Oncology Highlights - April 2018
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Enjoy reading! - The SMS-oncology team
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Drug screening methods based on the 2D cancer cell line collections have provided major advancement into genetic predictions of drug response in preclinical stage. However, due to their low resemblance to native tumor tissue results in the high failure rate of newly discovered drugs in clinical practice. A recent review by Jarno Drost & Hans Clevers following a publication on the Patient-derived tumor organoid (PDO) models to predict treatment outcomes highlight the clinical utility of in vitro 3D culture technologies in precision medicine. In this publication, researchers in Institute of Cancer Research in London used the colon and rectal cancer cells from 71 patients to grow miniature personalized 3-D tumors. A library of 55 drugs which are now in phase I to III clinical trials (e.g. olaparib, dasatanib, nilotinib) or in clinical practice were tested ex vivo in organoids and PDO-based orthotopic mouse tumor xenograft models. Responses and genotype–drug phenotype correlations were compared with the results of the patients in (co-) clinical trials. The findings indicated that PDO models predicted the positive response of the patient to a drug with 88% accuracy. Also, PDO tests forecasted the negative outcome with 100% accuracy. PDOs can be particularly useful in the era of battling resistance against single therapeutic agent with multidrug combination therapies and prediction of responders with the use of biomarkers. With regards to immunotherapy, several recent studies achieved to establish culture systems in which the healthy donor haematopoietic cells are expanded in vitro in co-cultures with tumor organoids. These systems allow the test for immunogenicity of T cell subtypes which can be expanded and subsequently used to treat patients. Application of high-throughput drug screening methods in PDOs is just beginning to be explored with a great potential behind it. The review is published in Nature Reviews Cancer, the study is published in Science.
Image source: Jarno Drost & Hans Clevers, Nature Reviews Cancer 2018
Through the development of next-generation sequencing (NGS)-based assays together with the parallel rapid progress in cancer biology and therapeutics, NGS-based diagnostic assays entered the clinics proving a successful clinical utility to direct therapeutic decision-making. Clinical translation of cancer genomics covers a broad palette of applications including the use of genomics to guide the selection of best targeted treatment for patients according to the tumor genomes (such as in immunotherapeutic agents), understanding the emerging resistance against anticancer therapy and their use for predicting patient outcomes. NGS assays enable the characterization of cancer genomes, transcriptomes, and epigenomes however statistical analysis of data from multiple NGS-based assays, in addition to the intrinsic complexity of cancer, introduce challenges. In a recent review, Michael Berger and Elaine Mardis highlights the advances and challenges of NGS in clinical cancer care. They touch the technology issues such as choice of comprehensive (whole-genome, whole-exome: expensive, time consuming) versus the more-targeted approach (limited in discovery power). Also importance of data mining / sharing is highlighted to ensure the significance of genomic findings. The common issues arise due to differences in NGS platforms and lack of standardized language or fields for clinical data elements, as well as inconsistent institutional policies on data privacy. On the clinical discovery side, NGS is becoming a part of immunotherapeutic decision-making. Correlation between tumor mutational burden (TMB) and sensitivity to immune-checkpoint inhibition, predicting neo-antigens through comparing NGS exome-sequencing data from tumors to nonmalignant cells for the design of antitumour vaccines, high resolution profiling of liquid biopsy for cfDNA, cfRNA and even microRNAs are some powerful examples. Authors conclude the ‘big data’ obtained from preclinical and clinical applications should enable integration approaches that combine genomic and clinical data, however expanding the patient access and reproducibility of NGS will be future challenges. The review was published in Nature Reviews Clinical Oncology.
Image source: Michael Berger and Elaine Mardis, Nature Reviews Clinical Oncology 2018
On April 24, Hong Kong exchange opened its listings to companies with no revenue, and a lineup of biotech unicorns are shifting their attention from NASDAQ to HKEX for their IPO application. Two big Chinese start-ups –Innovent Biologics and Ascentage Pharma - joined the queue of booming Chinese biotech scene, replacing Nasdaq as the go-to place for new listings. Innovent is looking to raise a $300 million to $500 million, with Ascentage lining up $300 million. After the four-year of development, HKEX’s new regime is open for business expanding the listings to include the biotech that do not meet any of the Main Board financial eligibility tests. Although it is suggested that the investors aren’t as mature as US investors for biotech industry which has extraordinary risks, IPO for biotech has been long in the horizon, they might well be schooled ready.
Despite their great potential, response rates (often around 10-20%) to immunotherapies remains a challenge in their application in clinic. A partnership between Institut Gustave-Roussy, a leading cancer center based near Paris, and the German company Protagen Diagnostics aim to better predict and analyze immune-related adverse events (AEs) in cancer patients being treated with immune checkpoint inhibitors. The collaboration will use SeroTag which is an antibody discovery platform from Protagen to detect the autoantibodies in patients receiving immunotherapies to help predict treatment response and guide clinical decisions. As the combination therapies enter to the clinics, the patients are at the risk of developing debilitating and sometimes fatal immune related AEs. Ongoing Gustave Roussy Immunotherapy Program (GRIP) aims to strengthen translational research accelerating the development of immunotherapy in clinics and bring access to larger number of patients. The collaboration will be a part of the GRIP with the clinical use of SeroTag to monitor cancer patients, detect irAEs, and conduct comprehensive risk profiling for those undergoing immunotherapy.
The Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for:
- Carmustine (Carmustine Obvius, Obvius) for the treatment of brain tumours, non-Hodgkin’s lymphoma and Hodgkin’s disease. The generic is a an alkylating agent which prevents DNA replication and transcription similar to its reference product Carmubris.
The CHMP recommended extensions of indications for:
- Pertuzumab (Perjeta, Roche) in combination with trastuzumab and chemotherapy in the adjuvant treatment of adult patients with HER2-positive early breast cancer at high risk of recurrence. The HER2 antogonist was already approved (in this combination) for the neoadjuvant treatment of adult patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer at high risk of recurrence
- Dasatanib (Spyrcel, Bristol-Myers Squibb) for pediatric patients that are newly diagnosed Ph+ CML in chronic phase (Ph+ CML‑CP) or Ph+ CML‑CP resistant or intolerant to prior therapy including imatinib. The TKi was already approved for adult patients in the same indication.
- Osimertinib (Tagrisso, AstraZeneca) as monotherapy for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations. The TKi is initially approved for locally advanced or metastatic EGFR T790M mutation-positive NSCLC in adult patients.
- Ipilumumab (Yervoy, Bristol-Myers Squibb) as monotherapy, for the treatment of advanced (unresectable or metastatic) melanoma in adults and adolescents (12 years of age and older) and in combination with nivolumab for the treatment of advanced (unresectable or metastatic) melanoma in adults. Monotherapy with this checkpoint inhibitor showed an increase in progression-free survival (PFS) and in combination with nivolumab showed an increase in overall survival (OS), currently only established in patients with low tumour PD-L1 expression.
The FDA granted regular approval for:
- Osimertinib (Tagrisso, AstraZeneca) for the first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.
- Nivolumab and ipilimumab (Opdivo and Yervoy, Bristol-Myers Squibb) in combination for the treatment of intermediate or poor risk, previously untreated advanced RCC.
Rucaparib (Rubraca, Clovis Oncology) for the maintenance treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Concurrently a complementary diagnostic test, FoundationFocus, was also approved to determine homologous recombination deficiency (HRD) status in tumor samples as the PARP inhibitor demonstrated a statistically significant improvement in estimated median PFS in ARIEL trial in the patients HRD+.