This month, the National Cancer Institute (NCI), along with the FDA, the Southwest Oncology Group (SWOG), several private foundations and five pharmaceutical companies, launched a prospective, biomarker-driven study of new drugs for squamous cell lung cancer.
The Lung-MAP trial is remarkable for its collaborative nature, and scope. The study will identify “actionable” molecular abnormalities in tumors specimens from thousands of patients with squamous cell lung cancer. The protocol allows doctors at many medical centers to enroll their patients locally. Meanwhile tumor samples will be checked in a central lab for hundreds of potential abnormalities. Patients are assigned to an investigative arm based on their tumor’s profile, which raises the likelihood of a response.
“This study breaks down some of the barriers that keep patients out of clinical trials,” said Dr. Thomas Lynch, Director of the Smiley Cancer Center at Yale, is a lung cancer specialist and board member of Bristol-Myers Squibb, a company that is not participating in the Lung-MAP study. The design of traditional clinical studies, even if structured to evaluate subsets of patients with particular genetic mutations, can limit their appeal. Many people with the disease won’t qualify, he considered. “If you screen 100 patients, and find just 10 have the abnormality relevant to the trial, that can be frustrating to patients and doctors.”
“What’s exciting about the way Lung-MAP is designed is that with the ‘master protocol,’ there’s something for everyone.” Everyone who enrolls is eligible for an investigational agent. “That doesn’t mean the drug will work, but at least there’s something to test for each patient,” Lynch said.
Lung cancer – what’s really a collection of distinct tumor types arising in the lung or airways – is the leading cause of cancer-related deaths in the United States. According to the CDC, rates among U.S. men and women have been on the decline or leveling off in recent years. Still, the NCI estimates that in 2014, over 224,000 Americans will receive a lung cancer diagnosis, and over 159,000 will die from it. The World Health Organization reports that lung cancer is the most common and lethal tumor worldwide, affecting some 1.8 million men and women, and killing some 1.6 million annually.
Squamous cell, the lung cancer form most closely tied to smoking, accounts for approximately a fourth of cases. The prognosis for patients with advanced disease is poor. “Most of the lung cancer breakthroughs have been in patients with EGFR and ALK mutations,” Lynch said. This trial, by examining mutations in tumor specimens from the squamous cell form of the disease, will allow scientists to identify changes in those tumors for which targeted drugs are not yet available. “This a large group of patients who don’t have great treatment options if their disease progresses,” he said.
Karen Latzka is a 50 year old accountant and lung cancer survivor who lives in Kaneohe, on Oahu, HI. In 2010, her physicians detected an advanced, Stage 3 squamous cell malignancy in her right lung. She was devastated then, at age 46. Initially doctors deemed her case inoperable. But after a course of chemotherapy and radiation, surgeons removed the tumor. Now, three years after completing additional standard treatment, she is in remission and doing well.
Like other lung cancer patients, Latzka fears a recurrence. She was thrilled to hear of the Lung-MAP trial. She learned of it through social media. ”Few protocols have focused on squamous cell lung cancer,” she said. “Squamous cell research has been crushed by smoking stigma.” For patients with this form of advanced cancer, medical options are limited. “If I have a recurrence, I want to benefit from the Lung-MAP trial,” she said.
The fact that the protocol has been designed collaboratively, with multiple pharmaceutical companies, academic researchers and advocacy groups is a plus, in her view. “This has a lot of potential for success, because there are so many great minds included,” Latzka said. But she recognizes that the trial may not help all or even the majority of patients with squamous cell lung cancer. “Is something going to happen with the five drugs they’re starting with? Maybe not. But it’s also possible we’ll see some real breakthroughs,” she said.
Histological section from a sample of lung squamous carcinoma (NIH, Cancer Genome Project image)
“Patients get very frustrated that they do all this sequencing, and then they don’t get on a trial,” said Ellen Sigal. She founded and chairs the Friends of Cancer Research, a policy group that spearheaded efforts to move this project forward. Her group works closely with the FDA, the NCI and other agencies to lessen obstacles to clinical drug development and approval. “This study has an arm for everyone,” she emphasized.
It’s a complicated trial, to say the least. The tumor specimens will be sent to a laboratory run by Foundation Medicine – a company headquartered in Cambridge, MA. Each sample will be checked for any of hundreds of genetic variants by next-generation sequencing, and for specific protein abnormalities by immunohistochemistry. Doctors leading the trial will receive the results and, by algorithm, assign patients to the appropriate experimental arm, or sub-study.
Each Lung-MAP sub-study involves a randomization process, so patients will receive either an experimental drug or, for comparison, standard care with chemotherapy such as docetaxel. Within each arm, the planned endpoints include both overall survival and progression free survival (PFS).
The trial appears on the NIH’s website, ClinicalTrials.gov, as NCT02154490. Or you can read about it on an independent website, Lung-Map.org.
The trial includes five experimental drugs, as follows: MEDI4736, a monoclonal antibody with immune-stimulating properties (it binds to PD-L1) and is manufactured by MedImmune. (This is the study drug that will be tested in patients whose squamous cell tumors lack otherwise “actionable” mutations in the current protocol); GDC-0032, a PI3K (kinase) inhibitor provided by Genentech; Palbociclib, an oral cyclin-dependent-kinase (CDK) inhibitor (said to selectively inhibit CDK-4 and -6), from Pfizer PFE -1.24%;AZD4547, an oral Fibroblast Growth Factor Receptor (FGFR) inhibitor, fromAstraZeneca ; and rilotumumab (an antibody to human Hepatocyte Growth Factor), from Amgen AMGN -1.72%. This intravenous drug will be given to patients along with erlotinib (Tarceva), an oral chemotherapy that is already FDA-approved for some cancer types.
“This is a nice way forward,” said David Wholley, director of Research Partnerships for the Foundation for the NIH (FNIH). His organization has been integral to planning Lung-MAP. He expects that 5,000 patients with squamous cell lung cancer will go on treatment within the study’s framework, over approximately five years. “The cost is about $34,000 per patient,” he said. “So the total estimated cost of the trial is around $169 million.” About two thirds of the study’s expenses will be covered by industry, largely through provision of the experimental drugs. The rest of the tab – $9,000 per patient – is covered by the NCI, mainly through its Clinical Trials Network, and also by the FNIH.
“From the company’s side, they’re able to treat these patients for about 25K per patients,” Wholley said. “While the NCI has reduced money for cooperative groups, this plan enables us to do the studies in a robust way.”
Outlet Full Name: Forbes
Author: Elaine Schattner