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NSCLC Patients Who Should Get First-Line EGFR Inhibitors Are on Immunotherapy Instead, Study Finds


NEW YORK – Non-small cell lung cancer patients, who should get EGFR-targeted therapies as a frontline option based on biomarker test results and according to the latest treatment guidelines, are receiving immunotherapy instead and are worse off for it, an analysis released Wednesday suggests.

In a real-world data analysis, researchers found that between November 2018 and December 2023, two out of five NSCLC patients with EGFR-mutated and PD-L1-expressing, or dual-positive, tumors received first-line treatment with a PD-1- or PD-L1-inhibiting immune checkpoint inhibitor, such as Merck's Keytruda (pembrolizumab) or Genentech's Tecentriq (atezolizumab). However, prescribing these types of drugs goes against what the National Comprehensive Cancer Network recommends as first-line treatment in this setting, which is an EGFR inhibitor like AstraZeneca's Tagrisso (osimertinib).

The analysis, conducted by health technology firm Komodo Health and genetic testing firm NeoGenomics, further revealed that patients who received immunotherapy on average died 51 days sooner than those who got EGFR-targeted therapy. Moreover, Black patients were more likely to get guideline-discordant care than their white counterparts.

The findings are "definitely disturbing," said Eric Haura, director of the Moffitt Lung Cancer Center of Excellence in Florida. "People are being treated against NCCN guidelines, and they are having worse outcomes."

Haura, however, cautioned that these data aren't published in a peer-reviewed journal and there are gaps in the analysis that the researchers should address, such as whether doctors may have considered patients' specific EGFR mutation when deciding between first-line immunotherapy and an EGFR-targeted drug. "Not all EGFR mutations are created equal" in terms of therapeutic actionability, Haura noted.

Ming He, senior medical director at COTA, an oncology-focused real-world data analysis firm, pointed out that it's not clear from the present analysis whether oncologists' practices are more guideline-concordant today than they were at the start of the data analysis period four years ago. He suggested researchers conduct a year-by-year analysis to track the direction clinical practice is headed. 

For this analysis, researchers sifted through claims data on 330 million US patients housed at Komodo and genomic profiling data from NeoGenomics and identified around 1,800 NSCLC patients whose doctors prescribed them either targeted EGFR therapy or a PD-1/PD-L1 inhibitor after learning their lung tumors were positive for an EGFR mutation and PD-L1 expression.

Doctors can order multimodal assays from NeoGenomics, including assessment of PD-L1 expression and either single genes like EGFR via PCR or multiple genes using a next-generation sequencing panel. Lindsey Gasparini, VP of informatics at NeoGenomics, noted that PD-L1 testing results are typically available to doctors within 24 and 48 hours, but then they must wait another eight to 10 days to learn patients' EGFR and other biomarker status. This puts oncologists "in a difficult spot," and "it's understandable that they are anxious to get patients treated as quickly as possible," Gasparini said. "Waiting the extra … days for EGFR or other biomarkers results can have important implications for patients' overall response to therapy."

Considering the time it takes to receive these results, researchers focused on a subset of 520 patients who got an EGFR or PD-1/PD-L1 inhibitor a month after their doctors had the opportunity to learn about their dual-positive status. They found that 40 percent received a PD-1/PD-L1 inhibitor as first-line treatment.

The NCCN, starting in 2017, began recommending that doctors prescribe first-line targeted therapy to some stage IV patients if they had alterations in EGFR, ALK, or ROS1 and prescribe immunotherapy to PD-L1 high expressers only if they didn't have these genomic alterations or their mutation status was unknown. Today, the NCCN "emphasizes" that doctors establish patients' mutation status for targetable genomic abnormalities, including their EGFR mutation status, before reaching for first-line immune checkpoint inhibitors (ICIs). "Patients with metastatic NSCLC and PD-L1 expression levels of 1 percent or more — but who also have a targetable driver oncogene molecular variant — should receive first-line targeted therapy for that oncogene and not first-line ICIs, because targeted therapies yield higher response rates (e.g., osimertinib, 80 percent) than ICIs (lower response rates) in the first-line setting, targeted therapy is better tolerated, and these patients are less likely to respond to single-agent ICIs," the NCCN states in guidelines.

The real-world data analysis from Komodo and NeoGenomics captures this outcomes difference. Researchers had information on how long approximately 140 patients lived after receiving treatment, 54 percent of whom got EGFR-targeted therapy and 46 percent had anti-PD1/PD-L1 therapy. Patients who got immunotherapy lived an average of 310 days, while those who were treated in line with NCCN's recommendations lived an average of 361 days.

In recommending first-line EGFR treatment for dual-positive patients, the NCCN cites a prospective study published in 2018 that had to be stopped early due to lack of response to Keytruda. Out of 11 evaluable patients who were dual-positive and anti-EGFR therapy-naïve, only one responded to Keytruda, but upon retesting, this patient was found to not have an EGFR mutation at all. Based on the lack of efficacy and the fact that two patients died in this study within six months of enrollment, researchers concluded that Keytruda is "not an appropriate therapeutic choice" in dual-positive patients, including for PD-L1 high-expressers with PD-L1 expression in 50 percent or more tumor cells. 

The overall survival benefits of treating EGFR-mutated NSCLC patients with an EGFR inhibitor first became even clearer with the latest readout from the ADAURA trial. In that study, adjuvant treatment with Tagrisso lowered the risk of death by 51 percent in patients with earlier-stage EGFR-mutated NSCLC who received the EGFR inhibitor for three years.

Haura said he wouldn't prescribe immune checkpoint inhibitors to patients with EGFR mutations, regardless of the level of PD-L1 expression, until they had exhausted all their targeted treatment options. "If I give them PD-1/PD-L1 therapy, I do it within a trial, since we know the efficacy rates are so low," he said.

Haura has frequently seen high PD-L1 expression in patients with EGFR alterations. "But that does not mean that they have a T-cell-infiltrated tumor or that they would respond to anti-PD-1 therapy," Haura noted.

Anti-PD-1/PD-L1 treatments are particularly efficacious against certain tumors with high PD-L1 expression. In preclinical studies, it looked like mutations in oncogenes like EGFR could make tumors have high PD-L1 expression, which made experts hopeful that this would also mean that dual-positive patients would benefit from immunotherapy. "That turned out not to be the case," said COTA's He. "That's the difference between preclinical and clinical research."

Komodo and NeoGenomics reported that dual-positive Black patients were more likely to have guideline-discordant care with 6 percent getting anti-EGFR therapy and 12 percent getting immunotherapy. In comparison, a higher proportion of white patients got guideline-concordant care with 46 percent given anti-EGFR therapy and 43 percent prescribed a PD-L1 inhibitor.

Scott Phillips, VP of data strategy at Komodo, noted that when researchers considered factors like patients' site of care, insurance coverage, and age, they found these factors didn't significantly influence the type of treatment they got. However, researchers did find with 99 percent confidence that the difference in the number of Black patients getting guideline-discordant and -concordant care is statistically significant.

He, who is an oncologist and adjunct faculty at UT Southwestern Medical Center, pointed out that there are very few patients in some of these demographic subsets, which makes it particularly important for researchers to parse the data more closely for possible explanations for why some patients may be getting immunotherapy. While it has been known for several years that patients with more common EGFR exon 19 deletions and exon 21 L858R mutations do well on tyrosine kinase inhibitors like Tagrisso, these treatments don't work well for patients with EGFR exon 20 insertion mutations.

Komodo's analysis spans from late 2018 to 2023, but targeted therapies that are effective for the 2 percent of NSCLC patients with EGFR exon 20 insertions only became available in the last few years and moved into the first-line setting even more recently with the approval in the US of Janssen's EGFR/MET inhibitor Rybrevant (amivantamab) plus chemotherapy just this year. He advised researchers to consider the treatment patients received by year and their specific EGFR mutation in a future analysis. "If you're going to state that the patients are being treated against NCCN guidelines, you want to definitely make sure that they have the correct sensitizing EGFR mutations," He said.

Disincentivizing precision

According to Komodo and NeoGenomics, their combined dataset may be the largest ever used to explore the specific issue of guideline-discordant care in dual-positive NSCLC patients, but it certainly isn't the first time researchers have uncovered that biomarkers aren't being factored into treatment decisions as they should be.

For example, the health technology firm Diaceutics and the advocacy organization Personalized Medicine Coalition published data two years ago suggesting that 49.7 percent of NSCLC patients eligible for precision therapies may not be receiving them due to biomarker testing-related challenges, including issues with procuring tumor biopsies, insufficiency of the tumor sample, and failure to apply test results to guide treatment decisions.

In 2017, molecular testing firm OmniSeq surveyed 100 physicians and found that more than two-thirds said they preferred to prescribe patients a checkpoint inhibitor rather than an experimental targeted drug based on genomic profiling. Back then, industry insiders suggested that providers may be more inclined to prescribe immunotherapy over targeted therapy because of the tantalizing promise of a cure with ICIs, even though only 20 percent to 30 percent can hope to see an enduring benefit. Moreover, doctors and patients often didn't want to or couldn't wait several weeks to learn the results from genomic profiling before getting on treatment.

In their analysis, Komodo and NeoGenomics attempted to adjust for biomarker test-related issues by considering only patients who started treatment at least 30 days after their physicians received confirmation of their dual-positive status. But even then, the broader healthcare environment in which patients get care can disincentivize giving targeted therapy or put pressure on doctors to act quickly and get patients on immunotherapy.

One possible disincentive cited by researchers has to do with the fact that oral targeted therapies like EGFR inhibitors are reimbursed as a patient prescription benefit while PD-1/PD-L1 inhibitors are typically infused at a physician's office or hospital and are reimbursed through the patient's medical benefit. In the case of immunotherapies, doctors and hospitals can buy the drugs for in-office infusion and bill insurers at a higher rate to cover the cost of the medicines and associated services. "On the prescription benefit side, the provider doesn't have any sort of financial incentive, but on the medical benefit side, it is possible to potentially make money" from giving infusions, Komodo's Phillips said.

Moreover, procuring targeted therapies from specialty pharmacies can sometimes take several weeks and multiple prescriptions after figuring out a patient's insurance and copays. "There could be friction along the way embedded in a physician's practice and business model with just getting people these medicines," Haura observed.

Haura said he has long worried about how these types of disincentives may be hindering patients from getting appropriate precision medicines. Nearly two decades ago, when first-generation EGFR inhibitors like AstraZeneca's Iressa (gefitinib) were starting to take hold as an option for EGFR-mutated NSCLC, Haura recalled being on advisory boards with private practice doctors who talked about "how unenthused they were" about these new drugs that didn't conform to their business models.

Moreover, ICIs and targeted therapies are expensive drugs that can rack up several hundred thousand dollars in annual treatment costs. Payors have pushed back against treatments that Haura has prescribed if, for example, the patient's ALK or EGFR mutation status isn't in the records, and he wondered whether appropriate treatment for dual-positive NSCLC patients is on insurance companies' radar.

Phillips suggested that at insurance companies, there may not be alignment between the side of the business reimbursing treatments under the patient's medical benefit and the side that deals with prescription drug benefits. "Someone looking at the medical benefit claim for an immunotherapy may not recognize that the patient should have gotten an EGFR inhibitor," Phillips said.

'Difficult working conditions'

Oncologists are also taking care of patients amid aggressive direct-to-consumer drug advertising and rapidly evolving science. According to one analysis, a third of the 81 top-advertised drugs in the US between 2015 and 2021 were immunomodulating agents, which Komodo and NeoGenomics cited as a factor spurring patient demand for PD-1/PD-L1 inhibitors despite what guidelines say.

It also takes time for scientific knowledge to disseminate through the medical establishment, He said, acknowledging that given "the hype and excitement around immunotherapy … perhaps that process took a little longer" when it came to standardizing treatment for dual-positive patients. Still, He suspects that if Komodo reanalyzed the data by year from 2018 to present day, it would show that most of the guideline-discordant care happened in earlier years and most patients today who have targetable EGFR mutations are treated appropriately. Komodo and NeoGenomics should do this reanalysis "just to make sure that practice patterns are headed in the correct direction," He said. "This is probably the most important thing."

On the other hand, oncologists today must grapple with an "explosion of information in genomic medicine," said Haura, acknowledging that sometimes he has to reference the literature and remind himself if a particular targeted drug is sensitive against a particular EGFR mutation. "It's easy to come up with the evil explanation for why this [guideline-discordant care] occurs, but it just may be very difficult working conditions and … maybe this is pointing to the need for better tools that help physicians manage this deluge of genomic information."

Komodo and NeoGenomics have no plans to publish this initial work in a peer-reviewed journal, but Phillips noted that as more data are collected in Komodo's and NeoGenomics' respective databases, they will look further into how, for example, dual-positive Black patients' age, geographic location, and insurance status influence treatment. The researchers considered patients' PD-L1 expression levels in this initial analysis, which wasn't associated with the therapies patients got, but they will look next at how patients' specific EGFR mutation type impacts treatment decisions, as He and Haura have both suggested.

Researchers hope to eventually publish this follow-on research or present it at a conference. "This is just the tip of the iceberg," Phillips said. "We need to continue to dive into the combination of patients' genetic information and their claims data and [investigate] how this trend is continuing to evolve."