Comprehensive molecular testing in lung cancer ‘absolutely crucial’ yet underutilized
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Precision medicine has shown great potential to improve treatment outcomes and prolong survival of patients with lung cancer, as biomarker-driven therapies continue to extend their reach in this space.
According to International Association for the Study of Lung Cancer, more than half of patients with lung cancer have tumors that harbor potentially actionable driver mutations. Therapies targeting these mutations, including but not limited to ALK, BRAF, EGFR, HER2, RET, KRAS and BRAF, now dominate the lung cancer treatment landscape, according to a study by Deb and colleagues published in Journal of Thoracic Oncology. Use of these targeted treatments can significantly prolong survival over that achieved with cytotoxic chemotherapy.
For this reason, current guidelines state that patients with advanced non-small cell lung cancer should undergo comprehensive molecular testing using next-generation sequencing (NGS) at diagnosis to identify those who may benefit from certain targeted therapies.
However, in real-world practice in the United States, molecular testing of NSCLC often occurs late in the diagnostic process or is not conducted at all. This appears especially true in small community cancer centers, where knowledge gaps and a lack of resources at the institutional, clinician and patient levels may block access to this testing.
“We’ve seen dramatic improvements in outcomes for patients living with lung cancer, and a significant part of that is the appropriate use of targeted therapies,” Heather A. Wakelee, MD, chief of the division of oncology at Stanford University and deputy director of the Stanford Cancer Institute, told Healio. “However, we can’t use the targeted therapy if we don’t know whether a patient’s tumor has the targets. We can’t provide the best possible treatment for a patient unless we understand their cancer, and knowing the molecular targets is absolutely crucial to giving someone the best chance for quality life for as long as possible.”
Healio spoke with lung cancer experts about the value of comprehensive molecular testing, challenges to its widespread use and ongoing efforts to promote guideline-concordant genotyping at community and academic centers.
‘If you don’t look, you don’t know’
When Wakelee began her oncology practice more than 20 years ago, patients with lung cancer had limited treatment options.
“At that time, we only had chemotherapy to offer patients with metastatic disease, and only surgery or radiation for those in earlier stages of disease,” she said. “The first sea change was the discovery of EGFR inhibitors, which was revolutionary for lung cancer care. We noticed that about 10% of patients with lung cancer had truly dramatic responses — they would feel better within days.”
Over the next few years, researchers identified the reason for these improvements — that some lung cancers have specific EGFR mutations that can be addressed through targeted therapy.
“We found that when we tested for that EGFR mutation in the tumor and when we found it, 70% to 80% of people who received the appropriate targeted medication had dramatic responses very quickly,” Wakelee said. “Over time, we’ve been able to develop better EGFR drugs, such that close to 90% of appropriate patients who start on the newest EGFR drugs have these dramatic responses. They’re nearly back to normal life just by taking a pill once a day.”
Patients who aren’t tested for these mutations may still respond to chemotherapy, Wakelee said. However, they may be missing a chance to double their chances of response, increase the duration of response, and experience improved quality of life with targeted treatment.
“If you don’t look, you don’t know, and some of these cancers can be very aggressive and not that responsive to chemotherapy,” Wakelee said. “So, if we don’t test for these mutations, we are depriving these patients of their best possible care.”
The next step in the evolution of targeted therapy for NSCLC occurred with the development of drugs targeting anaplastic lymphoma kinase (ALK) mutations. Wakelee said although only 5% of all lung cancer tumors carry ALK mutations, research has since identified approximately 10 potentially actionable driver mutations in NSCLC, which significantly increases the number of patients who have tumors with “actionable” mutations.
“If we can identify these driver mutations in a patient’s tumor, we have medications that work for more than half of the patients, and sometimes up to 80% to 90% of patients,” Wakelee said. “If we find that mutation, these targeted therapies work better than chemotherapy and they work longer.”
Wakelee recalled a discussion with a colleague about a patient who, as a retired physician, did not want chemotherapy.
“My colleague said, ‘He doesn’t want it. He just wants to go into hospice. What do you think?’” Wakelee said. “I said, if you haven’t done molecular testing, you don’t know. If he has one of these mutations, he can take a pill and have a fairly normal quality of life.”
Challenges to community cancer centers
Despite its promise for patients diagnosed with NSCLC, comprehensive molecular testing continues to be underused in community hospital settings.
Wendi L. Waugh, R.T.(R)(T), CMD, CTR, BS, administrative director of cancer services and ambulatory infusion at Southern Ohio Medical Center Cancer Center, does not dispute that all cancer centers should make molecular testing available to their patients with lung cancer.
“I certainly would say that everyone should be doing it — I’m all in when it comes to that,” Waugh told Healio. “However, I don’t necessarily believe that all community cancer centers should be processing and evaluating those results. NGS is complicated, and academic medical centers likely have more experts and more access to testing tools that enable them to do this well.”
Community cancer centers should have access to testing platforms, such as Foundation Medicine, Caris Life Sciences and Tempus Genetic Testing, Waugh said. However, she added that not all community hospitals are equipped to interpret the test results.
“It’s outside of our expertise to have complex labs. Every lab in every hospital across the U.S. is not going to have the capacity for this complex testing,” she said. “This testing is only going to increase — we’re looking at DNA, RNA and lots of genes. I’m all for these specialized labs that have expertise in evaluating these test results.”
Insurance is also a barrier to the use of molecular testing among patients with lung cancer in community hospitals. Waugh said insurance will not cover comprehensive NGS for early-stage lung cancers.
“Right now, insurance will only pay for a smaller panel of 12 actionable genes. There are 12 genes that, if we find a mutation, can be targeted with an FDA-approved regimen,” she said, “However, there are 300-plus genes that, if a mutation or abnormality were found, could make a patient eligible for a clinical trial. So, when we aren’t allowed to do full-spectrum testing on early-stage lung cancers, we may not be offering them everything that is out there to make an informed decision.”
Although molecular testing is covered by insurance for late-stage lung cancer, there is often a greater out-of-pocket cost, Waugh added. She relayed a story about a patient at her institution.
“This woman works as a librarian and her husband works as a pharmacist — they’re working class,” she said. “However, they did not qualify for any financial assistance. It turned out that the molecular testing cost them nearly $5,000 out of pocket.”
‘Huge benefit’ to patients
Another barrier to standard tissue-based comprehensive molecular testing for NSCLC is the need to collect an adequate tissue sample, which can increase the time to identify actionable drivers and may delay clinical decision-making.
Performing plasma (blood or “liquid”) and tissue (tumor) NGS concurrently for patients with metastatic nonsquamous NSCLC can increase the likelihood of comprehensive genotyping and reduce the turnaround time for results, according to a real-world cohort study led by Charu Aggarwal, MD, MPH, associate director of Penn Center for Precision Medicine, physician leader at Airways Malignancies Research, and Leslye M. Heisler associate professor for lung cancer excellence at University of Pennsylvania's Perelman School of Medicine, as well as a HemOnc Today Editorial Board member.
Aggarwal and colleagues sought to determine the effect of concurrent tissue and plasma NGS on comprehensiveness of genotyping and OS among 335 patients with newly diagnosed, stage IV nonsquamous NSCLC treated at University of Pennsylvania between January 2019 and December 2020. Researchers categorized genomic testing based on NCCN guidelines. They considered tests for mutations in EGFR, ALK, BRAF, ROS1, MET, RET and NTRK to be comprehensive, and those for mutations in two to six genes to be incomplete.
Of the patients evaluated, 98.5% underwent molecular testing, either comprehensive (86.9%) or incomplete (11.6%) No testing was conducted in 1.5% of patients.
About one-third of patients (32.7%) underwent testing with tissue-based NGS, whereas 67.5% underwent concurrent plasma- and tissue-based NGS. The groups had similar baseline characteristics, but the group that received concurrent testing had a higher percentage of patients who had never smoked cigarettes (30.2% vs. 14.8%).
All patients tested with concurrent plasma- and tissue-based NGS had results available before the start of first-line therapy, compared with 60.7% of those tested with only tissue-based NGS.
At median follow-up of 20.6 months, median OS was 18.6 months. Patients tested with concurrent plasma- and tissue-based NGS had numerically longer median OS than those who underwent only tissue-based NGS (23.2 months vs. 14.1 months), a difference that did not attain statistical significance. However, researchers found that no matter which testing modality patients received, those who underwent comprehensive molecular testing had longer OS than those with incomplete or no testing (22.1 months vs. 11.6 months, P = .017).
“We showed that tissue-plus-plasma sequencing increased the rates of comprehensive molecular testing compared with patients who underwent tissue testing alone,” Aggarwal told Healio. “We also found that patients who underwent tissue-plus-plasma sequencing were more likely to have results back before initiating first-line therapy than patients who underwent tissue sequencing alone.” That means more patients were able to get the best treatment first because they and their team knew more about the cancer before treatment initiation.
One of the most important findings from the study was the increase in OS, Aggarwal said.
“A key finding was that if you conduct comprehensive testing in these patients, especially if the results are available in time for first-line therapy, that leads to an increase in overall survival,” she said. “This is very important and a huge advantage to our patients.”
The need for education
The reasons for the low uptake of NGS in community hospitals are multifactorial, but lack of awareness at the clinician and institutional levels seems to be a major issue, according to experts with whom Healio spoke.
Wakelee said the disconnect between the everyday experiences of oncologists at large academic medical centers and those at community hospitals may be driving knowledge gaps regarding complete molecular testing and targeted therapies for NSCLC.
“If you’ve never seen the benefit, or if you have a health care system that’s pushing back against the testing, those are definitely barriers we’re facing,” she said. “The goal must be to increase awareness across all of oncology, not just among oncologists who are in places where complete molecular testing is more common.”
Another misunderstanding among oncologists without experience in molecular testing is that mutations rarely occur, Wakelee said.
“Some oncologists might think they’ll never find the mutation or that a mutation is only identified in 2% of cases, but it’s not as rare is they might think,” she said. “If one is seen in 2% and another is seen in 2% and so on, it adds up.”
Eagerness to initiate treatment immediately after diagnosis may also represent a barrier at the patient and clinician levels, according to Aggarwal.
“There are a lot of pain points,” she said. “Patients are eager to get started on chemotherapy, because the molecular results can take time to come back. Or it could be related to the fact that physicians want to get started quickly.”
Wakelee added that misunderstandings exist regarding which patient populations should undergo molecular testing.
“There is a preconception that these types of mutations only happen in people with lung cancer who have never smoked,” she said. “It’s true that it is more common in that group, but it is not exclusive to that group. When we talk about testing for everybody, there are some nuances to it. Anybody who has the adenocarcinoma type of lung cancer, which is the majority of NSCLC, should absolutely have these tests done.”
‘The survival story’
If more clinicians and community hospital systems understood the dramatically improved outcomes that are possible with targeted therapies, they would be convinced of the value of comprehensive molecular testing for NSCLC, Wakelee said.
“Maybe some oncologists haven’t seen patients having these amazing, dramatic responses,” she said, “We’ve had patients who are in the ICU, intubated, and when we find mutations and start the right drug, they are able to walk out of the hospital. These things can happen.”
Aggarwal agreed that offering assistance and education to community cancer centers will be essential to making molecular testing more widespread.
“We are focusing on education,” she said. “If a provider orders the test and then comes up with a molecular mutation, we have an effort where we are sending reminders to the physician not just to tell the patient that they can benefit from chemotherapy, but also telling them that clinical trials may be available.”
Aggarwal and colleagues also designed an electronic medical record-based “nudge intervention” that generated a plasma NGS order automatically at initial consultation as tissue-based NGS moved forward based on established institutional pathways.
“We want to take the pressure off providers through behavioral economics-informed education nudges to facilitate the ordering of these tests so it’s easy for providers,” she said.
Results of a prospective study of the intervention, presented at this year’s ASCO Quality Care Symposium, showed the nudges can promote guideline-concordant molecular genotyping at community and academic sites.
“We are expanding our efforts of intervention to four key satellite hospitals that are spread across the middle of Pennsylvania and New Jersey, and at one of our ethnically diverse sites,” she said. “There is a lot of excitement in this area, and we believe this will ultimately benefit patients at these sites.”
Ultimately, Aggarwal believes the benefits of comprehensive molecular testing and targeted therapies will lead to wider use.
“The key story is the survival story,” she said. “Our goal is to get the message out, to make it easier for physicians to order the tests, and to educate physicians on what to do once the test is ordered, because that’s also a big challenge. We’re attacking it from multiple angles.”
References:
- Aggarwal C, et al. Abstract 362. Presented at: ASCO Quality Care Symposium; Sept. 30-Oct. 1, 2022; Chicago.
- Aggarwal C, et al. J Clin Oncol. 2022;doi:10.1200/JCO/2022.40.16_suppl9022.
- Deb D, et al. J Thorac Oncol. 2022;doi:10.1016/j.jtho.2022.03.018.
For more information:
Charu Aggarwal, MD, MPH, can be reached at Penn Medicine, 3400 Civic Center Blvd. West Pavilion, 2nd Floor, Philadelphia, PA 19104; email: charu.aggarwal@pennmedicine.upenn.edu.
Heather A. Wakelee, MD, can be reached at Stanford Cancer Institute, 269 Campus Drive CCSR 1115, Stanford, CA 94305; email: hwakelee@stanford.edu.
Wendi L. Waugh, RT(R)(T), CMD, CTR, BS, can be reached at Southern Ohio Medical Center, 1805 27th St., Portsmouth, OH 45662; email: waughw@somc.org.
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Aggarwal C, et al. Abstract 362. Presented at: ASCO Quality Care Symposium; Sept. 30-Oct. 1, 2022; Chicago.
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