The European Lung Cancer Congress is a joint project of major multidisciplinary societies representing thoracic oncology specialists working together to advance science, disseminate education and improve the practice of lung cancer specialists worldwide. At this year’s event, attendees were able to learn about the current state of lung cancer treatment and update their knowledge on prevention, screening, detection and more.
Until now, it was not known how effective and safe consolidative stereotactic body radiotherapy (SBRT) is in patients with EGFR-mutated NSCLC who have developed oligo-residual disease after first-line treatment with third-generation EGFR-TKIs. To this end, a single-arm, multicenter phase II study was conducted in patients with EGFR-mutated NSCLC who received SBRT for oligo-residual disease after first-line treatment with third-generation EGFR-TKIs [1]. The primary endpoint was progression-free survival (PFS), secondary endpoints were overall survival (OS) and toxicity as assessed by CTCAE. In addition, a propensity score comparison was performed with a contemporary cohort of patients who received EGFR-TKIs only. Sixty-four patients were included in the study. With a median follow-up time of 18.2 months, the median PFS for all patients was 29.9 months, with the lower limit exceeding the predefined threshold. The median OS time was not reached and the 2-year OS rate was 88.8%. In patients with cranial oligo-residual disease who received cranial SBRT, the median PFS was 27.0 months. Adverse events (AEs) were manageable, with pneumonitis and esophagitis being the most common toxicities. A propensity score matching analysis showed a significant prolongation of PFS in the SBRT+TKI group compared to the TKI group alone. Accordingly, consolidative SBRT showed promising efficacy and an acceptable toxicity profile in patients with oligo-residual disease after first-line treatment with third-generation EGFR-TKIs. This treatment approach could delay acquired resistance and improve survival prospects.
EGFR mutations and their influence on resistance
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are standard first-line therapies for advanced non-small cell lung cancer (NSCLC) with EGFR mutations. However, despite optimal therapies, not all patients respond positively to them. The simultaneous presence of mutations can contribute to resistance. The aim of one study was to investigate the impact of concurrent mutations on the prognosis of patients receiving first-line EGFR-TKI treatment for EGFR-mutated NSCLC [2]. This was a retrospective cohort study at a single center that enrolled patients aged 19 years or older with EGFR-mutated advanced NSCLC using next generation sequencing (NGS). The participants were treated with EGFR-TKIs as first-line therapy. The primary endpoint was the time to discontinuation of treatment (time-to-treatment-discontinuation, TTD). 254 patients were included in the study. The most common tumor type was adenocarcinoma (98.42%). Among the co-mutations, the most frequent mutation was TP53 (61.8%). The median overall TTD of this cohort was 17 months. There were differences in median TTD between EGFR mutation without TP53 and EGFR mutation with TP53 (25 vs. 16 months).
NSCLC subgroup in focus
Unusual EGFR mutations represent a rare subgroup of non-small cell lung cancer. Data on the efficacy of different generations of tyrosine kinase inhibitors (TKIs) in these rare mutations are scattered and limited to mostly retrospective small cohorts, as these patients were usually excluded from clinical trials. In a systematic review, the efficacy of TKIs in patients with rare EGFR mutations, defined as mutations other than ex20ins or T790M, was examined in more detail [3]. Response rates (RRs) for different TKI generations were determined for single unusual mutations, for compound mutations and for the classes of classical-like and P-loop alpha-helix compressing mutations (PACC). 1836 patients from 38 studies were included in the final analysis. Most of the available data came from patients treated with first- or second-generation TKIs. G719X, S768I, E709X, L747X and E709-T710delinsD showed RRs between 47.8% and 72.3% for second-generation TKIs. The L861Q mutation showed 75% RRs for third-generation TKIs. Compound mutations with G719X, E709X or S768I consistently showed RRs above 50% for TKIs of the 2. and 3. for classical-like mutations, the RRs for first-, second- and third-generation TKIs were 35.4%, 51.9% and 67.9%, while for PACC mutations the RRs were 37.2%, 59.6% and 46.3%, respectively.
This systematic review supports the use of the second-generation TKI afatinib for G719X, S768I, E709X and L747X mutations and compound unusual mutations. For other uncommon mutations such as L861Q, a 3rd generation TKI such as osimertinib appears to be a reasonable option given its activity and toxicity profile.
The risk of myelosuppression with combination therapies
The addition of carboplatin doublet chemotherapy (CBCT) to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) improves progression-free survival in EGFR-mutated NSCLC. However, both drug classes are associated with myelosuppression, which manifests itself as neutropenia, anemia and/or thrombocytopenia. The rates of myelosuppression (any grade) for EGFR-TKIs alone and in combination with CBCT were investigated [4]. Sixteen studies, including 14 randomized controlled trials, were included in the literature review. Twelve studies investigated first-line treatments and four studies investigated second-line treatments or later treatments. The included studies investigated 1st and 3rd generation TKIs. Across all studies, the weighted average incidence of myelosuppressive events of any grade for first-generation TKIs plus CBCT compared to CBCT alone was 63.4% versus 44.7% for anemia, 61.8% versus 38.9% for neutropenia, and 48.2% versus 35.1% for thrombocytopenia. The incidence for myelosuppressive events of any grade for 3rd generation TKIs plus CBCT compared to CBCT alone was 71.7% vs. 44.7% for anemia, 88.7% vs. 38.9% for neutropenia, and 73.6% vs. 35.1% for thrombocytopenia. The combination of EGFR-TKI with CBCT therefore leads to higher rates of cytopenic events than with CBCT or TKI monotherapy alone. The risk was higher with 3rd generation TKIs, especially for neutropenia and thrombocytopenia.
STAS and its influence on the prognosis
The aim of one study was to analyze the prognostic impact of tumor spread through the air spaces (STAS) on thoracoscopic segmentectomy compared to lobectomy in clinical stage I non-small cell lung cancer (NSCLC) [5]. Patients undergoing thoracoscopic segmentectomy or lobectomy for clinical stage I NSCLC at a major thoracic hospital between September 2020 and September 2023 were included. The recurrence-free survival (RFS) and overall survival (OS) between the two procedures were evaluated using a Kaplan-Meier analysis with log-rank test. The Cox regression model was used to analyze the independent factors for survival. 785 patients were included, including 151 (19.2%) patients with STAS and 634 (80.8%) patients without STAS. The STAS-positive group showed significantly higher vascular and lymphatic invasion. The median follow-up time was 25.1 months. In the group without STAS, there were no differences in survival between segmentectomy and lobectomy (3-year RFS: 77.4% vs. 82.6%; 3-year OS: 87.5% vs. 95.3%). In contrast, patients with STAS were found to have poorer survival after segmentectomy compared to lobectomy (3-year RFS: 69.8% vs. 82.7%; 3-year OS: 58.4% vs. 89.0%). In multivariable analysis, segmentectomy was an independent prognostic factor for RFS in patients with STAS, as was pleural invasion. In addition, segmentectomy and older age were independent prognostic factors for OS in patients with STAS.
A path to gender-equitable medicine
The progression-free survival (PFS) of male lung cancer patients after anti-PD-1/PD-L1 treatment is significantly higher than that of female patients. One study aims to investigate the role and mechanism of estrogen in anti-PD-1/PD-L1 immunotherapy of lung adenocarcinoma [6]. To this end, an investigation of the expression levels and correlation of ERβ/SRSF2/PD-L1 and their relationship to the prognosis of lung adenocarcinoma patients was performed based on the tissue chips of 159 lung adenocarcinoma patients with complete follow-up data and 515 lung adenocarcinoma patients in the TCGA database. A subcutaneous lung cancer model was established in C57/BL mice with LLC cells treated with anti-PD-1 therapy (pembrolizumab), where the growth curves of different tumor groups were recorded and the final tumor volume and mass were measured. IHC, WB, qPCR and flow cytometry were used to further verify the mechanism of ERβ based on SRSF2 in gender differences in immunotherapy of lung adenocarcinoma with anti-PD-1.
Tissue chip immunohistochemistry staining and the TCGA database show that there is a significant correlation between ERβ, SRSF2 and PD-L1, and a high ERβ or PD-L1 level is associated with a poor prognosis. E2 and ERβ mediate the upregulation of PD-L1 expression by SRSF2 and enhance the proliferation, migration and invasion of H1299 cells, while knocking down SRSF2 or fulvestrant has the opposite effect. E2 can promote the growth of lung adenocarcinomas in mice. After treatment with pembrolizumab, male mice have a longer PFS, but female mice are more likely to benefit from treatment. Accordingly, it was shown that E2 and ERβ, which regulate SRSF2 and upregulate PD-L1 expression, could be a mechanism for gender-specific differences in the efficacy of anti-PD-1/PD-L1 immunotherapy.
Do not ignore bone metabolism
Recent discoveries show the endocrine role of the skeleton in regulating glucose homeostasis throughout the body. A study has now investigated individual bone glucose metabolism and its integration into a network in lung cancer patients before and after treatment [7]. Connections between the glucose metabolism of the bones and the progression of lung cancer as well as the treatment results were investigated. The data were obtained from the ACRIN 6668 study on patients with non-small cell lung cancer from the Cancer Imaging Archive . 34/242 patients in stage IIIB were selected. Dynamic whole-body PET/CT scans with 18F-FDG before and after treatment were analyzed to measure bone glucose metabolism. In patients treated after the treatment, the SUV peak in the lungs was significantly lower compared to patients before the treatment. SUV and HU differed significantly between the individual bones within each group. When comparing the groups, significant differences were found in the sternum (lower SUV) after treatment. PET and CT networks before treatment showed three different clusters. The post-treatment networks had three less pronounced clusters. There were significant differences in life expectancy between the clusters in the PET pretreatment network, with life expectancy being higher in clusters two and three than in cluster one. This effect was not observed in the clusters after PET treatment. This study showed that the SUV peak in the lung decreased significantly after chemotherapy, suggesting that the treatment reduced glucose uptake at the site of the primary tumor. The network analysis indicated a shift in the patients’ bone metabolism profiles, with treatment having a homogenizing effect on the PET networks. The differences in life expectancy between the clusters before treatment suggest that certain initial bone metabolic profiles can be correlated with survival time.
Congress: European Lung Cancer Congress (ELCC) 2024
Literature:
- Zhou Y, et al: Consolidative stereotactic radiotherapy in metastatic EGFR-mutant non-small cell lung cancer receiving first-line third-generation EGFR tyrosine kinase inhibitors: A prospective, multicenter, phase II trial. Poster 14P. European Lung Cancer Congress (ELCC), 20-23.03.2024, Prague.
- Kim J, et al: Evaluation of co-mutation in EGFR-mutant non-small cell lung cancer by next generation sequencing (NGS): Retrospective cohort study in South Korea. Poster 22P. European Lung Cancer Congress (ELCC), 20-23.03.2024, Prague.
- Borgeaud M, et al: Uncommon EGFR kinase domain mutations and responses to EGFR inhibitors: A systematic review. Poster 30P. European Lung Cancer Congress (ELCC), 20-23.03.2024, Prague.
- Girard N, et al: Myelosuppression risk from epidermal growth factor receptor-tyrosine kinase inhibitors, carboplatin chemotherapy, or both in EGFR mutated non-small cell lung cancer (NSCLC). Poster 31P. European Lung Cancer Congress (ELCC), 20-23.03.2024, Prague.
- Petersen RH, et al: Tumor spread through air spaces is a determiner for treatment of clinical stage I non-small cell lung cancer: Thoracoscopic segmentectomy vs lobectomy. Poster 117P. European Lung Cancer Congress (ELCC), 20-23.03.2024, Prague.
- Tang H, et al: The role and mechanism of estrogen receptor beta based on SRSF2 in gender differences of lung adenocarcinoma immunotherapy with anti-PD-1. Poster 119P. European Lung Cancer Congress (ELCC), 20-23.03.2024, Prague.
- Ronghe R, et al: Whole-body PET imaging to study bone metabolism in pre- and post-treatment lung cancer patients. European Lung Cancer Congress (ELCC), 20-23.03.2024, Prague.
InFo ONKOLOGIE & HÄMATOLOGIE 2024; 12(3): 24-25 (published on 3.7.24, ahead of print)
