Master Key Project Aims To Unlock Japan Rare Cancer Drug Development
Executive Summary
Japan's National Cancer Center is progressing a collaborative project with industry to encourage the development of targeted therapies for rare cancers, as part of wider efforts to support early access to personalized oncology drugs.
In common with many other countries, Japan's relatively low incidence of rare types of cancer has served to dampen industry R&D and clinical trials, given the challenges in recruiting patients to studies, the limited availability of relevant medical expertise, and the comparatively small commercial opportunity for any approved products.
Put together however, rare malignancies – totaling around 200 types in total – account for fully 15% of all cancer diagnoses in Japan, and an ongoing industry-academic collaboration led by the National Cancer Center (NCC) Hospital is aiming to promote genomics-led drug development to address unmet medical needs.
The concept of genomic profiling to encourage individualized therapy is not new, being a central part of the Japanese government's third and current Basic Plan to Promote Cancer Control.
What the NCC is trying to do through several initiatives is to foster the involvement of, and collaboration with, the pharma industry to get new effective therapies to patients more quickly.
"There is a real focus on genomic medicine now in Japan, and there have been recent policy discussions on how to get genomic-based therapies into wider medical use and reimbursed [under the national health insurance system]," Dr Yasuhiro Fujiwara, Deputy Director for Research and Director-General of the Strategic Planning Bureau at the NCC Hospital in Tokyo, told the Pink Sheet in an exclusive interview.
Master Key Components
The NCC says its Master Key Project is the first attempt globally to foster joint genomic medicine research between a national cancer center and the pharma industry.
Going back a few years, an early facet of the challenge was clearly defining "rare," which in oncology varies internationally. In Europe for instance, rare cancers are those with an annual incidence of fewer than six per 100,000 patients, while in the US it is defined as fewer than 15 per 100,000.
In Japan, a government study group in 2015 set the definition of "rare" at the same incidence level as Europe, along with the specific inclusion of "rare histological subtypes of major cancers."
Fujiwara, who has had stints at Japan's regulatory agency, the PMDA, and as a Deputy Secretary General of the Office of Medical Innovation in Japan's Cabinet Secretariat, explained that in its bid to encourage development of targeted therapies, the Master Key (marker-assisted selective therapy in rare cancers: knowledge database establishing registry protocol) program has two main components.
The first is a registry initiative which began earlier this year and is designed to collect genetic and clinical information, along with prognostic data, from patients with rare cancers and rare histological subtypes of common cancers. This will be used to set up a large database for sharing with participating companies.
The target here is for the registration of at least 100 case patients annually, and more than 250 have already enrolled since the registry started up in May 2017, Fujiwara noted, adding that some selected data will also be published.
The second main facet of Master Key is the implementation of a biomarker-driven "basket trial" concept, under which patients will be assigned to investigator- or sponsor-initiated clinical studies with appropriate molecular-targeted drugs, according to specific common biomarkers (genetic abnormalities or protein expression, or lack thereof) and regardless of cancer type.
Matching could be with drugs that are either still investigational, approved but being used off-label for the indication, or approved for the use. Some of the matches made so far include pan-RAF inhibitors for specific KRAS and BRAF mutations, and FGFR2 inhibitors for FGFR2-amplified tumors, for instance in esophageal cancer.
'Oncopanel' Diagnosis Tool
The other key plank of the initiative is ensuring rapid and accurate diagnosis to enable patient allocation to the basket trials.
To this end, the Master Key-affiliated TOP-GEAR project is running in parallel as an in-house NCC program to build up related expertise for next-generation genomic sequencing of cancer samples across all solid tumor types, making use of multiple technologies including immuno-histochemistry and FISH (fluorescence in situ hybridization).
A single-test "oncopanel" companion diagnostic has been developed (with Sysmex Corp.) that allows parallel profiling of 114 mutations/whole exon amplifications and 13 fusion genes customized for solid cancers, which will be used to compare biopsies with a database to identify gene abnormalities.
While the current cost of the oncopanel test borne out-of-pocket by patients is around JPY470,000 (roughly $4,100, excluding other related fees), "We are hoping to get NHI reimbursement," Fujiwara told the Pink Sheet.
Industry Participation
Around 13 clinical trials are now ongoing or in preparation under the Master Key initiative, which has been expanded to western Japan through the participation of Kyoto University Hospital, with other facilities nationwide also in negotiations, Fujiwara noted.
A typical study protocol would be for a 15-25-patient, single-arm Phase II trial, with Bayesian design and response rate as the primary endpoint.
11 drug companies, including major Japanese oncology players Takeda Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Astellas Pharma Inc. and Daiichi Sankyo Co. Ltd. – along with multinationals Pfizer Inc. and Novartis AG – have so far joined Master Key and are contributing investigational drugs and funding to the initiative, Fujiwara said.
The NCC sees this collaborative aspect as critical and providing multiple benefits besides a source of targeted therapies. It provides stable registry and study funding, while companies can access analyses of the registry data and use this as a reliable control for their own sponsored trials, which should also benefit from patient accrual in the rare disease setting.
In a related policy push, talks with policy-makers and regulators are ongoing around a conditional approval system, which could progress within this year for diagnostics and novel, molecular-targeted treatments related to the use of the oncopanel. The idea was accepted in principle at a policy meeting in August.
"This scheme would limit conditional approval coverage to 11 core hospitals with relevant expertise, with the facilities and companies to cooperate in postmarketing evaluation of samples, and pharmacokinetics/pharmacodynamic analyses where required," Fujiwara explained.
More widely, he said that the NCC Hospital is looking to set up a comprehensive system to support genomics-based medicine in Japan within next six years and also hoping to build collaborations with other centers in Asia.
NCC Expertise
The center hospital itself became a semi-independent agency in 2010, as part of which it is exploring avenues to generate operating income, including through links with the pharma industry and in-house, licenseable research.
The hospital already has 1,000-1,500 patients with rare cancers in clinical trials per year, and in 2014 set up a dedicated center for research and treatment in this area, and it also has a telephone hotline that has been taking up to 500 calls a month.
The NCC sees itself – along with key partners including the pharma industry – as playing a critical role in building out national networks in Japan for the research and treatment of rare cancer.
"Our ultimate aim is to expand more [drug] indications to rare cancers and improve early access [to novel new therapies] while ensuring safety and efficacy," Fujiwara said.
From the editors of PharmAsia News.