trebananib (AMG 386) / Amgen - LARVOL DELTA

Pembrolizumab (Anti-PD-1) and AMG386 (Angiopoietin-2 (Ang-2) in Patients With Advanced Solid Tumor (clinicaltrials.gov) - P1 | N=59 | Completed | Sponsor: Dana-Farber Cancer Institute | Active, not recruiting ➔ Completed | Trial completion date: Aug 2026 ➔ Dec 2024 | Trial primary completion date: Feb 2026 ➔ Dec 2024

Trial completion • Trial completion date • Trial primary completion date • Colorectal Cancer • Melanoma • Oncology • Ovarian Cancer • Renal Cell Carcinoma • Solid Tumor • BRAF

Pembrolizumab (anti-PD-1) and AMG386 (angiopoietin-2 (Ang-2) in Patients with Advanced Solid Tumor (clinicaltrials.gov) - P1 | N=60 | Active, not recruiting | Sponsor: Dana-Farber Cancer Institute | Trial completion date: Aug 2025 ➔ Aug 2026 | Trial primary completion date: Feb 2025 ➔ Feb 2026

Platinum resistant • Trial completion date • Trial primary completion date • Colorectal Cancer • Melanoma • Oncology • Ovarian Cancer • Renal Cell Carcinoma • Solid Tumor • BRAF

Second-line systemic treatment for metastatic colorectal cancer: A systematic review and Bayesian network meta-analysis based on RCT. (PubMed, PLoS One) - "For most people, FOLFOX + Bevacizumab may be the best second-line systemic treatment regimen for mCRC. For RAS-mutant populations, FOLFIRI + Bevacizumab + Panitumumab is recommended. However, the therapeutic effect may be affected by the patient's physiological state, and clinicians should apply it based on actual conditions."

Clinical • Journal • Metastases • Retrospective data • Review • Colorectal Cancer • Oncology • Solid Tumor • RAS

A Phase 1 Trial of Trebananib, an Angiopoietin 1 and 2 Neutralizing Peptibody, Combined with Pembrolizumab in Patients with Advanced Ovarian and Colorectal Cancer. (PubMed, Cancer Immunol Res) - P1 | "After development of acquired resistance, biopsy of one patient's KRAS wild-type, ERBB2 amplified tumor showed a substantial decline in tumor-associated T cells and an increase in immunosuppressive intratumoral macrophages. Future studies are needed to carefully assess whether clinicogenomic features, such as lack of liver metastases, ERBB2 amplification, and left-sided tumors, can predict increased sensitivity to PD1 immunotherapy combinations."

IO biomarker • Journal • Metastases • P1 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Ovarian Cancer • Solid Tumor • ANGPT1 • HER-2 • KRAS • POLE

Evaluating the efficacy and safety of trebananib in treating ovarian cancer and non-ovarian cancer patients: a meta-analysis and systematic review. (PubMed, Expert Rev Anticancer Ther) - "PROSPERO (No. CRD42023466988)."

Journal • Retrospective data • Review • Oncology • Ovarian Cancer • Solid Tumor

High IL12family levels are associated with pathologic complete response amongst HER2- patients in the neoadjuvant I-SPY2 TRIAL (AACR 2024) - "Correlations of IL signatures with multiplex immunofluorescence staining of immune infiltrates in the PD1-inhibitor (PD1i) arm were also assessed. High expression of IL signatures in HER2- patients, regardless of HR status, was associated with pCR especially in the Trebananib, Veliparib/Carboplatin (VC) and PD1i arms. In the PD1i arm, expression of almost all IL signatures was highly correlated with density of T, CD8+ cytotoxic T, CD8- T, and B cells and their colocalization with tumor cells; IL-6 signatures correlated with density of proliferating tumor cells.Within RPS subtypes, enrichment of IL signatures in HER2-/Immune+ such as pro-inflammatory IL-1 and IL-12 signaling was associated with pCR in the VC, PD1i, Ganetespib, and control arms... High pre-treatment expression of IL signatures was associated with HER2- receptor and RPS HER2-/Immune+ subtype-specific response to I-SPY2 agents, and the colocalization of immune and tumor cells in the tumor bed. In HER2-..."

Clinical • IO biomarker • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor • CD8 • HER-2 • IFNG • IL12A • IL6

Pembrolizumab (Anti-PD-1) and AMG386 (Angiopoietin-2 (Ang-2) in Patients With Advanced Solid Tumor (clinicaltrials.gov) - P1 | N=60 | Active, not recruiting | Sponsor: Dana-Farber Cancer Institute | Trial completion date: Aug 2024 ➔ Aug 2025 | Trial primary completion date: Feb 2024 ➔ Feb 2025

Metastases • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Melanoma • Oncology • Ovarian Cancer • Renal Cell Carcinoma • Solid Tumor • BRAF

Angiopoietin-2 and the Vascular Endothelial Growth Factor Promote Migration and Invasion in Hepatocellular Carcinoma- and Intrahepatic Cholangiocarcinoma-Derived Spheroids. (PubMed, Biomedicines) - "Inhibitors targeting ANG-2 (Trebananib) and the VEGF (Bevacizumab) effectively blocked the migration ability of spheroids that had been stimulated with rh-ANG-2 and rh-VEGF. Overall, our findings highlight the critical role played by ANG-2 and the VEGF in enhancing the ability of HCC- and iCCA-derived spheroids to migrate and invade, which are key processes in cancer progression."

Journal • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CDH1 • CDH2 • VEGFA • VIM

Neoadjuvant trebananib plus paclitaxel-based chemotherapy for stage II/III breast cancer in the adaptively randomized I-SPY2 trial - Efficacy and biomarker discovery. (PubMed, Clin Cancer Res) - "The Ang/Tie2 axis inhibitor trebananib combined with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes, with probabilities of superiority >90%. Further study of Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes is warranted."

Biomarker • Journal • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ANGPT1 • CD8 • HER-2

Pathological complete response predicts event-free and distant disease-free survival in the I-SPY2 TRIAL (SABCS 2017) - "...For patients with HR+ HER2- tumors, only 70-gene (Mammaprint) high-risk patients are enrolled. To date, 1200+ patients have been randomized to one of 14 arms: control (paclitaxel followed by AC); veliparib/carboplatin; neratinib; MK2206; trebananib; trastuzumab/pertuzumab; ado-trastuzumab emtansine/pertuzumab; pembrolizumabx4; ganitumab/metformin; ganetespib; PLX-3397. 7 agents graduated in at least one signature (> 85% probability of success in a 300-patient phase III confirmatory trial); 2 did not graduate; 1 stopped for toxicity, and 3 are enrolling (patritumab/trastuzumab, talazoparib/irinotecan, pembrolizumabx8)... The first long-term efficacy results from the I-SPY2 TRIAL demonstrate that achieving pCR is a very strong surrogate endpoint for improved EFS and DDFS in a high-risk population, across all treatment arms, regardless of subtype. I-SPY2 shows substantially lower estimated EFS hazards for patients achieving pCR, compared to the 5 yr EFS hazard ratio for pCR...

Retrospective data • HER2 Breast Cancer • Hormone Receptor Breast Cancer

Identifying breast cancer molecular phenotypes to predict response in a modern treatment landscape: Lessons from ~1000 patients across 10 arms of the I-SPY 2 TRIAL (SABCS 2018) - "Treatments included paclitaxel alone (or with trastuzumab (H) in HER2+) or combined with investigational agents: veliparib/carboplatin (VC); neratinib; MK2206; ganitumab; ganetespib; AMG386; TDM1/pertuzumab (P); H/P; and pembrolizumab (Pembro). Molecular phenotypes reflecting proliferation, immune engagement, HER2-activation, luminal/ER-signaling, and DNA repair deficiency may provide a roadmap to guide treatment prioritization for emerging therapeutics. "

Clinical • PARP Biomarker • PD(L)-1 Biomarker • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor

Application of Machine Learning to elucidate the biology predicting response in the I SPY 2 neoadjuvant breast cancer trial (BOP 2020) - " Our study involves 986 patients with pre treatment gene expression and pCR data across 10 treatment arms including inhibitors of HER2: neratinib (N), pertuzumab (P), TDM1/P; AKT (MK 2206; M); IGF1R (ganitumab); HSP90 (ganetespib); PARP/DNA repair (veliparib/carboplatin; VC); ANG 1/2 (AMG386); immune checkpoints (pembrolizumab; Pembro); and a shared control arm (Ctr). Our results suggests that hypothesis driven analysis restricted to assumed mechanisms of action of the experimental agents may be insufficient, and that exploration of possible off target effects may be needed to understand the underlying biology of response or resistance."

Clinical • Breast Cancer • Immune Modulation • Inflammation • Oncology • Solid Tumor • ANGPT1 • ER • HSP90AA1 • IGF1 • IGF1R • PARP

Pembrolizumab (Anti-PD-1) and AMG386 (Angiopoietin-2 (Ang-2) in Patients With Advanced Solid Tumor (clinicaltrials.gov) - P1 | N=60 | Active, not recruiting | Sponsor: Dana-Farber Cancer Institute | Trial primary completion date: Feb 2023 ➔ Feb 2024

Metastases • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Melanoma • Oncology • Ovarian Cancer • Renal Cell Carcinoma • Solid Tumor • BRAF

Can We Learn From Failures? A Systematic Review and Metanalysis of Phase III Trials in Platinum Resistant Ovarian Cancer (ESMO-GC 2023) - "Conclusions The two RCT testing the anti-angiogenic agents bevacizumab and trebananib combined with Cht were the only reporting a PFS benefit in PROC. A better understanding of PROC biology and its implementation in study design are crucial to improve drug development in this population. Legal entity responsible for the study The authors."

IO biomarker • P3 data • Review • Oncology • Ovarian Cancer • Solid Tumor

[VIRTUAL] Exploring resistance mechanism to pembrolizumab and ang-2 inhibitor trebananib (NCT03239145) using high-dimensional single-cell mass cytometry (CyTOF) (SITC 2020) - P1 | "Conclusions Our findings suggest that the activity of anti-PD-1 and ang-2 peptibody (trebananib) combination is hindered by an increase in immunosuppressive myeloid cells leading to decrease in memory and effector T cell populations. The association between baseline activated NK cell and the expansion of cytolytic NK cells with favorable outcomes should be further explored."

IO biomarker • Late-breaking abstract • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Oncology • Ovarian Cancer • Renal Cell Carcinoma • Solid Tumor • ANGPT1 • ANGPT2 • CD8 • NCAM1

Expression-based immune signatures as predictors of neoadjuvant targeted-/chemo-therapy response: Experience from the I-SPY 2 TRIAL of ~1000 patients across 10 therapies (SABCS 2018) - "...For instance, the T/B-cell co-expression module associates with response to Pembro and the Angiopoetin-1/-2 inhibitor AMG-386 in both HR-HER2- and HR+ERHHER2- subtypes...In the HER2+ subtype, the T/B-cell module and B-cell signature is associated with response to the AKT-inhibitor MK2206. Our exploratory study suggests that immune signatures are associated with response to multiple I-SPY 2 experimental agents and implicates different immune cell types as response-predictive within breast cancer subtypes. Single cell sequencing derived population specific signatures may help further de-convolute how different immune cell types contribute to therapy responsiveness. "

Clinical • PD(L)-1 Biomarker • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor

Molecular subtype to predict pathologic complete response in HER2-positive breast cancer in the I-SPY2 trial. (ASCO 2022) - P2 | "The I-SPY2 platform trial tests novel agents given neoadjuvantly with a backbone of taxol (T) and trastuzumab (H) followed by doxorubicin and cyclophosphamide. Agents investigated in HER2+ bc were TH (control), MK2206, AMG386, pertuzumab (P), neratinib (N (given in place of H), and TDM1+P (given in place of TH)... pCR rates for patients with HER2+ bc treated with investigational agents, particularly dual HER2-blockade, were promising. Molecular response predictive subtype classification provides insight on how to better target therapy. The HER2+/Luminal group had low pCR rates with dual HER2-blockade but may have higher pCR rate with the addition of an AKT inhibitor and identifies a subgroup of HER2+ tumors in need of novel approaches."

Clinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • DRD • HER-2

Chemokine12 (CK12) tertiary lymphoid gene expression signature as a predictor of response in 3 immunotherapy arms of the neoadjuvant ISPY 2 TRIAL - pembrolizumab with and without SD101, and durvalumab combined with olaparib - and in 9 other arms of the trial including platinum-based and dual-anti-HER2 therapies (SABCS 2021) - " Data from 1130 patients across 12 arms of I-SPY2 (control (ctr): 210; veliparib/carboplatin (VC): 71; neratinib (N): 114; MK2206: 93; ganitumab: 106; ganetespib: 93; AMG386: 134; TDM1/pertuzumab(P): 52; H/P: 44; pembrolizumab (pembro): 69; durvalumab/olaparib (durva/olap): 71; pembro/SD101: 72) were available for analysis. The CK12 signature is highly predictive of complete pathologic response to immuno-oncology agents and other therapeutics supporting the role of the crosstalk within the tumor immune microenvironment in predicting response across subtypes. This gene expression signature can be readily obtained from microarrays and warrants further investigation in future arms of ISPY2 as a predictive biomarker."

Clinical • IO biomarker • Breast Cancer • HER2 Breast Cancer • Melanoma • Oncology • ANGPT1 • CCL19 • CCL2 • CCL21 • CCL3 • CXCL10 • CXCL11 • CXCL13 • CXCL9 • HER-2

Pharmacodynamic and Antitumor Activity of BI 836880, a Dual VEGF and Angiopoietin 2 Inhibitor, Alone and Combined with Programmed Cell Death Protein-1 Inhibition. (PubMed, J Pharmacol Exp Ther) - "In vivo, BI 836880 exhibited significant antitumor activity in all patient-derived xenograft models tested, showing significantly greater tumor growth inhibition (TGI) than bevacizumab (VEGF inhibition) and AMG386 (ANG1/2 inhibition) in a range of models. Here, we show that BI 836880, a bispecific nanobody targeting VEGF and ANG2, demonstrates substantial antitumor activity in preclinical models. Combining VEGF/ANG2 inhibition with blockade of the PD-1 pathway can further improve antitumor activity."

Journal • PK/PD data • Lung Cancer • Oncology • Solid Tumor • ANGPT1

Bevacizumab With or Without Trebananib in Treating Patients With Recurrent Brain Tumors (clinicaltrials.gov) - P2 | N=137 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed

Trial completion • Brain Cancer • Glioblastoma • Glioma • Gliosarcoma • Immunology • Oligodendroglioma • Oncology • Sarcoma • Solid Tumor

A comprehensive systematic review and network meta-analysis: the role of anti-angiogenic agents in advanced epithelial ovarian cancer. (PubMed, Sci Rep) - "In recurrent EOC, concurrent use of trebananib (10 mg/kg) with chemotherapy was likely to be the best option (P-score: 0.88, HR 1.67, 95% CI 0.94; 2.94). The NMA indicated that bevacizumab plus chemotherapy followed by maintenance bevacizumab (P-score: 0.99) and pazopanib combined with chemotherapy (P-score: 0.79) both had the highest probability of being the best intervention for improving OS in high-risk chemotherapy-naïve and platinum-resistant EOC, respectively. AAAs may not play a significant clinical role in non-high-risk chemotherapy-naïve and platinum-sensitive EOC."

Journal • Retrospective data • Review • Oncology • Ovarian Cancer • Solid Tumor

Efficacy and safety of bevacizumab combined with other therapeutic regimens for treatment of recurrent glioblastoma: A network meta-analysis. (PubMed, World Neurosurg) - "Both Bev + CCNU and Bev + rindopepimut could be considered as effective therapies for treating the recurrent glioblastoma according to the network meta-analysis results. Among them, Bev + rindopepimut therapy seems to be safer and more effective. Moreover, we found that Bev + Iri also appeared to be an effective therapy in a retrospective study."

Journal • Retrospective data • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Association of activation levels of TIE2 with response to the angiogenesis inhibitor trebananib in HER2+ patients in the I-SPY 2 trial. (ASCO 2018) - P2; "While small sample sizes preclude drawing definitive conclusions, our results suggest that activation levels of the TIE2 receptor may be predictive of T efficacy in HER2+ patients and signaling activation downstream of TIE2 such as AKT-mTOR signaling may correlate with response in the HER2+ and TN populations. These results need to be independently validated to determine the significance of these findings."

Clinical • Oncology

Evaluation of ANG/TIE/hypoxia pathway genes and signatures as predictors of response to trebananib (AMG 386) in the neoadjuvant I-SPY 2 TRIAL for Stage II-III high-risk breast cancer (AACR 2018) - "...In I-SPY 2, all patients received at least standard chemotherapy (paclitaxel followed by doxorubicin/cyclophosphamide: T->AC)...For HER2+ patients, TR was administered with trastuzumab (TR+H+T->AC vs. H+T->AC)... Following our pre-specified analysis, ANGPT1 succeeds as a specific predictor of response to trebananib in I-SPY 2. In addition, ICAM1 and PECAM1 associate with response in the HR+HER2- subset; and in exploratory analysis immune signaling predicts response in the TN subset. These biomarkers may merit further evaluation in future trials."

Clinical • Breast Cancer

Phase Ib study to test the safety and activity of pembrolizumab (anti-PD-1) and trebananib (angiopoietin-2 inhibitor [Ang-2]) in patients with advanced solid tumors: Updated analysis of the colorectal cancer (CRC) cohort. (ASCO-GI 2020) - P1; "The combination of pembrolizumab and trebananib is well tolerated and demonstrated promising activity in patients with heavily treated MSS CRC. Clinical trial information: NCT03239145. Research Funding: Merck and Amgen"

Clinical • IO Biomarker • P1 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • ANGPT1 • ANGPT2 • PD-L1