MRD Status Alone Is Not Necessarily Predictive of Response to Immunotherapy in NSCLC

Thought minimal residual disease can serve as an indicator for poor outcomes for patients with non–small cell lung cancer, it is not necessarily a predictor of response to immunotherapy.

Minimal residual disease (MRD) can serve as an indicator for poor outcomes for patients with non–small cell lung cancer (NSCLC), although MRD status is not necessarily a predictor of response to immunotherapy in these patients, according to Tony S.K. Mok, MD, BMSc, FRCPC, FASCO.

“We have to look into PD-L1 [expression], as well. We need a prospective, randomized study, and hopefully, that will give us more information [on the role of MRD in NSCLC] in the future,” Mok, who is the chairman of the Department of Clinical Oncology and Li Shu Fan Professor of Clinical Oncology at The Chinese University of Hong Kong, said in a presentation during the 23rd Annual International Lung Cancer Congress®.1

In lung cancer, MRD status refers to the detection of circulating tumor DNA (ctDNA) associated with residual cancer after curative surgery, Mok noted. Although the role of MRD in patients with NSCLC has not been prospectively studied, analyses of past trials have been used to evaluate the role of ctDNA in these patients.

The phase 3 IMpower010 trial (NCT02486718) investigated atezolizumab (Tecentriq) vs best supportive care (BSC) in patients with stage II to IIIA NSCLC after receiving chemotherapy. A retrospective analysis of the study showed that patients who were ctDNA negative experienced a significant improvement in disease-free survival (DFS) compared with those who were ctDNA positive, irrespective of treatment arm.2 In all ctDNA-evaluable patients, the median DFS with atezolizumab and BSC was NR and 31.4 months, respectively (HR, 0.69; 95% CI, 0.53-0.89).

Among patients with ctDNA negativity, those treated with atezolizumab (n = 218) experienced a median DFS that was not reached (NR); the median DFS was also NR in the BSC arm (n = 204; HR, 0.72; 95% CI, 0.52-1.00). However, for those who were ctDNA positive, those treated with atezolizumab (n = 53) experienced a median DFS of 19.1 months vs 7.9 months in those given BSC (n = 59; HR, 0.61; 95% CI, 0.39-0.94).

However, ctDNA status was not predictive of the benefit of immunotherapy vs BSC in those who had a PD-L1 expression of less than 1% of tumor cells.

In patients with a PD-L1 expression of less than 1% on tumor cells and ctDNA positivity, the median DFS was 5.1 months and 8.0 months for atezolizumab (n = 15) and BSC (n = 22), respectively (HR, 0.88; 95% CI, 0.40-1.91). In patients with a PD-L1 expression of less than 1% on tumor cells and ctDNA negativity, the median DFS was NR in both the atezolizumab (n = 94) and BSC (n = 106) arms (HR, 0.95; 95% CI, 0.60-1.50).

Among those with a PD-L1 expression of 1% or higher on tumor cells and ctDNA positivity, patients treated with atezolizumab (n = 36) experienced a median DFS of 21.8 months vs 7.2 months in those who received BSC (n = 37; HR, 0.54; 0.31-0.93). In patients with a PD-L1 expression of 1% or higher on tumor cells and ctDNA negativity, treatment with atezolizumab (n = 124) resulted in a median DFS that was NR vs 37.3 months with BSC (n = 98; HR; 0.57; 95% CI, 0.36-0.90).

“This is retrospective, so we cannot take this as [a] definitive [observation],” Mok emphasized.

Timing of MRD Testing and Other Predictive Benefits

Perioperative testing for MRD occurs at 2 key points during a patient’s treatment, Mok explained. After a patient receives surgery, MRD status can help determine treatment selection in the adjuvant setting.

In the surveillance phase following surgery, MRD can be tested again to determine whether early treatment is required for disease recurrence; it can be used to detect disease progression ahead of symptom presentation or radiographic progression.3

Tumor volume can also play a role in the detection of ctDNA when evaluating MRD, Mok explained. A tumor volume of 1 cm3 carries a predicted variant allele frequency (VAF) of 0.006% (95% CI, 0.001%-0.03%), compared with 0.1% (95% CI, 0.05%-0.17%) and 1.3% (95% CI, 0.57%-3.1%) for tumor volumes of 10 cm3 and 100 cm3, respectively. The sensitivity of a multiplex-PCR next-generation sequencing platform was in excess of 99% at VAFs of 0.1% and higher, suggesting that a tumor volume of 10 cm3 or higher leads to the optimal ctDNA detection sensitivity.4

Although detection of ctDNA alone may not predict response to immunotherapy in patients with NSCLC, MRD status can predict disease recurrence, according to Mok. In samples taken from patients with stage IB to III NSCLC in an observational study of 2 clinical trials (NCT01385722 and NCT00349830), those in whom ctDNA was not detected following treatment experienced significantly lower rates of progression-free survival and DFS events compared with those who were ctDNA positive at any point following treatment (P < .001 and P < .001, respectively).5

Similarly, data from a retrospective cohort of patients in China showed that among patients with stage I NSCLC, 98.5% of those with undetectable MRD had not experienced disease recurrence whereas 85% of those with detectable MRD recurred.6 In those with stage II disease, those rates were 88.9% and 100%, respectively, and in those with stage III disease, the rates were 100% and 88.2%, respectively.

Examining the Future Role of MRD in NSCLC

Data from retrospective studies have showcased the potential use of MRD in informing treatment decisions and predicting recurrence in lung cancer, but the role of this marker has not yet been evaluated in a prospective, randomized trial.

To this end, the ongoing phase 3 MERMAID-1 (NCT04385368) and MERMAID-2 (NCT04642469) trials are both evaluating durvalumab (Imfinzi) in patients with NSCLC, and all will be assessed for MRD status.7,8

In MERMAID-1, patients with resectable stage II or III NSCLC will receive durvalumab or placebo plus chemotherapy. The primary end point of the trial will be DFS among patients with MRD-positive disease.

MERMAID-2 will evaluate the MRD status of patients with stage II or III NSCLC following adjuvant therapy. Only patients with MRD-positive disease, either at initial assessment or during surveillance, will be randomized to receive durvalumab alone or placebo. DFS will serve as the primary end point of the research.

Although these trials could shed further light on the role of MRD in patients with NSCLC, having an ample population of MRD-positive patients will be key in both studies, according to Mok. "If [the trials] get a very low incidence [of MRD positivity], the chance of completion of these trials would be quite minimal,” Mok concluded.


  1. Mok T. What will be the role of MRD in determining us of peri-operative immunotherapy. Presented at: 23rd Annual International Lung Cancer Congress; July 27-29, 2022; Huntington Beach, CA.
  2. Zhou C, Das Thakur M, Srivastava MK, et al. IMpower010: biomarkers of disease-free survival (DFS) in a Phase 3 study of atezolizumab (atezo) vs best supportive care (BSC) after adjuvant chemotherapy in stage IB-IIIA NSCLC. Ann Oncol. 2021;32(suppl 7):S1373-S1391. doi:10.1016/annonc/annonc784
  3. Wan JCM, Massie C, Garcia-Corbacho, et al. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat Rev Cancer. 2017:17(4)223-238. doi:10.1038/nrc.2017.7
  4. 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
  5. Choudhuri 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(12):1394-1403. doi:10.1158/2159-8290.CD-17-0716
  6. Zhang J-T, L S-Y, Gao W, et al. Longitudinal undetectable molecular residual disease defines potentially cured population in localized non-small cell lung cancer. Cancer Discov. 2022;12(7):1690-1701. doi:10.1158/2159-8290.CD-21-1486
  7. 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
  8. Phase III study to determine efficacy of durvalumab in stage II-III non-small cell lung cancer (NSCLC) after curative intent therapy. Updated June 27, 2022. Accessed July 28, 2022.