumin-bound paclitaxel • napabucasin (BBI608)
over1year
Synergistic combination of NCX 4040 and napabucasin induces immunogenic activation via upregulation of mitochondrial oxidative stress and STAT3 inhibition in cadmium transformed and metastatic prostate cancer cells (AACR 2023)
Flow cytometric analysis demonstrated that the drug combination shows a synergistic effect in producing excess mitochondrial and cellular ROS, causing apoptosis and in inducing cell cycle arrest in both BPH-Cd and DU145 cells. Taken together, our study demonstrates that NCX 4040 and Napabucasin in combination could be a potential anti-PCa therapy which warrants further evaluation for its clinical application.
Metastases • Oxidative stress
|
STAT3 (Signal Transducer And Activator Of Transcription 3) • STING (stimulator of interferon response cGAMP interactor 1) • CAT (Catalase)
|
napabucasin (BBI608)
over1year
NAD(P)H: quinone oxidoreductase 1 (NQO1)- A viable biomarker in colorectal cancer? (AACR 2023)
Based on meta-analysis and computational approach, NQO1 is a viable biomarker and targeted molecule in CRC. In vitro results showed that inhibiting NQO1 with the drug BBI 608 decreased cell proliferation in both CRC cell lines. Knockout or overexpression or site directed mutagenesis is essential for a better understanding about BBI 608 targeted NQO1 and its amino acids.
NQO1 (NAD(P)H dehydrogenase, quinone 1)
|
napabucasin (BBI608)
almost2years
Apoptotic tumor cell-derived microparticles loading Napabucasin inhibit CSCs and synergistic immune therapy. (PubMed, J Nanobiotechnology)
As a combined diagnostic and therapeutic nanoprobe, N-TMPs@NAP could successfully conduct PET/CT imaging, suppress CSCs, and synergistically stimulate anticancer immune responses. Additionally, this nanoprobe might someday be employed in clinical situations because TMPs for it can be produced from human tissue and NAP has FDA approval.
Journal • Tumor cell
|
STAT3 (Signal Transducer And Activator Of Transcription 3) • CD44 (CD44 Molecule) • STAT1 (Signal Transducer And Activator Of Transcription 1)
|
CD44 expression
|
napabucasin (BBI608)
almost2years
In Silico and In Vitro Study of Janus Kinases Inhibitors from Naphthoquinones. (PubMed, Molecules)
Napabucasin and 2'-methyl napabucasin exhibited potent cell growth inhibition in TF1 (IC = 9.57 and 18.10 μM) and HEL (IC = 3.31 and 6.65 μM) erythroleukemia cell lines, and they significantly inhibited JAK2/3 kinase activity (in a nanomolar range) better than the known JAK inhibitor, tofacitinib. From the molecular dynamics study, both compounds formed hydrogen bonds with Y931 and L932 residues and hydrophobically contacted with the conserved hinge region, G loop, and catalytic loop of the JAK2. Our obtained results suggested that napabucasin and its methylated analog were potential candidates for further development of novel anticancer drug targeting JAKs.
Preclinical • Journal
|
JAK3 (Janus Kinase 3)
|
napabucasin (BBI608) • tofacitinib
almost2years
The cancer stemness inhibitor napabucasin suppresses small cell lung cancer growth through SOX2 expression. (PubMed, Am J Cancer Res)
Furthermore, napabucasin significantly inhibited cisplatin-resistant SCLC cell xenograft growth in vivo by downregulating SOX2 and inducing apoptosis. These data demonstrate that napabucasin may be a novel drug for the clinical treatment of cisplatin-resistant SCLC.
Journal
|
STAT3 (Signal Transducer And Activator Of Transcription 3) • SOX2
|
SOX2 expression
|
cisplatin • napabucasin (BBI608)
2years
Maintaining Myofibroblastic-Like Cancer-Associated Fibroblasts by Cancer Stemness Signal Transduction Feedback Loop. (PubMed, Cureus)
Cancer and myCAF crosstalk increases myCAF maintenance and cancer cell stemness. In this study using human breast and liver cancer cell lines, maintenance of the OPN-induced myCAF phenotype also requires cancer stemness. This indicates that the myCAF phenotype requires two distinct signaling pathways: initiation and maintenance.
Journal
|
SPP1 (Secreted Phosphoprotein 1) • SOX2
|
napabucasin (BBI608)
2years
Proteomic time course of breast cancer cells highlights enhanced sensitivity to Stat3 and Src inhibitors prior to endocrine resistance development. (PubMed, Cancer Gene Ther)
Inhibitors of Stat3 (napabucasin) and Src (dasatinib), were effective at killing tamoxifen-treated MCF7 and T47D cells. This novel proteomic resource identifies key mechanisms enabling cell survival during tamoxifen treatment. It provides valuable insight into potential drug combinations and timing that may prevent the development of endocrine resistance.
Journal
|
STAT3 (Signal Transducer And Activator Of Transcription 3)
|
dasatinib • tamoxifen • napabucasin (BBI608)
2years
Novel mechanism of napabucasin, a naturally derived furanonaphthoquinone: apoptosis and autophagy induction in lung cancer cells through direct targeting on Akt/mTOR proteins. (PubMed, BMC Complement Med Ther)
Results show for the first time that NB exerts an anti-cancer activity through the direct interaction to Akt and mTOR proteins. The methyl moiety of acetyl group of NB is required for its potent anti-cancer activities. These data encourage further development of NB compounds for Akt and mTOR driven cancers.
Journal
|
MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • mTOR (Mechanistic target of rapamycin kinase) • MCL1 (Myeloid cell leukemia 1) • ANXA5 (Annexin A5)
|
napabucasin (BBI608)
over2years
Targeted inhibition of STAT3 induces immunogenic cell death of hepatocellular carcinoma cells via glycolysis. (PubMed, Mol Oncol)
In subcutaneous and orthotopic transplantation mouse tumour models, the STAT3 inhibitor napabucasin prevented tumour growth and induced the expression of calreticulin and the protein disulfide isomerase family A member 3 (PDIA3; also known as ERp57) but suppressed that of CD47 and GLUT1...Significantly, the anti-tumour immune memory response was induced by treatment targeting STAT3. These findings provide a new mechanism for targeting STAT3-induced ICD in HCC, and confirm STAT3 as a potential target for the treatment of HCC via reshaping the tumour immune microenvironment.
Journal • PD(L)-1 Biomarker • IO biomarker
|
CD8 (cluster of differentiation 8) • PD-1 (Programmed cell death 1) • LAG3 (Lymphocyte Activating 3) • STAT3 (Signal Transducer And Activator Of Transcription 3) • CALR (Calreticulin) • PDIA3 (Protein Disulfide Isomerase Family A Member 3)
|
CD8 expression
|
napabucasin (BBI608)
over2years
STAT3 inhibitor Napabucasin abrogates MDSC immunosuppressive capacity and prolongs survival of melanoma-bearing mice. (PubMed, J Immunother Cancer)
Our findings demonstrate that STAT3 inhibitor Napabucasin completely abrogated the immunosuppressive capacity of murine MDSC and human M-MDSC and improved melanoma-bearing mouse survival. Moreover, patients with malignant melanoma with high expression levels of activated STAT3 in M-MDSC displayed shorter PFS, indicating its role as a promising therapeutic target in patients with malignant melanoma and a predictive marker for their clinical outcome.
Preclinical • Journal
|
CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule)
|
napabucasin (BBI608)
over2years
Targeting STAT3 Signaling Facilitates Responsiveness of Pancreatic Cancer Cells to Chemoradiotherapy. (PubMed, Cancers (Basel))
Inhibition of STAT3 signaling was achieved by RNAi or the small-molecule inhibitor napabucasin...Importantly, genetical and pharmacological perturbation of the IL-6/STAT3 pathway resulted in CRT sensitization specifically in those cell lines, in which STAT3 activity was augmented by IL-6. In conclusion, our data underscore the general importance of IL-6/STAT3 signaling for CRT resistance and suggest that pathway inhibition may represents a putative treatment strategy in order to increase the fraction of patients with PDAC who are candidates for surgical approaches.
Journal
|
IL6 (Interleukin 6)
|
napabucasin (BBI608)
over2years
Therapeutic potential of activated natural killer cells in nasopharyngeal carcinoma (AACR 2022)
Importantly, augmented NPC43 cell death was observed in combined treatment (47.1±2.1%) compared to single treatment (NK alone: 9.2±6.5%; Napabucasin alone: 25.0±4.5%). In summary, this work demonstrated encouraging therapeutic potential of both NK therapy and in combination with STAT3 inhibitor Napabucasin for NPC treatment.
PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • CD69 (CD69 Molecule) • NKG2D (killer cell lectin like receptor K1)
|
PD-L1 expression • STAT3 expression
|
napabucasin (BBI608)
over2years
Targeting NAD(P)H:quinone oxidoreductase 1 (NQO1) in pancreatic ductal adenocarcinoma: An in silco, in vitro and in vivo approach (AACR 2022)
The combination of BBI608 with gemcitabine plus irradiation creates higher cytotoxicity (decreased proliferation, clonogenicity and increased Annexin V positive cells; p<0.001) in PDAC cell lines and the mice bearing subcutaneous PANC-02 and MIA PaCa-2 model. Collectively, this investigation offers mechanistic insight into the cytotoxicity initiated by BBI608 and suggests further investigation of its utility for PDAC therapy is warranted.
Preclinical
|
NQO1 (NAD(P)H dehydrogenase, quinone 1)
|
gemcitabine • napabucasin (BBI608)
3years
Special Combination of BBI608 and Pembrolizumab (clinicaltrials.gov)
P1/2, N=55, Terminated, Takayuki Yoshino | Trial completion date: Feb 2020 --> Aug 2021
Clinical • Trial completion date • Combination therapy
|
KRAS (KRAS proto-oncogene GTPase) • MSI (Microsatellite instability)
|
Keytruda (pembrolizumab) • napabucasin (BBI608)
over3years
STAT3 inhibitor BBI608 enhances the antitumor effect of gefitinib on EGFR-mutated non-small cell lung cancer cells. (PubMed, Hum Cell)
In vivo experiment, STAT3 inhibitor further suppressed the size of NSCLC tissues, and further down-regulated the expression of ROR1 and ABCB1 while up-regulated the expression of p53 in NSCLC tissues. In conclusion, STAT3 inhibitor enhanced the antitumor effect of gefitinib on EGFR-mutated NSCLC cells through regulating ROR1/ABCB1/P53 pathway.
Journal • IO biomarker
|
EGFR (Epidermal growth factor receptor) • BCL2 (B-cell CLL/lymphoma 2) • ABCB1 (ATP Binding Cassette Subfamily B Member 1) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • MMP2 (Matrix metallopeptidase 2) • CASP3 (Caspase 3) • MMP9 (Matrix metallopeptidase 9)
|
TP53 mutation • EGFR mutation • EGFR expression • BCL2 expression • ROR1 expression • TP53 expression • STAT3 expression • BAX expression
|
gefitinib • napabucasin (BBI608)
over3years
Phase I study of napabucasin in combination with FOLFIRI + bevacizumab in Japanese patients with metastatic colorectal cancer. (PubMed, Int J Clin Oncol)
Napabucasin 240 mg BID in combination with FOLFIRI and bevacizumab was tolerated, with a manageable safety profile in Japanese patients with metastatic CRC.
Clinical • P1 data • Journal • Combination therapy
|
STAT3 (Signal Transducer And Activator Of Transcription 3)
|
Avastin (bevacizumab) • 5-fluorouracil • irinotecan • leucovorin calcium • napabucasin (BBI608)
over3years
A Study of BBI608 Administered With Paclitaxel in Adult Patients With Advanced Malignancies (clinicaltrials.gov)
P1/2, N=565, Completed, Sumitomo Dainippon Pharma Oncology, Inc | Active, not recruiting --> Completed
Clinical • Trial completion
|
BRAF (B-raf proto-oncogene) • ER (Estrogen receptor) • ALK (Anaplastic lymphoma kinase) • PGR (Progesterone receptor)
|
HER-2 positive • BRAF V600E • HER-2 negative • BRAF V600 • ALK positive • BRAF V600K • ER negative • PGR negative
|
albumin-bound paclitaxel • napabucasin (BBI608)
over3years
Identification of Novel Therapeutic Targets for Fibrolamellar Carcinoma Using Patient Derived Xenografts and Direct from Patient Screening. (PubMed, Cancer Discov)
A high-throughput functional drug screen found primary and metastatic FLC were vulnerable to clinically available inhibitors of TOPO1 and HDAC, and to napabucasin...This demonstrates that a direct functional screen on patient tumors provides therapeutically informative data within a clinically useful time frame. Identifying these novel therapeutic targets and combination therapies is an urgent need, as effective therapeutics for FLC are currently unavailable.
Clinical • Journal
|
BCL2L1 (BCL2-like 1)
|
napabucasin (BBI608)
over3years
Napabucasin Drug-Drug Interaction Potential, Safety, Tolerability, and Pharmacokinetics Following Oral Dosing in Healthy Adult Volunteers. (PubMed, Clin Pharmacol Drug Dev)
Healthy volunteers who tolerated napabucasin during period 1 received probe drugs during period 2, and in period 3 received napabucasin (240 mg twice daily; days 1-11) plus a phenotyping cocktail containing omeprazole (CYP2C19), caffeine (CYP1A2), flurbiprofen (CYP2C9), bupropion (CYP2B6), dextromethorphan (CYP2D6), midazolam (CYP3A) (all oral; day 6), intravenous midazolam (day 7), repaglinide (CYP2C8; day 8), and rosuvastatin (breast cancer resistance protein/organic anion transporter 3; day 9)...No serious adverse events/deaths were reported. Generally, napabucasin is not expected to induce/inhibit drug clearance to a clinically meaningful degree.
Clinical • PK/PD data • Journal
|
CYP1A2 (Cytochrome P450, family 1, subfamily A, polypeptide 2)
|
napabucasin (BBI608) • midazolam hydrochloride • omeprazole
over3years
[VIRTUAL] Colorectal Cancer (CRC) (ASCO 2021)
Clinical and biologic factors influencing the selection and sequencing of therapy for patients with CRC Key efficacy and safety results from the Phase III KEYNOTE-177 study of first-line pembrolizumab versus chemotherapy for patients with MSI-high/mismatch repair-deficient (MSI-H/dMMR) unresectable or metastatic CRC; FDA approval of pembrolizumab as first-line therapy and implications for clinical practice Correlation between the location of the primary tumor and outcomes with EGFR antibody-based regimens; optimal incorporation of cetuximab and panitumumab into current metastatic CRC treatment algorithms Current clinical role of anti-PD-1 monotherapy (eg, nivolumab, pembrolizumab) and nivolumab/ipilimumab in the care of patients with MSI-H/dMMR relapsed or refractory metastatic CRC Ongoing investigations of immune checkpoint inhibitors alone or in combination with other systemic approaches (eg, chemotherapy, targeted therapy) in MSI-H/dMMR early-stage and advanced CRC (eg, CheckMate 8HW) Optimal selection of first-line therapy for patients with BRAF wild-type, microsatellite stable (MSS) metastatic CRC Biologic rationale for, available data with and ongoing Phase III investigations combining an anti-angiogenic agent with an immune checkpoint inhibitor (eg, LEAP-017) for patients with previously treated MSS metastatic CRC Findings from early-phase studies (eg, REGOMUNE, CAVE, ILLUMINATE-206) and ongoing evaluation of regimens combining immune checkpoint inhibitors with different systemic therapies (eg, regorafenib, cetuximab) in MSS metastatic CRC Key efficacy and safety findings from the Phase III BEACON CRC trial of encorafenib/cetuximab with or without binimetinib for patients with BRAF V600E-mutant metastatic CRC; FDA approval of encorafenib/cetuximab and appropriate integration into clinical practice Design, eligibility criteria and available efficacy results from the Phase II ANCHOR-CRC trial evaluating encorafenib, binimetinib and cetuximab in patients with previously untreated BRAF V600E-mutant metastatic CRC Incidence of HER2 overexpression and HER2 mutations in CRC; key efficacy findings from the Phase II DESTINY-CRC01 study of T-DXd for patients with HER2-expressing advanced CRC Spectrum, incidence and severity of toxicities associated with T-DXd in the DESTINY-CRC01 trial Available data with and ongoing investigations of HER2-directed approaches in advanced CRC (eg, HERACLES, DASH, DESTINY-CRC02, MOUNTAINEER) Long-term efficacy and safety findings with and clinical, biologic and/or practical factors influencing the sequencing of regorafenib and TAS-102 Available data with and potential role of TAS-102 in combination with bevacizumab or other systemic agents in metastatic CRC and/or in earlier disease stages Mechanism of action of napabucasin; implications of the negative results from the Phase III CanStem303C trial of napabucasin in combination with FOLFIRI with or without bevacizumab for previously treated metastatic CRC Other promising agents and strategies under investigation in CRC
MSi-H Biomarker • PD(L)-1 Biomarker • IO biomarker
|
HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • MSI (Microsatellite instability)
|
BRAF V600E • MSI-H/dMMR • HER-2 overexpression • BRAF V600 • HER-2 mutation
|
Keytruda (pembrolizumab) • Opdivo (nivolumab) • Avastin (bevacizumab) • Erbitux (cetuximab) • Yervoy (ipilimumab) • Vectibix (panitumumab) • Enhertu (fam-trastuzumab deruxtecan-nxki) • Mektovi (binimetinib) • Stivarga (regorafenib) • Braftovi (encorafenib) • Lonsurf (trifluridine/tipiracil) • napabucasin (BBI608)