The gist: This story describes the results of a clinical trial with volunteer patients to test an ovarian cancer treatment that combines the new drug trebananib with standard paclitaxel chemotherapy. The study focused specifically on women with recurrent epithelial ovarian cancer who had three or fewer previous treatments and had experienced no worsening of their disease (“platinum-free interval”) in 12 months or less. The researchers found that patients who took the trebananib plus paclitaxel treatment lived longer without their cancer worsening than patients who only took paclitaxel. However, trebananib seemed to increase the risk for edema as a side effect.
“The addition of trebananib to weekly paclitaxel significantly extended PFS in women with recurrent epithelial ovarian cancer, according to results of a double blind, placebo-controlled phase 3 trial.
“Researchers observed increased incidence of edema with trebananib (AMG 386, Amgen) compared with placebo, but differences in other adverse events typically associated with anti-vascular endothelial growth factor agents were minimal between the two study arms.
“ ‘The results from the TRINOVA-1 study are clinically significant because they validate both a new target and a new therapeutic agent in the setting of epithelial ovarian cancer,’ Bradley J. Monk, MD, of Creighton University School of Medicine at St. Joseph’s Hospital and Medical Center, and colleagues wrote. ‘Trebananib plus paclitaxel might provide a non-vascular endothelial growth factor anti-angiogenesis treatment option to women with recurrent epithelial ovarian cancer, if approved by regulatory agencies.’ ”
“The addition of ramucirumab to docetaxel improved outcomes over placebo with docetaxel as a second-line treatment of patients with advanced non-small-cell lung cancer (NSCLC), according to results of the REVEL trial presented at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.
“ ‘Despite advancements in genomics and identification of predictive biomarkers such as EGFR mutations or ALK rearrangement, there is still no… targeted therapy for the majority of patients with squamous and non-squamous carcinoma,’ said Maurice Pérol, MD, of the Cancer Research Center of Lyon in France. Ramucirumab specifically targets VEGFR-2 and inhibits angiogenesis, and it has been shown to improve outcomes in gastric cancer as monotherapy.”
Editor’s note: This article describes a treatment for advanced non-small cell lung cancer (NSCLC) that combines a new targeted drug called ramucirumab with the standard chemotherapy drug docetaxel. In a clinical trial to test the treatment in volunteer patients who had already received one previous treatment, it was found that ramucirumab plus docetaxel provided better patient outcomes than docetaxel plus a placebo.
“A new oral angiogenesis inhibitor for the treatment of lung cancer could be edging closer to the market: Approval application for nintedanib (Boehringer Ingelheim) has been filed in Europe and is being prepared for the United States.
“The data for nintedanib come from the phase 3 trial known as LUME-Lung-1, recently published in the Lancet Oncology.”
Editor’s note: We previously posted a story about the potential benefits of the drug nintedanib for some patients with non-small cell lung cancer (NSCLC).
New clinical trial results suggest that adding the drug nintedanib (Vargatef) to second-line chemotherapy can improve survival for some patients with non-small cell lung cancer (NSCLC). Patients with advanced NSCLC whose cancer had progressed after first-line chemotherapy received either Vargatef and the chemotherapy drug docetaxel (Taxotere) or Taxotere alone. On the whole, Vargatef was associated with slightly longer times without worsening of the cancer (3.4 months vs 2.7 in the Taxotere-only group), but no improvement in overall survival. However, in patients with lung adenocarcinoma, a subtype of NSCLC, the addition of Vargatef improved overall survival by over 2 months (12.6 months vs 10.3 with Taxotere alone). Vargatef disrupts the formation of new blood vessels that feed growing tumors.
Combining cetuximab (Erbitux), bevacizumab (Avastin), and traditional chemotherapy in patients with non-small cell lung cancer (NSCLC) appeared to be safe and effective in a phase II clinical trial. Patients with advanced non-squamous NSCLC received Erbitux and Avastin in addition to carboplatin (Paraplatin) and paclitaxel (Taxol/Abraxane) as first-line treatment, followed by maintenance treatment with Erbitux and Avastin. Tumors shrank in 56% of patients and stopped growing in an additional 21%. Serious side effects were relatively rare; the rate was comparable to that of either Erbitux or Avastin alone. Both Erbitux and Avastin have shown efficacy in NSCLC by themselves, but may be more effective when given together. An ongoing phase III clinical trial will further investigate this drug combination.
Berenguer-Daize C, Boudouresque F, Bastide C, Tounsi A, et al. Clinical Cancer Research. Oct 7, 2013.
“Purpose: To study the role of Adrenomedullin (AM) system (AM and its receptors ‘AMR; CLR, RAMP2 and RAMP3’) in cancer of prostate (CaP) androgen-independent growth. Experimental design: Androgen-dependent and independent CaP models were used to investigate the role and mechanisms of AM in CaP hormone-independent growth and tumor-associated angiogenesis and lymphangiogenesis. Results: AM and AMR were immunohistochemically localized in the carcinomatous epithelial compartment of CaP specimens of high-grade (Gleason score >7) suggesting a role of the AM system in the CaP growth. We used the androgen-independent Du145 cells for which we demonstrate that AM stimulated cell proliferation in vitro through the cAMP/CRAF/MEK/ERK pathway. The proliferation of Du145 and PC3 cells is decreased by anti-AM antibody (αAM) supporting that AM may function as a potent autocrine/paracrine growth factor for CaP androgen-independent cells. In vivo, αAM therapy inhibits Du145 androgen-independent xenografts growth and interestingly LNCaP androgen-dependent xenografts growth only in castrated animals suggesting strongly that AM might play an important role in tumor regrowth following androgen ablation. Histological examination of αAM-treated tumors showed evidence of disruption of tumor vascularity, with depletion of vascular as well as lymphatic endothelial cells and pericytes, and increased lymphatic endothelial cell apoptosis. Importantly, αAM potently blocks tumor-associated lymphangiogenesis, but does not affect established vasculature and lymphatic vessels in normal adult mice. Conclusion: We conclude that expression of AM upon androgen ablation in CaP plays an important role in hormone-independent tumor growth and in neovascularization by supplying/amplifying signals essential for pathological neoangiogenesis and lymphangiogenesis.”
Corn PG, Wang F, McKeehen W, Navone N. Clinical Cancer Research. Sep 19, 2013.
“Advanced prostate cancer carries a poor prognosis and novel therapies are needed. Research has focused on identifying mechanisms that promote angiogenesis and cellular proliferation during prostate cancer progression from the primary tumor to bone-the principal site of prostate cancer metastases. One candidate pathway is the fibroblast growth factor (FGF) axis. Aberrant expression of FGF ligands and FGF receptors leads to constitutive activation of multiple downstream pathways involved in prostate cancer progression, including mitogen-activated protein kinase, phosphoinositide 3-kinase, and phospholipase Cγ. The involvement of FGF pathways in multiple mechanisms relevant to prostate tumorigenesis s provides a rationale for the therapeutic blockade of this pathway, and two small-molecule tyrosine kinase inhibitors-dovitinib and nintedanib-are currently in phase 2 clinical development for advanced prostate cancer. Preliminary results from these trials suggest that FGF pathway inhibition represents a promising new strategy to treat castrate-resistant disease.”
Pecot CV, Rupaimoole R, Yang D, Akbani R, et al. Nature Communications. Sept 10, 2013.
We demonstrate a difference in clinical outcome based on miR-200’s role in blocking tumour angiogenesis. We demonstrate that miR-200 inhibits angiogenesis through direct and indirect mechanisms by targeting interleukin-8 and CXCL1 secreted by the tumour endothelial and cancer cells. Delivery of miR-200 members into the tumour endothelium resulted in marked reductions in metastasis and angiogenesis, and induced vascular normalization.