Emory’s Ticiana Leal, MD, Says Rise in Druggable Targets Boosts Importance of Biomarker Testing in NSCLC

It’s well known that targeted therapy has demonstrated improved survival in clinical trials of patients with non-small cell lung cancer (NSCLC). The change of fortune for these patients has been so rapid, said Emory University’s Ticiana Leal, MD, that investigators are now seeing accelerated survival at a population level, along a time frame associated with approval of these therapies.¹

Leal, who is associate professor, Department of Hematology and Medical Oncology, and director, Thoracic Medical Oncology, at Emory’s Winship Cancer Institute, shared the Medicare data that show this good news to start her July 25, 2023, talk on the importance of using biomarkers to treat NSCLC, part of the Atlanta session of the Institute for Value-Based Medicine^®, which The American Journal of Managed Care® presented with Winship Cancer Institute.

However, Leal noted, disparities remain between Hispanic and non-Hispanic populations.¹ “So, a lot more needs to be done,” she said. Tools exist to help close the gaps, but they must be used for all patients; as she would explain, it now makes sense to use tissue and plasma testing together.

“These advances in precision medicine, they’re really here to stay, and more specifically for lung adenocarcinoma,” Leal said. The genomic complexity of lung cancer and improved diagnostic testing means that clinicians “are able to identify a growing number of druggable targets that are quickly being incorporated into clinical practice.”

More than a dozen therapies and associated targets are now part of the clinical guidelines published by the National Comprehensive Cancer Network; these include tyrosine kinase inhibitors and antibody-drug conjugates, in both frontline and second-line settings. The days of single-gene testing to match the right drug with the right patient are over, she said.

“One of the greatest things [with the] selection of optimal therapy is the ability to do broad-based or comprehensive biomarker testing. And in my opinion, NGS [next-generation sequencing] is really the way to go.”

Are payers receptive to testing and to targeted therapies generally? During the question-and-answer session, Leal said some are easier to work with than others, and Emory’s pharmacy team excels at expediting approvals.

“Payers are increasingly supportive of the cost-effectiveness of targeted therapies,” she said.

Tissue, Liquid, or Both?

For many years, Leal explained, tissue-based testing was “the gold standard,” because tissue was needed to do a diagnostic biopsy. “If there’s insufficient tissue, then you go on to do a liquid biopsy,” she said.

But newer, complementary approaches may be optimal, “because you’re doing tissue-based testing and liquid-based testing at the same time,” and this may be a better strategy for patients with lung cancer.

For some patients, “there’s the plasma-first approach, which is when you do a diagnostic biopsy, and you really don’t have any tissue to perform the tissue-based testing and you’re unable to do another diagnostic biopsy for more tissue, [so] you use the NGS and liquid biopsy.”

Leal explained that the caveat to this approach is that if the liquid biopsy does not reveal a biomarker, a surgical biopsy may be needed to rule out any biomarker.

“This is very complex,” she said. For all the advances in biomarker testing, the challenges of tissue acquisition—and finding accessible sites—can still delay treatment.

She shared results of a study comparing patients who received “piecemeal” testing, meaning 1 marker at a time, with those who had a liquid biopsy. Using the liquid test alongside the tissue tests identified more actionable markers, with 96% concordance between the tissue and liquid markers for an FDA-approved therapy.²

“And the turnaround time [for the liquid biopsy] was significantly lower than with tissue-based testing, 9 vs 15 days,” Leal said. “So, we’re really improving the potential time to treatment initiation.”

A separate, single-institution study that added liquid biopsy to tissue testing boosted the rate of identification of targetable mutations from 20% to 35%.³

Not Enough Testing

Results from the real-world MYLUNG study, presented this year at the American Society of Clinical Oncology (ASCO) annual meeting, showed that 17% of patients still did not have biomarker testing before starting treatment for NSCLC, and only 54% had NGS.⁴ Leal said this is alarming given results at the same meeting that show the benefits of osimertinib for newly diagnosed NSCLC with an EGFR mutation.⁵ She sees missed opportunities to cure patients in early-stage settings.

“We saw at ASCO 2023, at the plenary session, for the first time ever, a significant improvement in survival in patients who receive a targeted therapy in the adjuvant setting,” she said. “And despite this, you’re seeing about 50% of patients receiving genotyping.”

Failing to test patients for PD-L1 status is crucial as chemoimmunotherapy becomes an important new adjuvant strategy, Leal said, “because only patients with PD-L1 positive disease are actually eligible for adjuvant immunotherapy in the adjuvant setting. So clearly, we still have a long way to go.”

Why are biomarker results not available before treatment? Leal pointed to results from MYLUNG that show patient and provider perceptions are the leading cause, at 54%. Other reasons are issues with tissue retrieval, 25%; clinical deterioration, 10%; patient-provider knowledge about testing options, 12.5%; and payer coverage, 8.3%. Leal said there are concerns that providers worry about the time needed to wait for biomarker results. Other data show that doing single-gene testing can limit the performance of NGS if done later, due to tissue inadequacy.⁴

“We’ve demonstrated in prior studies that go back to 2019 that the use of upfront NGS testing, vs single-gene testing, actually is cost-effective,” Leal said. This approach results in less time to actionable test results and less likelihood that patients take therapy that will not work.

Disparities in Testing

Leal presented data from Flatiron Health, which compared the likelihood of White vs Black patients to have NGS testing generally, and before first-line therapy. Data for 23,488 patients were evaluated, and differences were seen in NGS rates for White vs Black patients, respectively, before first-line therapy (36.6% v 29.7%, P , .0001) and at any given time (54.7% vs 43.8%, P = .0001) in the nonsquamous NSCLC cohort. Disparities in NGS testing rates at any time were also seen among patients with colorectal cancer (White 51.6% vs Black 41.8%; P = .0001), but no differences were seen in the breast cohort.⁶

Testing is not only important to guide treatment, but data show it also can improve patients’ chances of gaining access to clinical trials, she said.

“There is a significant need to improve biomarker testing in populations that are underrepresented, and specifically here in the Black population, but we’ve also seen this in the Hispanic population as well.”

What are some solutions? Leal discussed reflex testing, which saves time by empowering the pathologist to begin the process of NGS as soon as a diagnosis of NSCLC is clear from the biopsy. In addition to concurrent use of tissue and liquid biopsy, Leal called for better integration of biomarker results into the electronic health record.

Better multidisciplinary care and molecular tumor boards allow institutions to tap into regional strength, she said. Finally, patients and families should be educated about biomarkers.

“Whenever I see a patient and they get their biomarker results, I print it out. And I say these are your biomarkers, and I highlight what they need to know,” Leal said. Giving patients ownership over understanding their results, in language they can understand, helps them understand the importance of what is happening “and how it impacts their care and survival.”

References

1. Howlader N, Forjaz G, Mooradian MJ, et al. The effect of advances in lung-cancer treatment on population mortality. N Engl J Med. 2020;383(7):640-649. doi:10.1056/NEJMoa1916623

2. Leighl NB, Page RD, Raymond VM, et al. Clinical utility of comprehensive cell-free DNA analysis to identify genomic biomarkers in patients with newly diagnosed metastatic non-small cell lung cancer. Clin Cancer Res. 2019;25(15):4691-4700. doi:10.1158/1078-0432.CCR-19-0624

3. Aggarwal C, Thompson JC, Black TA, et al. Clinical implications of plasma-based genotyping with the delivery of personalized therapy in metastatic non-small cell lung cancer. JAMA Oncol. 2019;5(2):173-180. doi:10.1001/jamaoncol.2018.4305

4. Evangelist MC, Butrynski JE, Paschold JC, Ward PJ, Spira AI, Ali K. Contemporary biomarker testing rates in both early and advanced NSCLC: results from the MYLUNG pragmatic study. J Clin Oncol. 2023;41(suppl 16):abstr 9109. doi:10.1200/JCO.2023.41.16_suppl.9109

5. Tsuboi M, Herbst R, John T;ADAURA Investigators. Overall survival with osimertinib in resected EGFR-mutated NSCLC. N Engl J Med. 2023;389(2):137-147. doi:10.1056/NEJMoa2304594

6. Bruno DS, Hess LM, Li X, Su EW, Patel M. Disparities in biomarker testing and clinical trial enrollment among patients with lung, breast, or colorectal cancers in the United States. JCO Precis Oncol. 2022;e2100427. doi:10.1200/PO.21.00427