Advances in the identification of prognostic biomarkers in patients with metastatic lung cancer.

Scientific Culture and Innovation Unit

A study coordinated by researchers from the Puerta de Hierro-Segovia Research Institute in Arana, published in Pharmacological Research, They evaluated the blood levels of pembrolizumab as a potential prognostic biomarker in patients with metastatic non-small cell lung cancer. The results suggest that early analysis of this drug in blood could help identify patients with less likelihood of benefiting from immunotherapy and design more personalized treatments.

Dr. Mariano Provencio (in the center) and Dr. Alberto Cruz (with a dark shirt behind) pose with their team, responsible for this research.

Lung cancer is the leading cause of cancer mortality worldwide. Approximately 80-85% of all lung cancer cases correspond to non-small cell lung cancer (NSCLC), and more than half of patients are diagnosed in advanced stages with metastases, where curative options are limited and the prognosis is unfavorable. In recent years, survival in these patients has improved thanks to the development of new therapies, especially immunotherapy with drugs such as pembrolizumab, which favors the immune system's response against tumor cells. However, despite having demonstrated clinical benefits in previous studies, its results vary among patients. Therefore, it is necessary to identify biomarkers capable of predicting which patients will benefit most clinically in order to guide clinical decision-making and advance towards more personalized treatments.  

The research has been coordinated by the Translational Research Group in Lung Cancer of the Puerta de Hierro-Segovia Institute of Health Research (IDIPHISA), with the collaboration of the Medical Oncology services of the Puerta de Hierro University Hospital and the Medical Oncology and Hospital Pharmacy of the Severo Ochoa University Hospital. The objective of this work was to explore the relationship between the levels of pembrolizumab in the blood after the first treatment cycle and survival in patients with metastatic NSCLC, using data from the observational, multicenter study and the real-life clinical practice «BLI-O».

Relationship between pembrolizumab concentration in blood and survival

The researchers analyzed the plasma values of pembrolizumab in samples from 133 patients treated in 12 centers in Spain. These patients had previously been diagnosed with metastatic CPNM and treated with immunotherapy, either with pembrolizumab alone or in combination with chemotherapy.

The results of the drug concentration in the blood after the first cycle of treatment showed that patients with levels above 10 μg/mL were associated with a better prognosis. The data from these patients showed an improvement in overall survival and in progression-free survival, that is, the time without the disease progressing.

Pembrolizumab is a monoclonal antibody that, although it remains in the blood for a prolonged period, its elimination can vary between patients, affecting its plasma concentrations. Therefore, researchers studied factors such as gender, dose (fixed or adapted to the patient's weight), tumor burden (tumor size and extent) or albumin levels, a protein associated with the transport and elimination of drugs.

High tumor load or low albumin levels were associated with lower plasma levels of the drug, which could reduce its therapeutic efficacy. However, the differences observed according to gender and drug administration showed no changes in the survival of the patients.

Mechanism of action of immunotherapy

Immunotherapy is a treatment aimed at strengthening the immune system to identify and destroy tumor cells. In this case, pembrolizumab binds to a protein in the immune system called PD-1, preventing its interaction with other factors that would act as a brake on the immune system. In this context, our body’s defenses are unable to recognize or combat the tumor, which facilitates its growth. However, by blocking this interaction, pembrolizumab helps lift that brake and allows the immune system to act against the tumor cells.

The results showed that lower plasma levels of the drug blocked this mechanism less efficiently, with higher levels of free PD-1 being detected, which would contribute to the progression of the tumor. However, the study does not yet allow establishing a direct cause-and-effect relationship between the levels of the drug and the clinical evolution, although it could be a possible biological explanation.

Towards more personalized medicine

This work proposes that analyzing pembrolizumab levels in blood during the first weeks of treatment could help us understand how patients respond to immunotherapy and identify those patients with lower exposure to the drug to design more personalized treatments. As the authors indicate, not only is the drug important, but also how each patient processes it.

Although the researchers emphasize that more studies are needed to apply these findings in clinical practice, the results open up new perspectives in this field. The study contributes to the development of more precise medicine, in which clinical decision-making can include the characteristics of each patient and, therefore, advance towards a more personalized use of immunotherapy.

Reference: Martínez-Toledo C, Jiménez-Meseguer M, Molina-Alejandre M, Calvo V, Collazo-Lorduy A, Sierra-Rodero B, Blanco M, Martínez Cutillas M, Gil-González Á, Gutiérrez-Escobedo JM, Vázquez Estévez S, Fernández Núñez N, Diz-Taín P, Garrido Onecha ML, Martínez-Banaclocha N, Peña E, López Martín A, Peña-Cabia S, Sequero-López S, Rogado J, Sánchez-Hernández A, Coves Sarto J, Sala González Á, Mielgo X, García Marrero RD, García-Grande A, Cruz-Bermúdez A, Provencio M. Elevados niveles de pembrolizumab en plasma como biomarcador pronóstico en pacientes con NSCLC de la vida real. Pharmacol Res. 2026 Jun;228:108232. doi: 10.1016/j.phrs.2026.108232. Epub 5 May 2026. PMID: 42097413.