Oncology Highlights - October 2016
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.
Kind regards, the SMS-oncology team
Cancer cells also have Alzheimer’s; novel treatment options
A new study published in Developmental Cell highlights that amyloid bodies (A-bodies), known to play a role in the development of neurological diseases like Alzheimer’s, contribute to cancer progression as well. A-bodies are formed under “amyloidogenesis”, a physical process in which large amounts of proteins are stored into cells that enter a dormant state upon extracellular stress. The researchers found large quantities of A-bodies present in dormant cancer cells, which can be activated as progressing cancer cells again once the heat shock chaperone pathway disaggregates the A-bodies. Stopping the disaggregation process would be an attractive anti-cancer therapy. The team found that ribosomal intergenic noncoding RNA (rIGSRNA) can regulate the process of amyloid formation in cancer cells, indicating a possible drug target. The researchers believe that keeping cancer cells inactive, instead of getting rid of them, would be a novel treatment option for cancer. This brings hope as drugs targeting both rIGSRNA and the heat shock chaperone pathway are already on the market.
Ipilimumab resistance due to genomic IFN-γ defects
Among the “hot” immuno-oncology checkpoint inhibitors nowadays is ipilimumab, a monoclonal antibody that activates the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system. In this process the cytokine IFN-γ plays a critical role. Yervoy was approved for the treatment of metastatic melanoma by EMA and FDA in 2011 already, but reasons for benefitting the survival of only a subset (~20%) of patients were still unknown. Researchers now published the first clearly defined resistance pathway to ipilimumab in the journal Cell. They show that non-responders to ipilimumab have IFN-γ pathway gene defects in their tumor cells. Furthermore, IFN-γ receptor 1 (IFNGR1) knowdown mice with melanoma tumors were found to have impaired rejection upon ipilimumab therapy. Tumor genomic data, especially loss of IFN-γ, show a promising predictor for ipilimumab responses and for exploring new combinations to defeat this resistance.
New ways to treat aggressive brain tumors?
Glioblastoma is the most common and malignant brain tumor in adults. Despite the current use of multimodal therapy comprising surgical resection, radiation and chemotherapy, the median patient survival of only 14 months from diagnosis remains poor. These therapy methods focus on eradicating the bulk of the tumor mass, however a small subpopulation – the cancer stem cells (CSCs) – often escape this destiny. The so-called glioblastoma stem cells or glioma sphere-forming cells (GSCs) are capable of self-renewal, tumor initiation and differentiation into specialized cell types thereby enabling tumor recurrence, a major cause of glioblastoma mortality. Researchers now have found two enzymes in the GSCs called ADAM10 and ADAM17 to be associated with GSC migration and function of the tumor cells. They also observed a correlation with these enzymes and the stem/progenitor marker nestin as well as the extracellular matrix protein fibronectin. Collectively, these results may suggest possibilities for promoting GSC migration outside of the tumorigenic niche by targeting ADAM10 and ADAM17, and in such a fashion stimulate a differentiated phenotype that is more susceptible to treatment.
Gut bacteria stimulating immune system to boost chemotherapy
In recent research gut bacteria have shown to affect cancer in a way, either by promoting or halting tumor growth, although the particular type of species and their effects were unclear. A new publication in Immunity shows more insights into the complex interaction between chemotherapy, the immune system and gut bacteria. By investigating both mouse models and analyzing patient blood T cell responses, researchers found that in particular two gut bacteria species – Enterococcus hirae and Barnesiella intestinihominis – boost the effect of the common chemotherapy cyclophosphamide by activating T cells. The specific-memory Th1 cell immune responses that was stimulated by these bacteria predicted longer progression-free survival (PFS) in advanced lung and ovarian cancer patients treated with chemo-immunotherapy. According to Dr. Chamaillard leading the project, these results indicate possibilities for improving the design of anticancer treatments for increased efficacy, e.g. via optimizing the use of antibiotics, or supplementing with oncomicrobiotics. Further research is planned to discover which specific bacterial metabolites or immune-modulating molecules are responsible for this boosting effect.
Amyloidogenesis; the physical process in which large amounts of proteins are stored into cells that enter a dormant state upon extracellular stress (ref: Audus et al. 2016, Developmental Cell)
Astellas acquires Ganymed for up to $1.4B
Pharma giant Astellas announced this month to acquire Ganymed Pharmaceuticals for a deal worth up to $1.4B. The private German biotech company is developing their so-called Ideal Monoclonal Antibodies (IMABs) that bind to cancer-selective targets predominantly expressed in tumor cells with little or no expression in healthy tissue. With the deal, Astellas gains Ganymed’s lead program IMAB362 that is selective and specific for the tight junction protein Claudin-18.2 (CLDN18.2). IMAB362 showed impressive results in terms of overall survival and PFS in the phase IIb trial (FAST) in gastroesophageal cancer patients positive for CLDN18.2, thereby stealing the show at ASCO. Under the terms, Ganymed will receive €422 million ($461 million) upfront and up to an additional €860 million ($940 million) in milestones based on the progress of IMAB362.
EMA / FDA
The Committee for Medicinal Products for Human Use (CHMP) adopted a position opinion for:
- Venetoclax (Venclyxto, Ablynx) for the treatment of chronic lymphocytic leukaemia (CLL) in the presence of 17p deletion or TP53 mutation in adult patients who relapsed or are refractory to chemo-immunotherapy and a B-cell receptor pathway inhibitor. Venetoclax acts by inhibiting BCL-2 (B cell lymphoma-2), a protein overexpressed by B-cells in CLL, to induce apoptosis. The small molecule oral drug was granted orphan drug designation on December 2012.
- Nivolumab (Opdivo, Bristol-Myers Squibb) for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL) after autologous stem cell transplant (ASCT) and treatment with brentuximab vedotin. The PD1 inhibitor is already approved for use in melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC).
- Arsenic trioxide (Trisenox, Teva) for induction of remission and consolidation in adult patients with newly diagnosed low-to-intermediate risk acute promyelocytic leukaemia (APL) in combination with all-trans-retinoic acid (ATRA). The drug is already approved for relapsed/refractory APL.
The FDA granted approval to:
- Pembrolizumab (Keytruda, Merck) for the treatment of metastatic NSCLC patients with PD-L1 expression as determined by an FDA-approved test. This is the first FDA approval of a checkpoint inhibitor as first line therapy of lung cancer. The approval also involves an expansion of the PD1 inhibitor to include all patients with PD-L1-expressing NSCLC in second line.
- Olaratumab (Lartruvo, Eli Lilly) for the treatment of patients with soft tissue sarcoma (STS) not susceptible to radiotherapy or surgery and with a histologic subtype in which anthracycline is appropriate. The monoclonal antibody directed against PDGFRA was granted accelerated approval based on significant approval of overall survival of 26.5 months (olaratumab + doxorubicin) vs 14.7 months for those receiving doxorubicin alone. Being part of conditional approval, a randomized, controlled study is required for verification of the results.
- Atezolizumab (Tecentriq, Genentech Oncology) for the treatment of patients with metastatic NSCLC whose disease progressed during or following platinum-containing chemotherapy. With regards to patients with EGFR or ALK mutations, the PD-L1 inhibitor may only be given upon disease progression on FDA-approved therapy for these aberrations. Atezolizumab was already granted accelerated approval for metastatic urothelial carcinoma.
- Erlotinib (Tarceva, Astellas), in which the use of the tyrosine kinase inhibitor has been made similar for all lines of therapy (maintenance, second or greater line) in NSCLC patients as is currently already the case for first line therapy – this involves limiting the use to NSCLC patients whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. The EGFR inhibitor is also approved as first line treatment of metastatic pancreatic cancer, in combination with the chemotherapy gemcitabine.
EMA opens access to clinical data
As of 20 October 2016, the European Medicines Agency (EMA) gives open access to clinical data for new medicines for human use authorized in the European Union (EU). The website will include the clinical reports contained in all initial marketing authorization applications submitted on or after the policy took effect on January 1, 2015. The policy also applies to applications submitted on or after this same date to vary a marketing authorization for an extension or modification of indication or a line extension. By proactively publishing clinical data, EMA intends to help avoid duplication of clinical trials and encourage development of new medicines; build public trust and confidence in EMA's scientific and decision-making processes; and promote academics and researchers to re-assess clinical data.