ctDNA Carves a Precise Path for Early-Stage NSCLC Management

David R. Gandara, MD

The increasing prevalence of circulating tumor DNA (ctDNA) assays for minimal residual disease (MRD) detection in non–small cell lung cancer (NSCLC) supports the role of liquid biopsy in informing personalized adjuvant treatment strategies and predicting patient outcomes post-surgery, according to David R. Gandara, MD.

During a presentation at the 25th Annual International Lung Cancer Congress, Gandara highlighted the goal of using ctDNA assays to detect MRD in the adjuvant NSCLC setting, ways that ctDNA assays can be prognostic for treatment outcomes with standard adjuvant regimens, and future directions for MRD detection using ctDNA.¹

Gandara is the chief medical officer of the International Society of Liquid Biopsy, co-director of the Center for Experimental Therapeutics in Cancer, and senior advisor to the director of the University of California Davis Comprehensive Cancer Center in Sacramento. He is also an adjunct clinical professor of the Translational and Clinical Research Program at the University of Hawaii Cancer Center in Honolulu.

Defining the Role of ctDNA in Precision Oncology

Gandara began his presentation by explaining the ways in which ctDNA analysis can individualize patient care, both across oncology specialties, and in patients with early-stage NSCLC. He noted the existence of several potential sources for liquid biopsy in patients with cancer, including saliva, cerebrospinal fluid, pleural effusion, urine, bile, ascites, and supernatant from cytological preparations. However, he emphasized the prevalence of next-generation sequencing–derived blood-based assays in oncology clinical practice. ctDNA remains a common blood-based biopsy analyte, although other components of the blood, such as extracellular vesicles, are also under investigation, he said. Ultimately, ctDNA analysis can identify gene point mutations, amplifications, deletions, and rearrangements, although an increasing number of assays are able to detect epigenetic changes, according to Gandara.

“This turns out to be critical in the screening and early detection space and also in the MRD space,” he emphasized.

Using Liquid Biopsy to Analyze MRD Levels Post-Surgery

For the purposes of his presentation, Gandara limited the definition of MRD analysis to the post-surgery setting in patients with early-stage NSCLC. He then outlined the algorithm for MRD assay analysis, noting the importance of collecting a baseline blood sample pre-surgery for a plasma-informed analysis. He went on to explain that approximately 8 weeks post-surgery, another liquid biopsy is conducted to inform therapeutic decision-making.

“The purpose of an MRD assay is not…about the findings and what happens 5 years later,” Gandara emphasized. “The MRD assay purpose is so you can decide what to do post-surgery.”

Across tumor types, including bladder cancer, breast cancer, and colorectal cancer, detection of MRD post-surgery confers a poor prognosis, Gandara said. In NSCLC, a study of 255 samples from 40 patients who received curative-intent therapy for stage I to III lung cancer demonstrated that patients with detectable ctDNA at the MRD landmark analysis had significantly worse progression-free survival and overall survival outcomes vs those with no detectable ctDNA (P < .001).²

“The question, of course, is: Can we use this in a predictive fashion that is helpful to the [treatment] of that patient?” Gandara asked.¹

Extrapolating the Predictive and Prognostic Capabilities of Plasma ctDNA MRD Analysis

Gandara then brought the audience’s attention to MRD findings from 2 landmark phase 3 adjuvant NSCLC trials: IMpower010 (NCT02486718) and ADAURA (NCT02511106). The purpose of evaluating MRD in these trials was to determine whether plasma ctDNA MRD detection was only prognostic, or whether it could be predictive of improved clinical outcomes with specific therapeutic interventions, he noted.

In the primary analysis of IMpower010, treatment with adjuvant atezolizumab (Tecentriq) improved disease-free survival (DFS) vs best supportive care (BSC) in patients with resected stage II to IIIA NSCLC with PD-L1 expression on 1% or more of tumor cells (HR, 0.66; 95% CI, 0.50-0.88; P = .0039).³ However, among patients with PD-L1 expression on at least 1% of tumor cells and detectable MRD, the median DFS was 21.8 months in patients who received atezolizumab (n = 36) vs 7.2 months in those who received BSC (n = 37; HR, 0.54 [95% CI, 0.31-0.93]).⁴ In contrast, among patients with PD-L1 expression on at least 1% of tumor cells and undetectable MRD, the median DFS was not reached (NR) in patients who received atezolizumab (n = 124) vs 37.3 months in those who received BSC (n = 98; HR, 0.57 [95% CI, 0.36-0.90]).

“In both cases, the data favored the group that got atezolizumab; that’s good,” Gandara said.¹ “The bad [news] is that you can see pretty continuous relapse in both…groups of patients. To me, this assay in this clinical setting would not allow you to prospectively decide who to escalate, who to de-escalate, and it does not look from these curves that it can tell us who’s cured.”

Regarding ADAURA, in the primary analysis, the median DFS with adjuvant osimertinib (Tagrisso) was NR (95% CI, 38.8 months-not calculable) vs 19.6 months (95% CI, 16.6-24.5) with placebo (HR, 0.17; 99.06% CI, 0.11-0.26; P < .001) in patients with resected, EGFR-mutated stage II to IIIA NSCLC.⁵ Among 5 patients in the osimertinib arm with detectable MRD at baseline post-surgery, 4 cleared MRD at 5 years.⁶ None of the 13 patients in the placebo arm with detectable baseline MRD post-surgery cleared MRD at 5 years. MRD was eventually detected in 13% of evaluable patients from the osimertinib arm (n = 112) and 49% of those from the placebo arm (n = 108).

“Over time…[patients] with positive MRD had a worse prognosis; that’s exactly what we would expect,” Gandara elucidated.¹ “The MRD assays were informative, but these long-term observations don’t allow us to use this assay in this clinical setting to determine whether to escalate or de-escalate [therapy approximately 8 to 12 weeks after surgery].”

Gandara also shared data from the phase 3 CheckMate 816 trial (NCT02998528). This trial showed that patients with stage IB to IIIA resectable NSCLC who received neoadjuvant nivolumab (Opdivo) plus chemotherapy and achieved ctDNA clearance (n = 24) had a median event-free survival (EFS) that was NR (95% CI, 16.8-NR) vs 18.9 months (95% CI, 8.3-NR) in those who received the combination but did not achieve ctDNA clearance (n = 19; HR, 0.60 [95% CI, 0.20-1.82]).⁷ Among patients who received chemotherapy alone, those who achieved ctDNA clearance (n = 15) had a median EFS that was NR (95% CI, 19.6-NR) vs 16.8 months (95% CI, 8.3-NR) in those who did not achieve ctDNA clearance (n = 28; HR, 0.63 [95% CI, 0.20-2.01]). The pathologic complete response (pCR) rates among patients with ctDNA clearance were 46% and 13% in the nivolumab and chemotherapy alone arms, respectively. The pCR rates among patients without ctDNA clearance were 0% and 4% in these respective arms.

“My opinion here is that this is still research, and that the practicing oncologist would not use this information to make therapeutic decisions,” Gandara emphasized.¹

Peering Into the Future of MRD-Related Clinical Trials

The future remains bright for conducting prospective clinical trials that evaluate MRD across tumor types, Gandara explained. For instance, studies could investigate the escalation or de-escalation of adjuvant or consolidation therapy based on MRD or the omission of standard-of-care therapy based on MRD, he said. However, all these potential areas of future research necessitate the development of infallible ctDNA assays, he concluded.

Disclosures: Dr Gandara reports institutional research grants from Amgen, Astex, and Genentech; institutional consultant roles with Adagene, AstraZeneca, IO Biotech, Guardant Health, and Oncocyte; and advisory board participation with Roche/Genentech, Merck, Novartis, Boehringer Ingelheim, Regeneron, Sanofi, and Amgen.

References

1. Gandara DR. Applications for ctDNA in early-stage lung cancer. Presented at: 25th Annual International Lung Cancer Congress; July 25-27, 2024; Huntington Beach, CA.
2. Chaudhuri AA, Chabon JJ, Lovejoy AF, et al. Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer Discov. 2017;7(12):1394-1403. doi:10.1158/2159-8290.CD-17-0716
3. Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2021;398(10308):1344-1357. doi:10.1016/S0140-6736(21)02098-5
4. Zhou C, Das Thakur M, Srivastava MK, et al. IMpower010: biomarkers of disease-free survival (DFS) in a phase III study of atezolizumab (atezo) vs best supportive care (BSC) after adjuvant chemotherapy in stage IB-IIIA NSCLC. Ann Oncol. 2021;32(suppl 7):S1374. doi:10.1016/j.annonc.2021.10.018
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6. John T, Grohe C, Goldman JW, et al. Molecular residual disease (MRD) analysis from the ADAURA trial of adjuvant (adj) osimertinib in patients (pts) with resected EGFR-mutated (EGFRm) stage IB-IIIA non-small cell lung cancer (NSCLC). J Clin Oncol. 2024;42(suppl 16):8005. doi:10.1200/JCO.2024.42.16_suppl.8005
7. Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. 2022;386(21):1973-1985. doi:10.1056/NEJMoa2202170