Early Use of ctDNA May Accelerate Time to Treatment and Improve Survival in NSCLC

Charu Aggarwal, MD, MPH, FASCO

While there are considerable barriers to incorporating comprehensive genotyping, the use of circulating tumor (ct)DNA offers an improvement in molecular testing—and doing so earlier can accelerate the time to treatment and improve survival for patients with lung cancer, explained Charu Aggarwal, MD, MPH, FASCO.¹

“We are using liquid biopsy in various ways to improve testing. We are using it earlier in the time point with diagnostic biopsy,” Aggarwal said in a presentation during the 18th Annual New York Lung Cancers Symposium, an event hosted by Physicians’ Education Resource, LLC. “But we’re also implementing nudges. We are incorporating reflex pathways and then future efforts will focus on incorporation of ctDNA as a real-time biomarker for long-term response.”

Aggarwal is the Leslye M. Heisler Associate Professor of Lung Cancer Excellence, section chief of Thoracic and Head and Neck Medical Oncology, and director of Precision Oncology Innovation at the Penn Center for Cancer Care Innovation at the University of Pennsylvania.

It’s no secret that the incorporation of targeted therapies against a multitude of molecular abnormalities in lung cancer have improved survival outcomes for patients, Aggarwal noted, citing the third-generation EGFR TKI osimertinib (Tagrisso) as an example. Osimertinib elicited a median overall survival (OS) of 38.6 months (HR, 0.80; 95% CI, 0.64-1.00; P = .046)2 in the frontline EGFR-positive non–small cell lung cancer (NSCLC) setting according to data from the phase 3 FLAURA trial (NCT02296125). The second-generation ALK inhibitor alectinib (Alecensa) also demonstrated promising results and the median OS was not reached (HR, 0.67; 95% CI, 0.46-0.98; P = .0376)3 in the frontline ALK-positive population enrolled in the phase 3 ALEX trial (NCT02075840).

Actionable genomic alterations occur in approximately 50% of all patients with nonsquamous NSCLC and include: EGFR (30.3%), KRAS (29.9%), BRAF (5.5%), ERBB2 (3.8%), MET splice (3.0%), ALK fusion (4.4%), ROS1 fusion (1.9%), RET fusion (2.3%), MET amplification (2.5%), ERBB2 amplification (2.7%), MAP2K1 (0.7%), NRAS (1.2%), HRAS (1.2%), NF1 truncation (1.9%), FGR1/2 (0.7%), RIT1 (0.2%), and other genes (7.8%).

“It behooves us to remember that KRAS G12C as well as HER2 mutations are immediately actionable in the second-line setting at this moment in time, but soon to move in the first-line setting potentially, as new trials read out,” Aggarwal added.

However, the use of this personalized approach to treatment relies on comprehensive next generation sequencing (NGS), timely testing, and delivery of care, Aggarwal emphasized. “The survival benefit from targeted therapy is lost if targeted therapy is never delivered,” she said.

The Push for Molecular Data—and Early

The top 3 reasons to obtain molecular results from patients is simple, Aggarwal said: to personalize therapy, improve outcomes, and lower toxicity. In the clinic, ctDNA is being used to inform an initial diagnosis and treatment plan for a patient with lung cancer, to monitor the impact of targeted therapy and immunotherapy, and to determine long-term responses.

Integrating plasma NGS into clinical practice, concurrent with the use of a tissue biopsy, has demonstrated an improved detection of molecular alterations in NSCLC while also improving the delivery of targeted agents. For example, results published in a JAMA Oncology article showed that 35.8% of patients who underwent NGS with tissue and plasma were found to have a targetable molecular detection vs 20.5% of patients who only had a tissue biopsy.⁴

“This will continue to increase as our clinical trials demonstrate many more actionable targets,” said Aggarwal, who added that it’s “absolutely OK” to proceed with plasma ctDNA genotyping first with a new patient with lung cancer, and then request a tissue biopsy. “But even if [tissue] may be available, sometimes it is inadequate. Sometimes we don’t know whether it is inadequate.”

She also reflected on a real-world cohort study of patients with newly diagnosed stage IV nonsquamous NSCLC, in which investigators analyzed the impact of concurrent tissue and ctDNA NGS upon the comprehensiveness of molecular genotyping as well as OS. Data showed that patients with comprehensive molecular testing (comprised of EGFR, ALK, BRAF, ROS1, MET, RET, and NTRK) had improved OS (P = .02), and that the having their molecular results prior to frontline treatment also correlated with improved survival (P < .0001).⁵

“What was important and critical to see was that the availability of genotyping results before first-line therapy seemed to hold the biggest advantage in terms of improving OS. This holds true for patients who did not receive targeted therapy as well, potentially due to the fact that we could sequence therapies in a little better fashion,” Aggarwal said. “For example, if a patient came in with KRAS G12C, we were more confident in our ability to deliver chemoimmunotherapy or [immunotherapy], based on their PD-L1 status.”

Even with these data, the use of ctDNA in the clinic is not widespread. Therefore, Aggarwal spoke about a nudge intervention workflow, which would provide a patient’s provider team with a trigger to have the patient undergo NGS if the patient was treatment naive and had advanced squamous disease that was newly diagnosed. Additionally, she proposed an email-based reflex alert program, which would signal a patient’s internal review team with their targetable alteration results.

Results of this nudge workflow were presented at International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer, demonstrating an increase in comprehensive NGS from pre- to post-intervention in the academic (difference, 8.1%) and community (23.2%) settings; the total difference from pre- to post-intervention was 11.5% (P = .00007).1,6 When the nudge workflow was utilized prior to frontline treatment specifically, the total difference from pre- to post-intervention was 15.6%. Data also showed that 48.4% of patients had a detectable, actionable molecular alteration; these alterations were found in ctDNA/tissue combined (46.1%), ctDNA alone (30.3%), or tissue alone (23.7%).

Earlier integration of ctDNA NGS can improve care delivery and reduce the time to treatment, Aggarwal explained. In a 2022 review, investigators looked at patients with NSCLC who underwent ctDNA genotyping at the time of their initial biopsy. Results showed that those who had their treatment decisions at the first oncology visit were higher prospectively (74%) vs historically (46%; P = .005).⁶ Time to treatment was also reduced (P = .003).

“More patients with lung cancer with liquid biopsy performed at the time of initial diagnostic biopsy received a specific treatment recommendation,” Aggarwal noted. “They came to my office [and] I could tell them ‘you have a KRAS G12C mutation, I’m going to give you immunotherapy’, because I already know their PD-L1 level—this jumped from 46% to 74% [P = .005].”

Ongoing research efforts are evaluating how a telehealth-based approach can also improve the use of molecular genotyping in lung cancer, such as the TESTING trial (NCT05790460).⁷ Patients with suspected advanced disease will be randomized to a usual care arm of tissue biopsy, followed by a standard nurse navigation visit with molecular test, or a telehealth arm with a telehealth nurse navigation visit, which will order a tissue biopsy and concurrent plasma-based molecular test.

ctDNA: A Monitoring Tool

Beyond improving care delivery and survival, the use of ctDNA can also be used serially to monitor patients who are currently receiving molecular-based therapy. Clinicians can observe for compound and resistance mutations, and for dVAF, which is a marker for response in patients receiving pembrolizumab-based therapy.

“What is really meaningful is that liquid biopsy could help us in unusual circumstances where we’re not sure if this is [disease] progression [or not],” Aggarwal said.

One planned study out of University of Pennsylvania is also evaluating whether ctDNA assays can be used as guidance for discontinuation of immunotherapy. The hypothesis, Aggarwal said, is that if a patient with NSCLC has ctDNA clearance with a long-term ctDNA assay, they are estimated to be progression free for 6 months.

References

1. Aggarwal C. ctDNA in lung cancer. Presented at: 18th Annual New York Lung Cancers Symposium; November 11, 2023; New York, NY.
2. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Eng J Med. 2020;382(1):41-50. doi:10.1056/NEJMoa1913662
3. Mok T, Camidge DR, Gadgeel SM, et al. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann Oncol. 2020;31(8):1056-1064. doi:10.1016/j.annonc.2020.04.478
4. 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
5. Aggarwal C, Marmarelis ME, Hwang W-T, et al. Association between availability of molecular genotyping results and overall survival in patients with advanced nonsquamous non–small-cell lung cancer. JCO Precision Oncol. 2023;7:e2300191. doi:10.1200/PO.23.00191
6. Thompson JC, Aggarwal C, Wong J, et al. Plasma genotyping at the time of diagnostic tissue biopsy decreases time-to-treatment in patients with advanced NSCLC—results from a prospective pilot study. JTO Clin Res Reports. 2022;3(4):100301. doi:10.1016/j.jtocrr.2022.100301
7. Telehealth based synchronous navigation to improve molecularly-informed care for patients with lung cancer (TESTING). Clinicaltrials.gov. May 26, 2023. Accessed November 11, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05790460