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Immunotherapy has represented one of the main medical revolutions of recent decades, and is currently a consolidated treatment for different types of tumors at different stages and scenarios, and is present in a multitude of clinical trials. One of the diseases in which it is most developed is non-small cell lung cancer. The combination of radiotherapy and immunotherapy in cancer in general and lung cancer in particular currently represents one of the main focuses of basic and clinical research in oncology, due to the synergy of this interaction, which can improve tumor response, resulting in improved survival and disease control. In this review we present the biochemical and molecular basis of the interaction between radiotherapy and immunotherapy. We also present the current clinical status of this interaction in each of the stages and cases of non-small cell lung cancer, with the main results obtained in the different studies both in terms of tumor response and survival as well as toxicity. Finally, we mention the main studies underway and the challenges of this interaction in the coming years, including how these treatments should be combined to achieve the greatest efficacy with the fewest possible side effects (dose, type of radiotherapy and drugs, sequence of treatments).

The advent of targeted therapy has transformed the treatment paradigm and survival of patients with metastatic non-small cell lung cancer (NSCLC) with driver mutations. The development of acquired resistances during treatment with tyrosine kinase inhibitors (TKIs) impedes a prolonged survival in many patients. This fact is leading to the use of locally ablative therapies such as stereotactic ablative radiotherapy (SABR) to counter these resistances. SABR is a non-invasive treatment that can be delivered in multiple locations and has already proven effective in oligometastatic disease. Clinical evidence suggests that the combination of SABR with TKIs prolongs progression-free survival (PFS) in metastatic NSCLC patients with mutations in epidermal growth factor receptor (EGFR), with international guidelines recommending their use in unfavorable scenarios such as oligoprogressive disease. In this publication, we have reviewed the available evidence on EGFR-TKIs resistance mechanisms and the combination of SABR with TKI in metastatic NSCLC with EGFR mutations. We also describe the utility and clinical recommendations of this combination in oligometastatic and oligoprogressive disease.

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The irruption of the immunotherapy for the treatment of non-small cell lung cancer (NSCLC) based on Immune Checkpoint Inhibitors (ICI) PD-1 and PD-L1 inhibitors is considered a treatment revolution. However, only a small percentage of patients benefit with ICI treatment over the long term, and precise biomarkers that can recognize these individuals before or early during treatment have so far eluded. PD-L1 expression and tumor mutational burden (TMB) are the most well studied biomarkers for predicting response to PD- (L)1 blockade-based ICI prior to treatment. TMB is still being clinically assessed whereas PD-L1 has several drawbacks for prediction of persistent benefit. Our aim is to evaluate the basal state and dynamic changes of cell-free DNA (cfDNA) concentration to predict and monitor response in NSCLC patients starting ICI. A total of 248 cfDNA concentration measurements were performed from 87 NSCLC patients. The quantification was done before the start of the treatment, at the second ICI cycle, after 6 and 12 months in treatment, and at progression if it was within the first 12 months. Quality and quantity of the cfDNA was assessed using Qubit High Sensitivity and Bioanalyzer 2100. We first explored the association with response of the basal cell-free DNA concentration using Mann-Whitney-Wilcoxon test. The longitudinal analysis between different time points was tested with Wilcoxon signed-rank tests. Response was ascertained using RECIST parameters at 3, 6, and 12 months. We evaluated the utility of the cfDNA concentration as a prognostic factor using Mantel-Cox test. The response association results indicate that early and long-term response is associated with lower levels of basal cfDNA (p<0.002, 3 months; p<0.001, 6 months; p<0.05, 12 months). The longitudinal analysis could also detect a decrease in cfDNA from the second cycle to the month 6 of treatment in responders (p<0.05), and an increase in non-responders (p<0.05). To identify a prognostic concentration threshold, statistical stratification of cfDNA levels based on the selected maximum rank method of cfDNA levels was used to group them into low and high concentration. Patients with high basal cfDNA concentrations showed both worse FPS (log-rank 3.4x10-03, Medians: Low 12.57 [8.36 - 18.46] High 5.50 [3.03 - 10.06]) and OS (log-rank 3.2x10-05, Medians: Low 21.26 [15.33 - 33.96] High 5.45 [3.10 - 15.66]). With these results, we provide proof-of-principle that specifically detecting tumor cfDNA by PCR or NGS methods would not be necessary to predict the long-term clinical benefit to ICI in NSCLC patients. Moreover, concentration cut-offs can be defined to categorize the patients in potential responders and non-responders before the start of the treatment. This would constitute a cost-effective and easily implementable prognostic tool that could be particularly useful for avoiding loss of treatment windows of opportunities. Citation Format: Isabel Barragan, Elisabeth Perez-Ruiz, Juan Luis Onieva, Maria Garrido-Ramos, Beatriz Martinez-Galvez, Jaime Dubbelman, Emilio Alba, Juan Zafra, Manuel Cobo, Javier Oliver, Antonio Rueda-Dominguez. Cell-free DNA concentration as a prognostic biomarker in patients with non-small cell lung cancer under immunotherapy treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1044.