Oncology Highlights - July 2017
Reading our newsletter will only take a few minutes and allows you to keep up to date with last month’s news items on oncology drug development!
The SMS-oncology team
Side effects CRISPR-Cas9 presumably not as bad as proposed
Last month’s newsletter reported the results of an article published in Nature concerning CRISPR-Cas9 editing, which supposedly resulted in more than 1000 unexpected mutations, including over 100 large deletions and insertions. The authors claimed that by sequencing the entire genome, they would have found off-target mutations missed by the original studies that only looked at sites resembling the target sequence. Doubts were raised concerning the reported claims from the very beginning with the study size to start with – the study involved only three mice – and critics already called for the article to be withdrawn. A new article proposed a more plausible explanation for the controversial results. The critical point is that the now debated article’s authors assumed the three studied mice were genetically identical, because their parents were closely related. However, looking at the way the mice colony was maintained, it is more likely that the two CRISPR-Cas9-treated mice are actually more closely related genetically to each other than to the control mouse. Moreover, the shared mutations in the edited mice did not resemble the targeted DNA sequences. Therefore, it does not explain why CRISPR would have caused mutations on those sites in two different mice. The contradictory results were published in bioRxiv.
New insights on the relationship between BRCA1 and breast or ovarian cancer
Women with a mutation of the BRCA1 gene have up to a 65 % probability of developing breast cancer by the age of 70, and a 39 % probability of developing ovarian cancer. Study results from researchers from The University of Texas Health Science Center have further clarified the role of BRCA1 in tumorigenesis, of which the mechanism was not clearly understood until now. They found that gene expression-related stress is higher in BRCA1 mutation carrying luminal epithelial cells, the cells where the gene-related breast tumors originate. Here, BRCA1 binds NELF which mediates promoter-proximal RNA polymerase II (Pol II) pausing. Pol II pausing results in R-loop accumulation, which are transcriptional by-products that influence both gene regulation and chromatin reorganization. The authors identified that this R-loop accumulation in luminal mammary cells in both BRCA1 mutation positive patients and BRCA knockdown mice, and is an important contributor to breast cancer development. The study was published in Nature Communications.
Strong association between Parkinson disease and Melanoma
A new study suggests an association between melanoma and Parkinson disease (PD). Researchers from the Mayo Clinic found that patients with PD have a 3.8 fold increased risk of developing melanoma, and patients with melanoma have a 4.2 fold higher risk of developing PD. With such a strong association between these diseases, the article's authors advised treating physicians to counsel melanoma patients about PD risk and to monitor melanoma surveillance in PD patients. The research group now focuses on finding the link between the two diseases by identifying common genes, immune responses, and environmental exposures. The results were published in Mayo Clinic Proceedings.
New non-invasive method to predict the recurrence of bladder cancer
Researchers from the University Hospital of Lyon have developed a novel test to detect returning bladder cancer earlier and more accurately than existing methods. The new method tests urine samples for the abhorrent protein TERT, and has a sensitivity in recurring cancer of 81 % and specificity of 89% compared to a sensitivity of only 34 % with the current standard method, cytology. Moreover, the new test detects recurrence before it spreads to the muscle wall, enabling an easier a possibly better treatment. The test also can differentiate between bladder cancer and urinary tract infections. Study results were published in The British Journal of Cancer.
EMAThe Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for:
- Avelumab (Bavencio, Merck) for the treatment of metastatic Merkel cell carcinoma. The PD-L1 inhibitor was designated as an orphan medicinal product in December 2015.
- Lutetium (177Lu) oxodotreotide (Lutathera, Advanced Accelerator Applications) for the treatment of well differentiated gastroenteropancreatic neuroendocrine tumours (GEP-NETs). The radiopharmaceutical agent was designated as an orphan medicinal product in January 2008.
- Midostaurin (Rydapt, Novartis) for the treatment of adult patients with newly diagnosed FLT3 mutation-positive acute myeloid leukaemia (AML) and for the treatment of adult patients with systemic mastocytosis with associated haematological neoplasm (SM AHN), or mast cell leukaemia (MCL). The protein kinase inhibitor (PKI) was designated as an orphan medicinal product in July 2004.
- Atezolizumab (Tecentriq, Roche) for the treatment of locally advanced or metastatic urothelial carcinoma (UC) and locally advanced or metastatic non-small cell lung cancer (NSCLC). The fully humanized monoclonal antibody is engineered against PD-L1.
- Obinutuzumab (Gazyvaro, Roche) in combination with chemotherapy for the treatment of patients with previously untreated advanced follicular lymphoma (FL). The anti-CD20 monoclonal antibody was already approved for adult patients with previously untreated chronic lymphocytic leukaemia (CLL) or with comorbidities making them unsuitable for full-dose fludarabine based therapy, and for patients with FL who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen.
- Pembrolizumab (Keytruda, Merck) for the treatment of locally advanced or metastatic UC in adults who have previous received platinum-containing chemotherapy or patients who are not eligible for cisplatin-containing chemotherapy.
The U.S. Food and Drug Administration adopted a positive opinion for:
- Blinatumomab (Blincyto, Amgen) for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in adults and children. The anti-CD19 monoclonal antibody already received accelerated approval in December 2014 for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL, which confirms the clinical benefit required under the accelerated approval.
- Neratinib (Nerlynx, Puma Biotechnology) for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy. The Tyrosine Kinase Inhibitor (TKI) showed an invasive disease-free survival (iDFS) of 94.2% in patients treated with neratinib compared with 91.9% in those receiving placebo.
New guidelines for the design of early-phase clinical trials of cellular and gene therapy products
The Center for Biologics Evaluation and Research (CBER) has developed new guidelines to assist sponsors and investigators in designing early phase clinical trials with cellular therapies (CT) and gene therapies (GT), collectively referred to as CGT products. This guidance provides recommendations regarding to clinical trials in which the primary objectives are the initial assessments of safety, tolerability, or feasibility of administration of investigational products. This includes most phase 1 trials, the initial introduction of an investigational new drug into humans, and some phase 2 trials of CGT products.