Scientists at Fred Hutchinson Cancer Research Center are working towards a less invasive, more informative biopsy technique as well as a more precise protocol to identify potential treatments for people with lung cancer, the most deadly cancer in the U.S.
The researchers, part of the Hutch’s lung cancer Specialized Program of Research Excellence, or SPORE, are part of two large national collaborations designed to find more precise ways to diagnose and treat the disease.
“As part of our lung cancer SPORE, we’re taking research discoveries at the bench and getting those into the clinic quickly,” said Dr. Viswam Nair, a pulmonologist and clinical researcher at the Hutch and its clinical-care partner Seattle Cancer Care Alliance.
“I’m very optimistic about the work we’re doing and the enthusiasm and passion of the people at the Hutch to make an impact for all cancer patients.”
Hutch researchers Drs. Mary Redman, Michael LeBlanc and dozens of their colleagues just published findings from the first phase of Lung-MAP, the first biomarker-driven master protocol launched within the National Cancer Institute, in the prestigious British journal The Lancet Oncology.
Lung-MAP is a large NCI-funded precision medicine initiative designed to create a research “roadmap” to discover and use targeted therapies for a subset of non-small cell lung cancer patients. The paper marked the completion of its first phase. The large collaborative project is now in its second phase.
“The whole concept was to create an infrastructure to evaluate targeted therapies paired with biomarkers designed to allow for FDA [Food and Drug Administration] approval. And do it in an efficient way,” said Redman, who heads the biostatistics core for the Hutch lung cancer SPORE and serves as lead statistician for the Lung Cancer Committee of the SWOG Cancer Research Network, which scientifically and operationally led Lung-MAP’s investigational component.
Part of a unique public-private partnership, Lung-MAP involves hundreds of cancer centers, more than a dozen pharmaceutical companies, SWOG and the entire adult NCI's National Clinical Trials Network, the Foundation for the National Institutes of Health, Foundation Medicine and a slew of advocacy groups, most prominently Friends of Cancer Research, but also the American Lung Association, LUNGevity Foundation and more.
With their five-year project involving multiple substudies, the researchers’ goal was to create a new screening and investigational treatment protocol, or template, for metastatic lung cancer patients who relapse after first-line treatment.
“We wanted to create a setting where, no matter what, the patient gets to be part of an investigational study,” Redman said. “And they could do it quickly.”
Master protocols set the standard for how trials are conducted, Redman said. They usually fall into two categories: umbrella trials, which are disease-specific, and basket trials, which look at biomarkers across cancer types, enrolling patients with a particular mutation like KRAS or ALK.
Lung-MAP is an umbrella trial, she said, “and only looking at lung cancers and evaluating biomarkers within that.” Eventually, the template will be used in other cancers, as well.
“We’ve helped inform the conduct of master protocols worldwide,” Redman said.
For this first phase of Lung-MAP, researchers looked at a subset of non-small cell lung cancers, or NSCLCs, known as squamous. NSCLCs make up about 85% of all lung cancers. The squamous type makes up 25% of all NSCLCs.
“When we initiated the trial in this aggressive disease setting, the median survival was eight months,” Redman said. “You can’t tell those patients that they have to wait and ‘we’ll see’ if you can go onto a study.’ We’re trying to meet an unmet need.”
A unique, collaborative cancer clinical trial that uses genetic screening to match patients to investigational new treatments for NSCLCs, Lung-MAP will eventually help patients and clinicians make faster, more informed decisions about the type of targeted treatment that might best work for their particular cancer (or cancer mutation). It will also provide clinicians with information on which targeted treatments don’t work, helping patients avoid unnecessary treatments (and side effects).
“Discovery of targeted therapies is challenging … but important to pursue,” the Lung-MAP researchers wrote in their paper. This is particularly true in cancers driven by rare mutations, where traditional stand-alone clinical trials are unfeasible or take too long to accrue participants.
The Lung-MAP study started with 1,864 people whose tumor tissue was screened for mutations using FDA-approved next-generation sequencing. Genomic DNA was extracted from specimens, amplified, sequenced, analyzed for over 300 genes and additionally screened for MET expression by immunohistochemistry.
Once the analysis was complete, patients were assigned to substudies dictated by their tumors’ predictive biomarkers (or mutations), then were matched to drugs that could potentially target them (pharmaceutical partners provided the drugs).
Conducted between 2014 and 2019, Lung-MAP successfully found biomarker results in 1,674 of the patients screened, and in nearly 84% of those people, 1,404, were assigned to a substudy. Substudy assignments were provided within 16 days from tissue submission for patients with progression and within one day of notification of progression for pre-screened patients.
All told, there were nine substudies evaluating the use of various drugs or drug combinations in metastatic squamous NSCLC patients with predictive biomarkers.
Redman said the first phase of Lung-MAP was not able to come up with new drug approvals, but the initiative was still a success because they “demonstrated that this could be done.”
“We haven’t had successes in the sense that we’ve had drugs come out as positive [working against the cancers], but we have answered questions very efficiently,” she said. “The success is in terms of the overall infrastructure of the study.”
Case in point, one drug Lung-MAP researchers examined in patients with cell-cycle gene alterations — which happens in many cancers — didn’t work for patients.
But that was still an incredibly important finding.
“We wanted to see if a drug that works in breast cancer would work in squamous lung cancers because clinicians were trying it and the question was still open: Was it a driver of an oncogene or not?” she said. “And it looks like sometimes it’s a driver — in a different cancer. In lung cancer, it’s more of ‘passenger.’ Sometimes they’re drivers, sometimes they’re passengers.”
The key point is they put the question to rest, she said.
“Patients could be given these drugs off-label, like a ‘Hail Mary’ by the clinician — and that absolutely could harm them,” Redman said.
Lung-MAP has already begun its second phase of investigation, evaluating targeted therapies for all histological types of metastatic NSCLC. The researchers have also folded in immunotherapy combinations for anti-PD-1 and anti-PD-L1 therapy-relapsed disease.
“It’s pretty clear immunotherapy has transformed the treatment of lung cancer,” she said. “It’s not a cure but we’re trying to do what we can to enhance the activity of immunotherapy to patients who aren’t benefitting or developing resistance. And Lung-MAP is well-suited to answer those questions.”
While Lung-MAP will advance the use of precision treatments in lung cancers (and eventually beyond), another team of Hutch lung cancer researchers is working on a less-invasive way to biopsy these cancers in the first place.
Nair and his team, including Hutch lung cancer SPORE principal investigator Dr. McGarry Houghton, just received a five-year, $2.1 million grant from the NCI to get more bang, in the form of biological data, out of a device known as a bronchoscope.
By coupling high-tech genomic analysis with a low-tech procedure — a bath of the lungs called bronchoalveolar lavage (BAL, for short) — they hope to create a new type of liquid biopsy for lung cancer. Not with blood, but with the fluid from BAL.
“That’s the hope,” Nair said. “It’s a new application of an old technology.”
Currently, lung cancer biopsies can be difficult and risky, Nair said, particularly fine-needle biopsies that punch through the chest wall or excise tissue using a bronchoscope. One wrong move can result in significant complications. Additionally, biopsies via bronchoscope often don’t capture enough tumor tissue to obtain a cancer’s full molecular makeup, especially to pinpoint one of today’s new targeted or immune therapies.
Nair hopes BAL can act as another type of biopsy — literally a liquid biopsy of the lung — that’s not only easier (both for patients and doctors) but also packed with enough molecular data to guide treatment.
In proof-of-concept work, he and colleagues from Stanford "saw that we could indeed find genomic signatures in lavage fluid” that matched that of the tumor.
Now with this five-year U01 grant, Nair, Houghton and others in the Hutch’s lung cancer SPORE will collaborate with Vanderbilt University in Nashville, and Dr. Tina Lockwood at the University of Washington’s Department of Laboratory Medicine, to develop accurate assays and protocols for the processing and analysis of lavage fluid, a crucial precursor to testing the clinical utility of using BAL fluid to diagnose and guide treatment in lung cancer. The Hutch’s Dr. Ziding Feng will provide statistical support for the project.
“When you biopsy a tumor, you’re just getting one part of it,” Nair said. “Lavage could be more advantageous. You’re washing the whole tumor, around it, near it. The fluid is a reservoir of genomic and cellular biomarkers of the lung tumor macroenvironment. We think it will be important to study.”
Janet Freeman-Daily, a Seattle-area metastatic NSCLC patient advocate who works with Hutch SPORE researchers, said she’s very familiar with the test and is encouraged the bronchoscope is being repurposed to become a less-invasive biopsy.
“It’s always better if you’re not poking holes in people,” said the 64-year-old former rocket scientist and co-founder of TheROS1ders, a lung cancer patient advocacy group for patients with ROS1 mutations. “Two days after they found a mass in my lungs in 2011, I had a bronchoscopy. And I’ve had two since then.”
Freeman-Daily was anesthetized during her three procedures — “They give you the same drug as with a colonoscopy” — and said she suffered no long-term side effects.
“Sometimes they go in looking for irregular cells that could be cancer,” she said. “Lavage is when they put the liquid down. I had obstructive pneumonia and they used a bronchoscope to make it easier for me to breathe. They’re used for more than one thing.”
Nair hopes they can also be used to answer questions about the molecular makeup, and exploitable vulnerabilities, of lung cancers.
“Lung cancer biopsies require a lot of skill,” he said. “But bronchoalveolar lavage is very easy to do and it’s very safe. You put a scope into the airway, inject saline, let it hang out for a few seconds and then aspirate it and send it off to the lab. We can use it to find or rule out infections or look at cells in the lung or get cancer cells. It’s a fundamental tool that we use to assess the lung environment.”
Nair believes there’s potential for much more — and this grant will allow him to dig in.
“We want to start understanding how we can use this fluid by analyzing the molecular characteristics,” he said. “And there are also lots of different variables that can affect how much of this fluid we can get, how useful it will be, and how accurate it will be.”
It’s still early days yet, but the grant will help build the infrastructure to study its clinical utility.
“We’re looking at the fluid for genomic analysis and the T cells within it for cellular analysis,” Nair said. Researchers will first optimize the cells that are collected and then develop assays “to really understand what’s happening at the tumor level.”
“We’re lavaging the macroenvironment of the tumor,” he said. “And it reflects what’s happening in the microenvironment of the tumor itself. But to what degree? That’s what we’re trying to find out.”
Funding for the Lung-MAP study was provided by the National Cancer Institute and by AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Genentech and Pfizer through the Foundation for the National Institutes of Health, in partnership with Friends of Cancer Research. The BAL fluid biopsy grant was awarded by the National Cancer Institute.
Diane Mapes is a staff writer at Fred Hutchinson Cancer Research Center. She has written extensively about health issues for NBC News, TODAY, CNN, MSN, Seattle Magazine and other publications. A breast cancer survivor, she blogs at doublewhammied.com and tweets @double_whammied. Email her at firstname.lastname@example.org.
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