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Oncology Highlights - September 2018

Oncology Highlights - September 2018

Stay informed on the latest news within oncology drug development! Subscribe to our newsletter to keep up to date with last month’s science, industry and regulatory oncology highlights!

Enjoy reading! - The SMS-oncology team

 

Publications

A cure within us: Nobel Prize in Physiology or Medicine 2018 awarded to 2 pioneers in IO

Although cancer immunotherapy seems as a recent innovation at a first glance, it goes back to 150 years ago where scientists attempted to use the infectious agents to stimulate the immune system to fight against cancer. Since then, many discoveries in the fields of basic immunology and tumor biology advanced our understanding. Along with previous Nobel Prizes in cancer treatment for hormone treatment for prostate cancer (Huggins, 1966), chemotherapy (Elion and Hitchins,1988), and bone marrow transplantation for leukemia (Thomas 1990), seminal research of James P. Allison and Tasuku Honjo revolutionized contemporary oncology practice. On Monday 1 October 2018, Nobel Prize for Medicine is awarded to James P. Allison of the United States and Tasuku Honjo of Japan for their discovery of cancer therapy by inhibition of negative immune regulation better known as ‘checkpoint inhibitors’ Dr. Allison identified a checkpoint called CTLA-4 in the 1990s. With a cancer treatment in mind, he developed an antibody to block the function of CTLA-4 unleashing the immune system to attack cancer cells. Around the same years, in 1992, Tasuku Honjo discovered PD-1, another T cell brake protein on the T cell surface which has proven to have dramatic effects in 2012 a key study for leading to long-term remission and possible cure. We are only at the beginning of the immuno-oncology era and there is yet much progress to be done. The Nobel committee's acknowledgment on the accomplishments of the two laureates marks the beginning of this era with an entirely new principle for cancer therapy. (Image credits: nobelprizemedicine.org/)

 

High glucose levels link to cancer through decrease in DNA methylation

Diabetes can predispose to cancer, however the underlying mechanisms were not known until now. In a recent study scientists revealed the association between prolonged high blood glucose levels and cancer pathology due to decreased DNA hydroxymethylation in diabetes patients. DNA cytosine methylation (5mC) is an epigenetic mark that silences gene expression and is deregulated often in cancer. 5mC can be removed via an intermediate mark, hydroxymethylcytosine, (5hmC) catalyzed by the ten-eleven translocation (TET) family of dioxygenases. Comparing the peripheral blood mononuclear cells (PBMCs) derived from healthy and diabetic individuals revealed that diabetes is associated with a decrease in 5hmC and TET levels resulting in increase in gene expression over 30.000 genomic regions associated with cancer pathways. TET enzyme is regulated by AMP-activated kinase (AMPK) which is a nutrient and energy sensor that is potently activated by low glucose and inactivated by high glucose. AMPK inactivation results in TET degradation and subsequently decrease in silencing marks within genome. In summary, AMPK–TET2–5hmC axis is impaired in hyperglycaemic conditions which has potential implications for cancer therapy. The article is published in Nature. (Image credits: Lara Crow/Springer Nature Limited)

 

Switching the gears in CAR-Ts

182 patients to date have been treated by CAR-T cell immunotherapy with successful overall response in leukemias and lymphomas. However efficacy of this ground breaking method remains limited against solid tumors. Markers that are overexpressed in solid tumors such as Pancreatic ductal adenocarcinoma (PDAC) are often found also in healthy cells (such as Her2) making it difficult to target due to cellular toxicities. Researchers developed a new CAR-T method to overcome the problem with switchable systems. In this system CAR-T cell is controlled by tumor antigen-specific recombinant Fab-based ‘switch’ to afford a fully tunable response to control the activity. The “switch molecule” acts as an adapter between the tumor and CAR-T cells which increases the specificity and also makes the treatment safe. In patient-derived PDAC mice models scientists targeted switchable CAR-T against Her2 and showed complete elimination of cancer cells, including those that had spread to the liver and lungs, upon five “switch” injections. There are other creative switch methods under development by various groups such as doxycycline or viral inducible CARs. These results suggest efficacious treatment is possible while affording the potential safety of a control switch. The article is published in Gut - BMJ. (Image credits: Raj D et al., Gut 2018)

 

Industry

Roche acquires UK IO biotech Tusk Therapeutics

Roche pays €70M upfront and with a commitment of €585M more in milestones to have access to Tusk Therapeutics’ CD25 pipeline. Founded by Belgian Oncology Venture Droia in 2014, Tusk has licensing agreements with Cancer Research Technology (CRT) and UCL and owns two late-preclinical programs: a first-in-class anti-CD25 antibody and an immunomodulatory anti-CD38 antibody. Based on the research of Sergio Quezeda (Cancer Research UK, UCL Cancer Institute) anti-CD25 program is developed for inhibiting suppressive regulatory T cells (Tregs) in the tumor microenvironment. The buyout gives Roche the Treg IP, and allows the team at Tusk spin out into a new company called Black Belt Therapeutics. The other program of Tusk on anti-CD38 is designed to suppress Tregs and to boost an immune response in multiple myeloma. Roche has been trying to move forward amongst competitive PD-1/PD-L1 space. With the latest positive results of IMpower133 study (atezolizumab in combination with chemotherapy) which improved OS and PFS in extensive stage small cell lung cancer, Roche steals a front seat in September on immuno-oncology.

 

Affimed and Genentech partnership to ROCK

The German biotech Affimed and Genentech announced their collaboration for developing NK Cell Engager Immunotherapies using Affimed’s Redirected Optimized Cell Killing (ROCK) platform. With an $96M upfront payment, Genentech -a member of the Roche group- will be able to utilize this proprietary platform to identify and progress innate immune cell engager-based immunotherapies. The ROCK platform is used to generate highly customizable natural killer (NK) cell and T cell-engaging antibodies to boost immunotherapy response. The partnership also includes candidate antibodies that are developed from the ROCK platform and numerous undisclosed solid tumor and blood cancer targets. Affimed will also be eligible to receive up to an extra $5B over milestones, as well as royalties on sales. The partnership will become one of the top 10 most valuable immuno-oncology collaborations of 2018 so far.

 

EMA/FDA

EMA

The Committee for Medicinal Products for Human Use (CHMP) recommended granting marketing authorisation for:

  • Brigatinib (Alunbrig, Takeda), for the treatment of adult patients with anaplastic lymphoma kinase positive advanced non-small cell lung cancer previously treated with crizotinib. This next generation ALK inhibitor  has proven superior activity over crizotinib and hence has a potential to be in first-line therapy soon.

The CHMP extended the marketing authorization for:

  • Paclitaxel micellar (Apealea, Oasmia Pharmaceutical) in combination with carboplatin for treatment of adult patients ovarian cancer. Apealea is a Cremophor- and albumin-free formulation of the well-known cytostatic paclitaxel combined with Oasmia’s excipient technology XR17. Approval comes after Phase III study showed non-inferiority between the two treatment groups of Apealea in combination with carboplatin versus Taxol in combination with carboplatin.

FDA

The FDA granted regular approval for:

  • Dacomitinib (Vizimpro, Pfizer) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test. Earlier this year, the FDA granted Priority Review for VIZIMPRO for the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR-activating mutations
  • Duvelisib (Copiktra, Verastem) for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies. Duvelisib also received the accelerated approval for adult patients with relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies. This first and only oral dual phosphoinositide-3-kinase (PI3K)-delta, P13K-gamma inhibitor on the market play a role in the formation and maintenance of the supportive tumor microenvironment.
  • Moxetumomab pasudotox-tdfk (Lumoxiti, AstraZeneca) for adult patients with relapsed or refractory hairy cell leukemia (HCL) who received at least two prior systemic therapies. CD22-directed cytotoxin is the first medicine approved by FDA for this condition in more than 20 years.

Guidelines

Two draft guidelines from FDA have been published:

Adaptive designs for clinical trials of drugs and biologics: The guidance describes important principles for designing, conducting, and reporting the results from an adaptive clinical trial. It  advises sponsors on the types of information FDA needs to evaluate the results from clinical trials with adaptive designs, including Bayesian adaptive and complex trials that rely on computer simulations for their design. As FDA indicates in the document, adaptive designs can provide a variety of advantages over non-adaptive designs in statistical efficiency, ethical considerations, answering broader questions and acceptability to stakeholders with flexibility.

Master protocols: efficient clinical trial design strategies to expedite development of oncology drugs and biologics: This guidance provides recommendations to the design and conduct of clinical trials intended to simultaneously evaluate more than one investigational drug and/or more than one cancer type within the same overall trial structure (master protocols) in adult and pediatric cancers. In general, the recommended phase 2 dose (RP2D) has been established for an investigational drug or drugs evaluated in a master protocol. The term master protocol is used to describe with variable terms such as umbrella, basket, or platform designs. The guidance document describes the potential opportunities and challenges posed by these designs. FDA recommends: 1-) using a single SoC control arm, 2-) in case of novel combination of investigational drugs, a strong scientific evidence to be provided, 3-) early discussion of combinatorial use of biomarkers , 4-) adding and stopping treatment arms when needed, 5-) providing the charter for an independent radiologic review committee and the independent data monitoring committee (IDMC).