Clinical trials help determine whether new cancer treatments are safe and effective, and they provide access to cutting-edge drugs that patients wouldn’t otherwise be able to have. But the clinical trial system is notoriously inefficient, slow, expensive, and laborious. Now, a new and ambitious clinical trial design called the Lung Cancer Master Protocol seeks to overhaul the system, promising to benefit patients and drug companies alike.
The existing system is particularly unsuitable for the targeted and immune therapies that comprise a majority of the investigational cancer drugs in this decade. The Master Protocol focuses on squamous lung cancer to test a combination of several novel approaches to clinical trial design (about one-quarter of all lung cancer cases are squamous).
An entirely novel aspect of the Master Protocol is an alliance of several partners not previously known for close collaboration: the National Cancer Institute (NCI); the Foundation of the National Institutes of Health (FNIH); the U.S. Food and Drug Administration (FDA); the advocacy group, Friends of Cancer Research; and, of course, the pharmaceutical industry.
Unlike conventional trials, the Master Protocol does not focus on a single drug or drug combination, but rather, on a number of drugs that are expected to be effective against squamous lung tumors having distinct drug targets (genetic mutations), which are detected by molecular testing. Similar but smaller genetic target-driven protocols are already being tested in lung and breast cancers, but they are much more limited in scope, do not involve multiparty efforts, and do not aim to bring many drugs or pharma companies into the mix.
Most importantly, the Master Protocol will attempt to pull off an entirely new model for patient enrollment that is very different from the traditional process. In the Master protocol, patients’ tumors are screened for multiple genetic mutations. Based on the mutations found and the availability of drugs targeting these mutations, patients are sorted into appropriate groups. Each group, or “arm,” uses a drug or drug combination matching the mutation identified in a patients’ tumors.
The Master Protocol’s Steering Committee is comprised of representatives from all of the participating partners: NCI, FNIH, patient foundations, and industry. It has identified 24 drugs that target 16 different mutations, all known to occur in squamous lung cancer.
Master Protocol resources will be pulled to screen about 1,000 patients per year, starting in 2014. Patients will be enrolled through the North American Lung Intergroup, with some 500 participating sites in the U.S. and Canada. This staggering number of participating sites might help attract additional pharma companies to join the protocol. The central management of the protocol promises to reduce the usual exorbitant costs associated with clinical trials.
Foundation Medicine, a company picked through a competitive bidding process, will perform molecular testing to detect genetic mutations that can serve as drug targets. The Foundation One test analyzes well over 200 cancer genes in each tumor sample. The ability to screen a large number of cancer-related genes will enable matching of patients to the right drugs. It will also eliminate the need for participating pharma companies to find their own partnering services for molecular tests, many of which analyze only one gene at a time.
The first stage of the Master Protocol will be phase II, meaning that the drugs are already known to be safe and are ready to be tested for their ability to shrink tumors. The ‘endpoint,’ or goal of this stage will be progression-free survival—the amount of time that passes during which patients’ do not experience the relapse or return of cancer; that is, tumor growth is kept under control. Based on the phase II results, drugs will be advanced to phase III, where the endpoint will be overall survival—the number of patients still alive for a certain period of time after starting treatment. This proposed structure is closely linked to the overall goal of the trial: to, “streamline the drug-approval process by bringing pharmaceutical companies together to test multiple experimental drugs in late-stage clinical trials under a single, ‘master’ protocol” (Nature).
Drugs for the following genetic targets will be tested:
CDK4/6 (targeted by the drug palbociclib; company: Pfizer)
PI3K (drug: pictilisib; company: Genentech/Roche)
MET (drug: rilotumumab; company: Amgen)
FGFR (drug: AZD4547; company: AstraZeneka)
PD-L1(drug: MEDI4736; company: MedImmune)
There are benefits for all parties involved in the Master Protocol: an efficient enrollment process that allows screening of a large number of patients; fast-tracked access to investigational drugs for patients, especially for those with rare mutations; operational efficiency and adaptive design (drugs can be dropped or added quickly according to ongoing results); and consistency (every drug is being tested in an identical manner).
The prospect of speeding up the process of drug approval by the FDA makes the Master Protocol a very attractive adaptive design model, highly compatible with drug development in this era of targeted and immune therapies for cancer. Hopefully, the Master Protocol and other bold attempts to revamp the antiquated clinical trial system will help to bring it into the 21st century, ultimately benefiting patients. For now, patients with squamous lung cancer stand to benefit from faster access to promising investigational drugs.