MRD Offers a Potential Predictive Strategy to Further Personalize Treatment in NSCLC

Although the predictive utility of minimal residual disease (MRD) has yet to be fully realized in non–small cell lung cancer (NSCLC), it has the potential to guide treatment decisions in earlier lines of treatment, including the adjuvant setting, said David R. Gandara, MD, in a presentation during the 22nd Annual International Lung Cancer Congress® (ILCC), a program hosted by the Physicians’ Education Resource®, LLC.¹

“Looking at what is happening, not only in lung cancer but in multiple other tumor types, [the integration of predictive MRD] has the most promise of anything we will talk about at ILCC,” said Gandara, a professor, director of the Thoracic Oncology Program, and senior advisor to the director at the University of California Davis Comprehensive Cancer Center.

Establishing the Utility of Liquid Biopsy in Advanced NSCLC

MRD has an established prognostic role in the treatment of patients with advanced NSCLC, Gandara said. However, before this, liquid biopsy with circulating tumor DNA (ctDNA), for example, demonstrated potential applications throughout the management of patients with NSCLC, from screening to diagnosis to disease monitoring to determining mechanisms of resistance to therapy.

However, like many technologies that have been used in later-line settings, the field of NSCLC is hoping to incorporate liquid biopsy, and, in particular, MRD testing, into earlier lines of treatment, explained Gandara.

“Doing [liquid biopsy] in the advanced-stage setting, means that we can possibly apply it to early-stage disease if we have assays that are sensitive and specific enough,” said Gandara.

MRD: Predictive and Prognostic?

A 2017 study, which was published in Cancer Discovery, demonstrated that ctDNA analysis can identify post-treatment MRD in patients with localized lung cancer and do so earlier than radiologic imaging, which was standard at the time.² The findings from the study showed that 94% of patients had detectable ctDNA in the first post-treatment blood sample as assessed by cancer personalized profiling by deep sequencing (CAPP-seq).

“We have already established to some extent that we can use MRD detection and that this correlates with prognosis,” Gandara added.

Findings from another study (NCT03004755), published in Nature in 2017, demonstrated that phylogenetic ctDNA profiling can predict disease recurrence; however, the technology was limited at the time in terms of universal application to an MRD setting, Gandara explained.^1,3

Subsequently, findings from a large, retrospective study of 21,807 patients with treated, late-stage cancer, including NSCLC, showed that cell-free DNA sequencing was able to identify subclonal structures and emerging resistance mechanisms.⁴

An 85% detection rate with the Guardant360 plasma next-generation sequencing assay was reported from the analysis. In thoracic cancers, the detection rates were 93% in small cell lung cancer and 87% in NSCLC. Notably, the median variant allele frequency (VAF) rate was 0.41% (range, 0.03%-97.6%).

“Remember in blood, when we talk about VAF, we are talking about comparison to all the DNA that is in the blood, not just the tumor DNA,” Gandara said.

Now, with positive data emerging from studies conducted in the adjuvant setting, such as the phase 3 ADAURA (NCT02511106) and IMpower010 (NCT02486718) trials, the question remains as to whether MRD will predict for which patients should receive adjuvant therapy vs who is effectively cured after surgery, Gandara explained.

Definitive Data and Ongoing Research Efforts

Studies are ongoing with the goal of addressing the question of whether MRD assessment has utility in the adjuvant setting, Gandara said.

For example, the ongoing phase 3 MERMAID-1 trial (NCT04385368) is evaluating MRD assessment in patients with surgically resected stage II/III NSCLC.⁵ After surgery, patients will undergo plasma collection for MRD status testing. Then, patients will be randomized 1:1 to receive durvalumab (Imfinzi) plus chemotherapy followed by durvalumab or placebo plus chemotherapy followed by placebo for up to 12 months. The primary end point of the study is investigator-assessed disease-free survival in the MRD-positive analysis set with MRD status serving as a stratification factor.

The study investigators will use whole-exome sequencing to identify tumor-specific variants within a patient’s surgical specimen. Then tumor-specific DNA in the plasma can be detected in the adjuvant setting.

Additionally, the phase 3 MERMAID-2 trial (NCT04642469) has recently begun enrollment of patients with stage II/III NSCLC who underwent curative-intent therapy.⁶ The study is evaluating the efficacy of durvalumab vs placebo in patients with MRD-positive disease; patients with MRD-negative disease will receive surveillance instead of durvalumab or placebo for up to 96 weeks.

“[The MERMAID-2 trial] is relevant and will give us information in a new way. Both [the MERMAID-1 and MERMAID-2 trials] will be important studies,” Gandara concluded.

References

1. Gandara DR. Minimal residual disease in non-small cell lung cancer (NSCLC): emerging role in therapeutic decision making. Presented at: 22nd Annual International Lung Cancer Congress®; July 29-31, 2021; hybrid interactive conference.
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. Abbosh C, Birkbak NJ, Wilson GA, et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature. 2017;545(7655):446-451. doi:10.1038/nature22364
4. Zill OA, Banks KC, Fairclough SR, et al. The landscape of actionable genomic alterations in cell-free circulating tumor DNA from 21,807 advanced cancer patients. Clin Cancer Res. 2018;24(15):3528-3538. doi:10.1158/1078-0432.CCR-17-3837
5. Peters S, Spigel D, Ahn M, et al. MERMAID-1: a phase III study of adjuvant durvalumab plus chemotherapy in resected NSCLC patients with MRD+ post-surgery. J Thorac Oncol. 2021;16(3):S258-S259. doi:10.1016/j.jtho.2021.01.376
6. Phase III study to determine efficacy of durvalumab in stage II-III non-small cell lung cancer (NSCLC) after curative intent therapy. ClinicalTrials.gov. Updated July 15, 2021. Accessed July 29, 2021. https://clinicaltrials.gov/ct2/show/NCT04642469.