ctDNA Clearance and MRD May Identify NSCLC Patients Who Benefit Most from Perioperative Nivolumab

Circulating tumor DNA (ctDNA) clearance and molecular residual disease (MRD) status may help identify which patients with resectable non-small cell lung cancer (搜索)搜索该疾病 (NSCLC) derive the greatest benefit from perioperative immunotherapy, according to new research led by The University of Texas MD Anderson Cancer Center查看公司主页 and published in Nature.

The study analyzed biomarker and clinical outcome data from the Phase 3 CheckMate 77T trial, which previously demonstrated improved outcomes with immunotherapy given before and after surgery (perioperative). The researchers found that the best indicators of a positive outcome were ctDNA clearance before surgery and achieving a pathologic complete response (pCR), meaning no remaining cancer was detected at surgery.

"Perioperative immunotherapy has transformed care for many patients with resectable lung cancer, but we still need better markers to understand who benefits most from treatment," said Tina Cascone, M.D., Ph.D., associate professor of Thoracic/Head and Neck Medical Oncology. "These results suggest that monitoring ctDNA before surgery may provide important insights into treatment response and long-term outcomes, bringing us closer to more personalized approaches."

Why Biomarkers Matter in Resectable Lung Cancer

Patients with resectable NSCLC often face a substantial risk of recurrence after surgery. As a result, researchers have been investigating whether biomarkers can help identify residual disease earlier and predict which patients are most likely to experience long-term benefits from immunotherapy.

ctDNA consists of fragments of tumor DNA that can be detected in a blood sample. A reduction or disappearance of ctDNA during treatment may indicate that therapy is eliminating cancer cells. Conversely, the presence of ctDNA after treatment can indicate MRD, meaning cancer cells remain in the body but are not detectable by conventional methods.

In this study, researchers evaluated ctDNA dynamics, MRD status, and tumor genomic alterations in 190 patients enrolled in the CheckMate 77T trial, comprising 98 patients in the nivolumab查看药品详情 group and 92 in the placebo group.

ctDNA Clearance as a Dynamic Biomarker of Response

Unlike static baseline biomarkers such as PD-L1 (搜索)搜索该靶点 expression and tumor mutational burden (TMB), ctDNA provides a dynamic measurement of tumor-derived molecular material during treatment. Among patients with detectable and evaluable ctDNA before and after neoadjuvant therapy, ctDNA clearance occurred substantially more frequently following nivolumab查看药品详情 plus chemotherapy.

Patients receiving nivolumab查看药品详情 were nearly twice as likely to have ctDNA clearance before surgery compared with those in the chemotherapy plus placebo group (66% vs. 38%). Specifically, clearance occurred in 66% (50/76) of nivolumab-treated patients versus 38% (24/64) of placebo-treated patients.

The addition of PD-1 blockade to neoadjuvant chemotherapy was therefore associated with a higher probability of eliminating detectable circulating tumor-derived DNA before surgery.

Linking Molecular and Pathological Response

A particularly important finding was the association between molecular response and pathological tumor regression. Among nivolumab查看药品详情-treated patients who achieved presurgical ctDNA clearance, 50% (25/50) achieved pCR. In contrast, among patients without ctDNA clearance, 0% (0/25) achieved pCR.

In the placebo group, pCR occurred in 12% (3/24) of patients with ctDNA clearance and 2% (1/40) of patients without clearance. Overall, patients who received nivolumab查看药品详情 were more likely to have a pathologic complete response at surgery compared to those treated with placebo (50% vs. 12%).

The absence of pCR among nivolumab查看药品详情-treated patients without ctDNA clearance suggests a strong association between persistent circulating tumor DNA and residual viable tumor at surgery. At the same time, ctDNA clearance and pCR were not completely concordant: approximately half of nivolumab-treated patients who cleared ctDNA did not achieve pCR, indicating that these biomarkers capture related but non-identical dimensions of therapeutic response.

When the investigators examined event-free survival (EFS) according to combined ctDNA clearance and pCR status, achievement of both was associated with favorable EFS compared with patients who cleared ctDNA but did not achieve pCR (EFS HR: 0.29; 95% CI, 0.10–0.85), and compared with patients who achieved neither (EFS HR: 0.23; 95% CI, 0.08–0.65).

Postoperative MRD and Recurrence Risk

The analysis also evaluated ctDNA after surgery, when detectable tumor-derived DNA can serve as a marker of molecular residual disease. Among patients who were MRD-negative after surgery and before adjuvant therapy, subsequent MRD conversion occurred in 8% (4/48) of patients receiving nivolumab查看药品详情 and 20% (9/44) of patients receiving placebo.

Critically, all 13 patients who converted from MRD-negative to MRD-positive during the adjuvant period subsequently developed disease recurrence. This finding establishes postoperative ctDNA dynamics as a particularly strong prognostic signal within this dataset.

Patients with detectable MRD immediately before adjuvant treatment represented another high-risk subgroup. None of the patients who were MRD-positive before adjuvant therapy subsequently converted to MRD-negative during the adjuvant treatment period. Recurrence occurred in 3/4 patients (75%) receiving nivolumab查看药品详情 and 8/8 patients (100%) receiving placebo.

Genomic Context of Perioperative Nivolumab Benefit

The investigators explored the relationship between treatment efficacy and genomic alterations involving KRAS (搜索)搜索该靶点, KEAP1 (搜索)搜索该靶点, STK11 (搜索)搜索该靶点, TP53 (搜索)搜索该靶点, CDKN2A (搜索)搜索该靶点, and SMARCA4 (搜索)搜索该靶点. Among nivolumab查看药品详情-treated patients, pCR was observed in 47% of tumors harboring KRAS alterations, 29% with KEAP1 alterations, 40% with STK11 alterations, and 34% with TP53 alterations. The corresponding pCR rates in the placebo group were 5%, 0%, 0%, and 3%, respectively.

Patients whose tumors harbored genetic alterations typically associated with poor outcomes, including alterations in the KEAP1 (搜索)搜索该靶点, STK11 (搜索)搜索该靶点, CDKN2A (搜索)搜索该靶点 and SMARCA4 (搜索)搜索该靶点 genes, also appeared to benefit from perioperative nivolumab查看药品详情. When patients harboring single or co-occurring alterations in KEAP1, STK11, CDKN2A and/or SMARCA4 were analyzed collectively, perioperative nivolumab was associated with longer EFS compared with placebo (EFS HR: 0.48; 95% CI, 0.28–0.83). Among patients without alterations in these genes, the EFS HR was 0.90 (95% CI, 0.48–1.69).

These observations are particularly relevant for KEAP1 (搜索)搜索该靶点 and STK11 (搜索)搜索该靶点, given their established association with adverse biology and reduced immunotherapy sensitivity in advanced NSCLC. Nevertheless, these analyses are exploratory, and the available data do not establish individual genomic alterations as validated predictive biomarkers for perioperative nivolumab查看药品详情.

Beyond Single Biomarkers: Machine-Learning Integration

TMB was also evaluated as a potential biomarker. Using a threshold of 10 mutations per megabase, the relative EFS effect of nivolumab查看药品详情 appeared broadly similar across TMB categories (TMB <10 mut/Mb: HR 0.65; 95% CI, 0.39–1.11; TMB ≥10 mut/Mb: HR 0.62; 95% CI, 0.32–1.20). Thus, TMB considered as an isolated dichotomous biomarker did not clearly discriminate relative treatment benefit in this analysis.

A random survival forest model integrating clinical and molecular variables associated with EFS identified presurgical ctDNA clearance, non-N2 nodal status, pCR, squamous histology, and nivolumab查看药品详情 treatment as features associated with a lower risk of an EFS event. Within the nivolumab-treated population, the most informative variables included pCR, higher TMB, higher tumor PD-L1 (搜索)搜索该靶点 expression, non-N2 disease, and presurgical ctDNA clearance.

This analysis highlights an increasingly important concept in precision immuno-oncology: response to perioperative immune checkpoint blockade may be unlikely to be captured adequately by any single biomarker. The machine-learning analysis remains exploratory and does not constitute a clinically validated decision model.

Clinical Outcomes and Safety

With a median follow-up of 41.0 months, the updated analysis continued to demonstrate improved EFS with perioperative nivolumab查看药品详情 (EFS HR: 0.61; 95% CI, 0.46–0.80), with 30-month EFS rates of 61% versus 43%. Overall survival remained immature, with median OS not reached in either group and 30-month OS rates of 78% with nivolumab and 72% with placebo (HR 0.85; 97.63% CI, 0.58–1.25).

With longer follow-up, no new safety signals were identified. Treatment-related adverse events of any grade occurred in 89% of patients receiving nivolumab查看药品详情 and 87% receiving placebo, while grade 3–4 treatment-related adverse events occurred in 32% and 25%, respectively. Two previously reported treatment-related deaths due to pneumonitis occurred in the nivolumab group, with no treatment-related deaths in the placebo group.

Implications for Future Lung Cancer Treatment

After more than three years of follow-up, nivolumab查看药品详情 continued to improve event-free survival compared with placebo without compromising patients' quality of life. The findings suggest blood-based biomarkers such as ctDNA clearance and MRD may help doctors better monitor treatment response and identify patients at higher risk of recurrence.

The particularly strong association between conversion to MRD positivity and subsequent recurrence provides a biological rationale for prospective trials testing ctDNA-guided postoperative treatment strategies. However, this was an exploratory study, and additional research is needed before these tools can be routinely used in clinical practice. CheckMate 77T was not designed to test an MRD-guided therapeutic strategy, and these data should not yet be interpreted as evidence supporting treatment escalation based on MRD positivity.