Dual Immunotherapy and ctDNA-Based Molecular Tracking in Resectable Mesothelioma
In this article
🫁 A Turning Point in Pleural Mesothelioma Treatment
Pleural mesotheliomais an aggressive, hard-to-treat cancer arising from the lung lining (pleura), mostly associated with asbestos exposure . Approximately 30 thousand people worldwide receive this diagnosis each year. Unfortunately, it is usually detected late, and survival remains limited with current treatments.
Over the past 20 years, aggressive triple-modality treatments combining chemotherapy, surgery, and radiotherapy were tested without the expected major progress. A turning point came with immune checkpoint inhibitors (ICIs) , which release the immune system's brakes. Studies such as CheckMate-743 showed that nivolumab (anti–PD-1) + ipilimumab (anti–CTLA-4) significantly prolongs survival in advanced disease, and this regimen is now an approved standard.
But what about resectable cases? As in lung cancer, could immunotherapy before and after surgery (perioperative) eliminate microscopic disease and provide long-term benefit? A phase II study in Nature Medicine, published September 8, 2025, explores this question.
How Was the Study Conducted?
- Patient population: Resectable epithelioid or biphasic pleural mesothelioma (excluding sarcomatoid), ECOG 0–1, 30 patients in total.
- Arms:
- Arm A (Nivolumab): 16 patients → 240 mg every 2 weeks, 3 cycles.
- Arm B (Nivolumab + Ipilimumab): 14 patients → Nivo 3 mg/kg (3 cycles, every 2 weeks) + Ipi 1 mg/kg (first cycle only).
- Followed by planned surgery, optional chemotherapy/radiotherapy, and 1 year of adjuvant nivolumab.
- Special feature: Treatment response was monitored not only by imaging but also by circulating tumor DNA (ctDNA) in blood. The assay used was: Labcorp's Plasma Detect™ (CAP/CLIA-accredited, tumor-informed, WGS-based MRD test).
📊 Comparative Results (Arm A vs Arm B)
The two arms' median PFS and OS outcomes.
⏱️ Survival Times (Median)
- Arm A (Nivo): PFS 9.6 months, OS 19.3 months
- Arm B (Nivo+Ipi): PFS 19.8 months, OS 28.6 months (a signal favoring combination therapy in this small phase II study)
📊 What Was Found?
🔧 Proceeding to Surgery
In Arm A, 81.3%, and in Arm B, 85.7% of patients underwent surgery as planned; immunotherapy did not delay surgery.
🛠️ Rate of Proceeding to Surgery (%)
🕒 ctDNA Time Points—Timeline
The line graph below schematically illustrates the overall cohort's reported ctDNA positivity rates (%) at: C1D1, C2D1, C3D1, preoperative and postoperative.
🧬 Molecular Monitoring With ctDNA
- At C3 (3rd-cycle day), ctDNA negative patients had PFS of: 19.8 months vs positive: 1.4 months (P=0.027).
- Preoperatively, ctDNA negative patients had PFS of: 23.3 months vs positive: 2.5 months (P=0.0059).
- ≥95% reduction in cfDNA TF or ctDNA negativity throughout → significantly better PFS.
- In all patients unable to undergo surgery or complete resection, ctDNA remained persistently positive .
- In some cases appearing stable on imaging, ctDNA cleared early and PFS was long → ctDNA may provide an earlier signal than mRECIST .
🧪 PFS by ctDNA Status (Months)
Comparison of median PFS at C3 and preoperative time points.
🛡️ Grade ≥3 Immune-Related Adverse Event Rates (%)
Serious immune-related adverse event rates were low during neoadjuvant treatment.
🔍 What Does It Mean?
- Perioperative immunotherapy is feasible and safe.
- Nivo+Ipi showed a signal of longer PFS/OS in a small sample—a hypothesis-generating finding.
- ctDNA (WGS-based)is a strong candidate biomarker for predicting progression to surgery and early recurrence risk.
⚠️ Limitations
- Small sample (n=30), nonrandomized sequential arms.
- Adjuvant treatment rates and histological distributions may differ between arms.
- ctDNA infrastructure requires advanced technology; access and reimbursement vary by center.
🌟 Final Thoughts
This study shows that, in resectable pleural mesothelioma, immunotherapy is feasible, safe, and promising and molecular monitoring with ctDNA may be a powerful tool for personalizing treatment decisions. The next step is randomized phase 3 trials and testing ctDNA-guided strategies.
📚 Sources
Nature Medicine (Open Access)
Reuss JE, Lee PK, Mehran RJ, et al. Perioperative nivolumab or nivolumab plus ipilimumab in resectable diffuse pleural mesothelioma: a phase 2 trial and ctDNA analyses. Article link
IASLC WCLC 2025
OA12.03 — Perioperative nivolumab with or without ipilimumab in resectable diffuse pleural mesothelioma. Congress page
ClinicalTrials.gov
NCT03918252 — Perioperative Nivolumab ± Ipilimumab in Resectable DPM. Registry page
Methods—ctDNA (Labcorp Plasma Detect™)
The tumor-informed, whole-genome sequencing (WGS)-based MRD assay used in this study: Labcorp Plasma Detect™ (CLIA/CAP). Consult Labcorp's technical documentation and the methods supplements for general information about assay specifications.
Was this article helpful?
Your feedback helps us improve our content.
Reader comments
Share your comment
Your name and comment are published only after administrator approval. Your email address is never shown to visitors.
Be the first to comment.