Oncology Highlights - August 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
It goes without saying that targeting the immune evasion mechanism of PD-L1/ PD-1 signaling through the inhibitors have been ground breaking amongst the anti-cancer treatments of the past decade. However many patients with PD-L1-producing cancers do not respond to these therapies. In order to understand the mechanism behind the non-responders, researchers in University of Pennsylvania and Mayo Clinic studied extracellular vesicle (exome) content as such vesicles may be carriers of bioactive molecules that influence the extracellular environment and the immune system. Their findings showed that melanoma, lung and breast cancer cells not only express the PD-L1 ligand on the surface but also release small vesicles carrying PD-L1 to blood stream to systemically suppress immunity. They also showed a positive correlation between the increase in circulating exosomal PD-L1 during early stages of treatment and its stimulant IFN-γ which fluctuated during anti-PD-L1 therapy. Their findings suggests that the initial levels and the fold change of exosomal PD-L1 levels in blood stream can provide a rationale for the application of exosomal PD-L1 as a predictor for anti-PD-1 therapy. The study is published in Nature.
Early detection of melanoma is key in determining outcomes, as the 5 year survival can be as low as 10% if discovered only in advanced stage. Through the recent developments in digital health technologies, many digital applications rush to the oncology market to aid skin cancer diagnosis. During the 98th Annual Meeting of British Association of Dermatologists’, researchers evaluated the accuracy and clinical utility of various skin apps. Such technology can improve awareness and detection, however some apps were more successful than others for distinguishing malignant and benign moles and lesions the study found. Flaws in algorithms and rare skin symptoms resulted in lower diagnostic accuracy indicating that the review of medical specialists is required. However, the same problem is valid across and reflective of a widespread issue within the field of digital health. Often funded by Medtech investing VCs, start-ups rush the development process without adequate input from medical experts and testing. As the digital oncology market continues to grow, healthcare-sector regulatory bodies should plan digital reporting guidelines and robust randomized clinical trials to provide concrete evidence to identify the trustworthy technologies. The article is published in Lancet.
Currently there are no established markers to accurately identify the patients who will respond to anti-PD-1/PD-L1 immunotherapy resulting in as low as 15 to 30% respond rates. One indication that correlates with positive outcome is the tumor immunogenic environment which can be characterized by imaging and radiomic signature. In a recent study researchers show for the first time artificial intelligence (AI) processing of the images to predict such an immunotherapy response. Based on a machine learning approach, the team initially trained the algorithm to use relevant information extracted from CT scans from MOSCATO study1 which also contained tumor genome data. Just using the images, the algorithm learned to predict what the genome revealed about the tumor immunologic environment and established a radiomic signature. The algorithm put on the test in a real situation to correlate the efficacy of immunotherapy using CT scans in 5 phase I trials of anti-PD-1/PD-L1 immunotherapy. The program found that the patients with effective therapy had higher radiomic scores as did those with better overall survival. The results prove for the first time that an AI method and imaging could predict a biological phenomenon. The article is published in Lancet.
August (immuno) oncology M&A overview: Genmab & Immatics, bluebird bio and Gritstone Oncology, bluebird bio and Regeneron, Affimed and Genetech
M&As have not stalled during the summer period. Genmab and Immatics Biotechnologies agreed to partner for developing next-generation bispecific cancer immunotherapies through a collaboration that could generate more than $2.8 billion for Immatics. XPRESIDENT® platform of Immatics -designed to identify novel cancer epitopes- and T-cell receptor (TCR) technologies will be licensed by Genmab with an upfront payment of $54M. In a similar approach for identifying TCRs, bluebird bio and Gritstone oncology signed a deal aiming to power up development of cell therapies. Collaboration will enable blue bird using the Gritstone Oncology’s proprietary EDGE™ artificial intelligence platform which is designed to identify tumor-specific targets and natural TCRs. Gristone will provide bluebird with 10 neoantigens with an upfront payment of $20M and later $10M in the form of a series C preferred equity investment. Earlier this month bluebird bio signed another big deal with Regeneron for collaboration to support pre-clinical CAR-T and T cell receptor programs. Leveraging Regeneron’s VelociSuite® to enable the creation of fully-human antibodies and T cell receptors, the costs will be split equally until the clinical stage. Another cell based immune oncology expert, Affimed announced the strategic partnership with Genentech to develop novel Natural Killer (NK) Cell engager-based immunotherapeutics for multiple cancer targets. Upon agreement, Affimed will receive an upfront $96M and other near-term committed payment.
After a month of scoring CHMP recommendations for Kymriah and Yescarta in Europe, both Novartis and Gilead received the final marketing authorization from European Commission in August. Following the approvals, before marketing new drugs, companies are entering though negotiations with authorities in individual countries to decide pricing and reimbursement which might create issues due to drug prize. In a recent disappointment for Gilead, Britian’s National Insititute for Health and Care Excellence (NICE) rejected Yescarta finding it too expensive to justify its use on Britain’s state-funded health service. Despite to this, marketing approvals cover 28 countries across Europe, indicating a high demand and need for expanding manufacturing capability. Speed is the essence to manufacturing CAR-T drugs and both drug makers are willing to invest in best production sites possible. Gilead announced earlier to build a manufacturing facility in Amsterdam, home base of Kite Pharma expecting to employ 300 employees and be in full operation by 2020. The Swiss drug maker plans to spend CHF90M ($91.5M) over three years on an existing building at a production site in Stein, Switzerland creating 450 jobs by 2021.
The Committee for Medicinal Products for Human Use (CHMP) did not hold a meeting during August.
The FDA granted regular approval for:
- Lenvatinib capsules (Lenvima, Eisai) for first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). This approval was based on results from REFLECT study (Study 304) which is the first-ever positive Phase 3 trial against an active comparator in unresectable HCC.
The FDA extended the prescribing information for:
- Pembroluzimab (Keytruda, Merck) and atezolizumab (Tecentriq, Roche) to require the use of an FDA-approved companion diagnostic test to determine PD-L1 levels in tumor tissue from patients with locally advanced or metastatic urothelial cancer who are cisplatin-ineligible. FDA approved two different companion diagnostic tests, one for use with Keytruda and one for use with Tecentriq.
- Pembroluzimab (Keytruda, Merck) in combination with pemetrexed and platinum as first-line treatment of patients with metastatic, non-squamous non-small cell lung cancer (NSqNSCLC), with no EGFR or ALK genomic tumor aberrations. Approval of the expanded label for KEYTRUDA based on data from the KEYNOTE-189 trial and an important milestone being the first checkpoint inhibitor therapy in 1L in this patient population.
- Nivolumab (Opdivo, Bristol-Myers Squibb) for patients with metastatic small cell lung cancer (SCLC) with progression after platinum-based chemotherapy and at least one other line of therapy. This approval makes Opdivo, the first new medication in almost 20 years for this specific subset of patients, as well as the first and only immunotherapy option for them.
Two draft guidelines from FDA have been published:
Use of placebo in oncology trials: Sponsors are advised to use a placebo-controlled design only in select circumstances such as “where surveillance is standard of care,” or with specific trial “design features” (e.g. if the trial uses an add-on design, when the endpoint intended to support a labeling claim has a high degree of subjectivity, such as patient reported outcomes).” A rationale for the trial design and proposal for blinding and unblinding should be provided to FDA.
Expansion cohorts in first-in-human oncology trials: Aiming for seamless clinical research, the draft guidance discusses ways sponsors can shorten the traditional three phases into one continuous trial as an expansion cohort trial. Accelerating the development process from first in human (FIH) to marketing, expansion cohort trials can bring efficiency to drug development, potentially reducing development costs and time. This guidance provides FDA’s advice for expansion cohort trials on (1) characteristics of drug products best suited, (2) IND requirements (3) when to interact with FDA and (4) safety guidelines.