Lung Cancer Patients Face a Fragmented, Complex Testing Landscape for HER2-Targeted Therapies

Future investigations should explore the potential of the markerless system to measure gait parameters in pathological gaits.

Introduction overview

NEW YORK – Patients seeking treatment for advanced lung cancer are now evaluated for HER2 alterations via several tests in a fragmented process that can lead to extra biopsies and less-than-optimal treatment plans. HER2 mutation testing became a point of interest for patients with non-small cell lung cancer (NSCLC) a few years ago, after the US Food and Drug Administration approved AstraZeneca and Daiichi Sankyo's HER2 antibody-drug conjugate (ADC) Enhertu (trastuzumab deruxtecan) for those with unresectable or metastatic tumors after systemic therapy. Then, earlier this month, the agency approved Boehringer Ingelheim's HER2-targeted tyrosine kinase inhibitor Hernexeos (zongertinib) for the same subpopulation. Alongside Enhertu's approval in 2022, the FDA approved two companion tests to identify the between 2 percent and 4 percent of NSCLC patients with HER2 mutations: Thermo Fisher Scientific's tissue-based Oncomine Dx Target Test and Guardant Health's Guardant360 CDx liquid biopsy test. With Hernexeos, the agency also approved Thermo Fisher's Oncomine Dx Target Test as a companion diagnostic to identify best responders. Another boost for the Boehringer Ingelheim drug came last week when the National Comprehensive Cancer Network added Hernexeos to its clinical practice guidelines for oncology as a preferred subsequent therapy option for advanced NSCLC patients with HER2-mutated tumors after systemic therapy. While Hernexeos is the second drug to reach the market for this subset of patients, it is the only oral targeted therapy option. The availability of more treatment options for HER2-mutated NSCLC underscores the need for biomarker testing. "What we're seeing in the NSCLC space, and it is also emphasized by NCCN guidelines that recommend Hernexeos, is when we have targeted therapies for specific rare mutations or cancer types, the importance of getting that testing done, really understanding what that test means, and then treating [patients] with the most appropriate targeted therapy," said Vicky Brown, senior VP and therapeutic area head of oncology, rare, disease, and eye health at Boehringer Ingelheim. There are now several biomarker-specific NSCLC treatments approved by the FDA, and the NCCN recommends that doctors test for them to identify the right treatment approach. For example, in addition to HER2/ERBB2 mutations, the guidelines mention testing for EGFR mutations, ALK rearrangements, ROS1 rearrangements, BRAF V600E mutations, NTRK gene fusions, MET exon 14 skipping mutations, RET rearrangements, KRAS G12C mutations, and NRG1 gene fusions as well as protein-based tests for PD-L1 levels and HER2 overexpression. Standard NGS panels can gauge HER2 mutations, and ideally every patient with advanced NSCLC should receive NGS testing that includes it. However, getting access to NGS testing and a conclusive result for HER2 status isn't always a straightforward process for doctors and patients. "Patients are still struggling with accessing any type of biomarker result as different types of tests are integrated into the workflow," said Nikki Martin, senior director of precision medicine initiatives at the research and advocacy organization LUNGevity. Previously, she said, most advanced lung cancer patients could identify the right treatment option after testing on an NGS panel and a PD-L1 immunohistochemistry (IHC) test. Now, new types of single-gene tests and protein expression tests for ADCs have become available, increasing demand for patients' limited biopsy samples. "You definitely run the risk of patients falling through the cracks and not receiving complete biomarker results." Importantly, patients now must have two different kinds of HER2 tests to gauge their eligibility for different HER2-targeted therapies: NGS and IHC. An NGS-based HER2 mutation test can show whether a patient is a candidate for Hernexeos and Enhertu. However, patients who don't have HER2 mutations may also be eligible for Enhertu if their cancer cells overexpress HER2 with an IHC score of 3+, a result that would not show up in NGS testing. The FDA approved a tissue-agnostic indication for Enhertu in April 2024, making it an option for patients with unresectable or metastatic HER2-positive solid tumors who have failed prior therapy and have no remaining treatment options. While relatively few NSCLC patients harbor HER2 mutations, up to 38 percent of NSCLS cases overexpress HER2. "Four or five years ago, when I heard HER2, I thought of breast cancer, and that was always an IHC test in breast," said Upal Basu Roy, VP of research at LUNGevity. Now that patients should be sequenced for HER2 mutations and tested for HER2 overexpression by IHC, "the question becomes which test to prioritize," he said. "We don't have a good answer to that." Even when a patient receives both tests, Basu Roy said it's not clear what to do with the information. "There's one drug which is an antibody-drug conjugate that has an IHC diagnostic, and another that's purely based on sequencing," he said. "As a treating physician, it's really confusing. That's where we need clear direction on the fact that first of all, HER2 comes in different shapes and sizes, and it's also picked up by different tests, and [different] drugs are attached to these tests." Basu Roy emphasized that clinicians need to be aware that if an IHC test for HER2 overexpression is negative, that does not mean there's no HER2 mutation. "We can't give up NGS just because a HER2 IHC has come out negative," he said. Another testing option that can improve the odds that patients are correctly diagnosed is a liquid biopsy test, in which the laboratory detects mutations in circulating tumor DNA via NGS. Liquid biopsy results are typically available within seven days to 10 days, as opposed to the four weeks it can take for NGS tumor testing results. It can be especially valuable in cases where patients do not have enough tissue available for NGS testing. If the liquid biopsy test comes back positive for a HER2 mutation, that result is reliable enough to go ahead with HER2-targeted treatment, according to John Heymach, chair of head and neck medical oncology at MD Anderson Cancer Center. "Up to 25 percent of patients do not have a sufficient quantity of biopsy tissue for NGS," he said. "Liquid biopsy can identify important mutations in more than half of those patients." However, he added, for the remainder, a repeat tumor biopsy is necessary to assess molecular biomarkers including HER2. An AstraZeneca spokesperson said the company partners with oncology societies and provides additional education on best practices including webinars, videos, and consensus publications to increase clarity on the optimal patient identification for HER. Isabel Preeshagul, a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center, said NSCLC patients routinely receive the full battery of testing at her institution, including NGS tissue testing via MSK-IMPACT, liquid biopsy, and relevant IHC tests. Ideally, she would prefer to wait until she has results from all the tests, including tissue NGS. "But, ideally doesn't always happen," she said. "We have to look at the patient that's in front of us. Sometimes, if they're really symptomatic, we have to use our best judgment." Martin noted that it can be a challenge to complete all of the needed testing using the amount of tissue collected via a standard fine-needle aspiration, and that even when enough tissue is available, the testing workflow can present challenges. Hospitals may conduct some or all testing in-house, send the tissue out to a single third-party laboratory, or divide the tissue between different vendors. For example, Martin said, the hospital may send part of the tissue sample to one lab for NGS testing and another for IHC testing. "It just depends on what their contracted relationships are and how they want to prioritize management of the tissue," Martin said. "I have heard that some pathology labs will try to pre-slice the tissue so that they can maximize the amount [available] for testing." According to Martin, a core-needle biopsy is now the "gold standard" for collecting tissue for diagnostic testing from advanced NSCLC patients. However, she noted that the core-needle biopsy is more invasive than a fine-needle biopsy and could be too risky for some patients. Patients who can't tolerate a core-needle biopsy or for other reasons don't have enough tissue sample for NGS testing may require an additional biopsy later to collect that tissue. Susan Scott, a medical thoracic oncologist at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, said it "happens all the time" that patients don't have enough tissue in their biopsy sample for NGS. "Sometimes we're able to bridge that gap by testing the blood," she said. "But sometimes we have to repeat biopsies." Quest Diagnostics has responded to the tissue crunch with protocols that try to ensure NSCLC patients will have sufficient sample for current and future diagnostic needs. One of the protocols the company uses is a rapid on-site evaluation, which involves having a pathologist on-site during specimen collection to give feedback to the oncologist or pulmonologist. "We identify the tumors present," said Darren Wheeler, VP of pathology and medical services at Quest. "We make sure we have something diagnostic on the cytology, then we initiate a follow-up [core biopsy], if possible." Wheeler said the core sample ensures there's enough tissue for as much downstream testing as needed. Subsequently, Quest trains pathologists not to order the minimum number of stains required for diagnosis, but to account for immediate IHC testing as well as leaving a number of unstained slides for later molecular testing and IHC testing. Even when patients have all of the correct tests, connecting them with the right therapies can still go wrong, according to LUNGevity's Basu Roy. "The next [challenge] is getting the right interpretation of the test, because HER2 is so complex, and most of the mutations show up in a part of the HER2 gene called exon 20," he said. "A lot of molecular reports don't specifically call that out, so it may happen that the clinician doesn't prescribe one of the [HER2-targeted] drugs because it's not very clear." "It's confusing to me, and this is all I do, every day," Preeshagul said about making sense of all the testing NSCLC patients receive. She recommends using NCCN guidelines, reading journals, and talking with colleagues to sort out complex test reports. "No one works in a silo," she said. "We have to work together to care for these patients the best way we can." The most recent data that LUNGevity's Martin has seen suggest that only about 50 percent of cancer patients who are eligible for NGS testing of their tumor specimen are receiving it. "The biggest challenges are going to be rural patients," she said. "The workflow process is a big struggle, and adding in a new test is going to add an additional strain to an already strained system." LUNGevity is working to educate patients and providers about the added significance of HER2 mutations and the tests required for evaluating patients with advanced NSCLC. "We support efforts like [continuing medical education] targeting pathologists, oncologists, and other members of the multidisciplinary team," Martin said. "Everyone needs to understand the difference [between a HER2 mutation and HER2 overexpression] and the complexity of the testing environment so that workflows are reflective of the guidelines." Basu Roy emphasized that while there is a lot of education available on the various drugs, more education is needed for providers on the testing workflow. "Tissue acquisition in the 21st century needs to look a little bit different given the fragmentation of all of the tests that we require," he said. "And on the oncology side, there needs to be a focus on the completeness of the test result, that a HER2-negative case is definitely negative, and on making sure they have a clear pathway in place and a clear hand-off to the oncologist." On the whole, Boehringer Ingelheim's Brown sees HER2 mutation testing increasing. "What we're doing to also drive increased awareness and usage of testing is making sure that we are partnering closely with advocacy and patient groups to empower them to know they should be receiving biomarker testing," she said, "and importantly, to understand what those results mean and that there are targeted therapies we can use to treat them."