In patients with newly diagnosed, PD-L1–positive, advanced non–small cell lung cancer (NSCLC) who tested negative for driver mutations, implementation of plasma-guided treatment intensification—from monotherapy with the PD-1 inhibitor pembrolizumab to platinum doublet chemotherapy plus pembrolizumab—was associated with a median progression-free survival that compared favorably with historical controls, based on data presented during the 2025 ASCO Annual Meeting.1 The prospective clinical trial also appeared to result in less upfront exposure to platinum doublet chemotherapy than would be expected with assessment of the PD-L1 tumor proportion score.
“There is clinical uncertainty as to which patients require first-line treatment with chemoimmunotherapy vs immune checkpoint inhibitor monotherapy,” according to Julia K. Rotow, MD, Clinical Director, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, and Assistant Professor of Medicine, Harvard Medical School, Boston, and colleagues. “Although PD-L1 expression can predict for immune checkpoint inhibitor response, it is an imperfect biomarker. Early circulating tumor DNA [ctDNA] kinetics may offer an individualized assessment of treatment response, allowing us to optimize clinical decision-making.”
Study Design
A total of 40 patients received first-line treatment with pembrolizumab. On the first day of the second cycle, 36 completed plasma response assessment. Plasma response was defined as a reduction of at least 50% in the maximum variant allele fraction and/or persistent low-shedding status. Radiographic response was assessed at the third cycle.
Patients who showed a radiographic response or had radiographic stable disease along with a plasma response continued pembrolizumab monotherapy. Those with stable disease or asymptomatic disease progression but without a plasma response were escalated to a combination of carboplatin-based doublet chemotherapy (paclitaxel for squamous histology or pemetrexed for nonsquamous) plus pembrolizumab. Patients who experienced symptomatic radiographic disease progression discontinued treatment.
“Early circulating tumor DNA kinetics may offer an individualized assessment of treatment response, allowing us to optimize clinical decision-making.”— JULIA K. ROTOW, MD
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According to the investigators, based on the integrated plasma and radiographic response assessment, 21 patients were assigned to continue with pembrolizumab monotherapy, and 19 patients received this treatment (7 with radiographic partial response at cycle 3 and 12 with radiographic stable disease with plasma response). And nine plasma nonresponders with radiographic stable disease were assigned to escalate to pembrolizumab plus platinum doublet therapy, and seven patients received this therapy. Reasons for treatment discontinuation prior to cycle 3 treatment allocation included disease progression (n = 3), adverse events (n = 2), or death (n = 1). Age, gender, performance status, histology, and PD-L1 tumor proportion score were found to be similar across the treatment arms.
The primary endpoint was the 6-month progression-free survival rate with the platinum doublet therapy. Safety, feasibility, and survival outcomes were evaluated as secondary endpoints, according to Dr. Rotow.
Key Results
The overall response rate with this adaptive treatment strategy was 50%; stable disease was reported in 22.5% of patients. Those with vs without plasma response experienced a higher radiographic response rate (81% vs 21%). The median durations of progression-free and overall survival were 11.0 and 14.9 months, respectively.
Toxicities were found to be consistent with the known adverse event profiles of platinum doublet chemotherapy and pembrolizumab, according to Dr. Rotow. “The rates of grade 3 or higher adverse events were very low,” she noted. Three patients with high PD-L1 tumor proportion scores and a history of tobacco use died during their first two cycles of pembrolizumab monotherapy; two died of disease progression, and one died of a treatment-unrelated adverse event.
“[Based on subgroup analyses], both progression-free and overall survival were similar among PD-L1–high and PD-L1–low subsets,” Dr. Rotow commented. “However, plasma response predicted strongly for improved [outcomes].” The median progression-free survival was 16.4 months in patients with a plasma response and 4.8 months in those without (hazard ratio [HR] = 0.34); the median overall survival was 34.3 and 8.6 months, respectively (HR = 0.15).
On study, a total of 16% of PD-L1–high patients ultimately received chemoimmunotherapy instead of standard immunotherapy alone; most with PD-L1–low disease (80%) received immunotherapy rather than standard chemoimmunotherapy. “Fewer patients were treated with platinum doublet chemotherapy than would have been predicted by PD-L1 status alone (17.5% vs 37.5%),” noted Dr. Rotow and colleagues. Overall, 50% of patients received platinum doublet therapy either on study or as their next line of treatment, and 68.8% remained free of disease progression on a platinum doublet at 6 months.
Dr. Rotow concluded: “Plasma-guided intensification from immunotherapy monotherapy to platinum doublet [plus] pembrolizumab is feasible in metastatic NSCLC, resulting in a median progression-free survival of 11.0 months, with fewer exposed to platinum doublet chemotherapy than might have been predicted by standard clinical biomarkers. ctDNA predicted strongly for both progression-free survival and overall survival in this patient population, and ctDNA kinetics is an important emerging tool to guide clinical decision-making in upfront therapy in NSCLC, though further validation within a randomized study is needed to clarify the implications for clinical practice.”
DISCLOSURE: Dr. Rotow has received honoraria from AstraZeneca, Daiichi Sankyo, and Pfizer; has served as a consultant or advisor to AbbVie, Amgen, AstraZeneca, BioAtla, BMS, Boehringer Ingelheim, Daiichi Sankyo, G1 Therapeutics, Genentech, Guardant Health, Jazz Pharmaceuticals, Johnson & Johnson/Janssen, Merus, Nuvation Bio, Pfizer, Sanofi/Regeneron, Summit Therapeutics, and Takeda; has received research funding from AbbVie, Altor BioScience, AstraZeneca, BioAtla, Black Diamond Therapeutics, Blueprint Medicines, Daiichi Sankyo, DualityBio, Enliven Therapeutics, EpimAb, ImmunityBio, Loxo, ORIC Pharmaceuticals, RedCloud Biotech, Regeneron, Summit Therapeutics, and Synthekine; and has received reimbursement for travel, accommodations, or expenses from AstraZeneca, Black Diamond Therapeutics, BMS, Johnson & Johnson/Janssen, and Merus. For full disclosures of the other study authors, visit coi.asco.org.
REFERENCE
- Rotow JK, Heavey G, Nishino M, et al: Plasma-guided adaptive first-line chemoimmunotherapy for non-small cell lung cancer. 2025 ASCO Annual Meeting. Abstract 8515. Presented June 2, 2025.
