Dagmar Krenbek

Background: Non-small cell lung cancer (NSCLC), particularly in advanced stages, has poor prognosis. The main objective of the study is to evaluate real-world treatment outcomes in advanced NSCLC patients harboring an EGFR mutation and being treated with TKIs. Methods: The EGFR mutation status was ascertained by next-generation sequencing. The observational cohort study used prospectively maintained registry data. Patient data were collected at two high-volume institutions in Austria between November 2020 and February 2025. The prevalence of EGFR mutations was 11% (145 out of 1267 patients). Results: Among 53 patients (stage IIIB or higher) with an EGFR mutation, median overall survival (OS) and median progression-free survival (PFS) were 17.7 months (95% CI: 10.4–24.9) and 14.2 months (95% CI: 7.4–20.9), respectively. A total of 36 patients harbored common EGFR mutations (exon 19 deletion or L858R point mutation) and exhibited a significantly better OS than those with an uncommon EGFR genotype (p < 0.005). Patients with exon 19 deletion (n = 25) showed the longest mOS, followed by those with L858R mutation (32.5 vs. 17 months). In multivariable analysis, the EGFR common mutation subtype (HR = 3.71 95%CI: 1.23–11.2) was associated with better OS. Patients with common EGFR genotypes, especially exon 19 deletion obtained longer OS and PFS compared with those with uncommon mutations in exon 18–21. Conclusions: The results underscore the prognostic role of distinct EGFR genotypes and the urgency of determining the mutation status in non-small cell lung cancer patients to ensure the best treatment decision. The study also highlights the challenges regarding to EGFR uncommon mutations and the resulting need for further research to investigate alternative treatment options.

Background: Non-small cell lung cancer (NSCLC), particularly in advanced stages, has poor prognosis. The main objective of the study is to evaluate real-world treatment outcomes in advanced NSCLC patients harboring an EGFR mutation and being treated with TKIs. Methods: The EGFR mutation status was ascertained by next-generation sequencing. The observational cohort study used prospectively maintained registry data. Patient data were collected at two high-volume institutions in Austria between November 2020 and February 2025. The prevalence EGFR mutations was 11% (145 out of 1,267 patients). Results: Among 53 patients (stage IIIB or higher) with an EGFR mutation, median overall survival (OS) and median progression-free survival (PFS) were 17.7 months (95% CI: 10.4-24.9) and 14.2 months (95% CI: 7.4-20.9), respectively. A total of 36 patients harbored common EGFR mutations (exon 19 deletion or L858R point mutation) and exhibited a significantly better OS than those with an uncommon EGFR genotype (p < 0.005). Patients with exon 19 deletion (n = 25) showed the longest mOS, followed by those with L858R mutation (32.5 vs. 17 months). In multivariable analysis, EGFR common mutation subtype (HR = 3.71 95%CI: 1.23 – 11.2) was associated with better OS. Patients with common EGFR genotypes, especially exon 19 deletion obtained longer OS and PFS compared with those with uncommon mutations in exon 18-21. Conclusion: The results underscore the prognostic role of distinct EGFR genotypes and the urgency to determine the mutation status in non-small cell lung cancer patients to ensure the best treatment decision. The study also highlights the challenges regarding to EGFR uncommon mu-tations and the resulting need for further research to investigate alternative treatment options.

Rationale: The success of tyrosine kinase inhibtors in the neoadjuvant and adjuvant setting provides a rationale for exploring selpercatinib in the perioperative setting to improve patient outcomes in early-stage lung cancer. However, selpercatinib is currently only approved as first-line treatment for advanced rearrangement during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), limiting its use and potential benefit for earlier stage patients. Hence, this case report explores selpercatinib’s potential use in early-stage disease to address this treatment gap and improve patient outcomes. Patient concerns: We report the case of a 75-year-old female with no history of smoking who was referred to our institute with a chest computed tomography scan revealing a mass in the right lower lung lobe. Diagnoses: The patient was diagnosed with RET fusion-positive lung adenocarcinoma based on findings from radiologic findings from computed tomography (CT) and positron emission tomography-CT scans, histopathological examination, and molecular profiling through next-generation sequencing. Interventions: The patient was treated with 4 cycles of carboplatin and pemetrexed. A follow-up CT scan revealed the progression of the mediastinal lymph node, leading to the decision to initiate selpercatinib treatment. Due to a major size reduction of the primary lesion and the absence of tumor cells in the lymph nodes, the patient underwent curative lobectomy and lymphadenectomy. Outcomes: Preoperative selpercatinib induced tumor regression, enabling surgical resection. Histopathological examination of the resected tumor revealed a major pathological response to preoperative selpercatinib treatment. Lessons: This case highlights the potential of selpercatinib in the perioperative setting, suggesting that it induces tumor regression and enabling of curative surgery in early-stage RET fusion-positive NSCLC. Our findings support the further investigation of selpercatinib in early stages and provide a rationale for future treatment strategies of early-stage RET fusion-positive NSCLC patients.

Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) often shows incomplete responses and progression despite tyrosine kinase inhibitor (TKI) therapy. Preliminary data suggest that combining brigatinib, an ALK-selective TKI, with surgery or radiotherapy may improve outcomes. We retrospectively analyzed patients with advanced ALK-positive NSCLC who received brigatinib as first-line treatment combined with local therapy to assess safety and efficacy of this approach in a real-world setting. Among 9 patients, 6 (67%) had stage III and 3 (33%) had stage IV adenocarcinoma. Five patients received surgery, 3 received radiotherapy, and 1 received both. Brigatinib-related adverse events (AEs) occurred in 78% of patients, primarily mild (grade ≤ 2). Severe AEs (grade ≥ 3) were seen in 22% of patients and included dyspnea and hypertension. Brigatinib was discontinued in 22% of patients due to toxicity. Local therapy-related AEs were mostly grade 1. The objective response rate was 89%, with 2 complete and 6 partial responses. At data cutoff, brigatinib was ongoing in 55% of patients, with a median treatment duration of 14 months and a 2-year progression-free survival rate of 100%. Combining brigatinib with local therapy appears safe and potentially more effective for advanced ALK-positive NSCLC. Further studies are warranted.

Background: Pleural mesothelioma (PM) is a rare type of cancer with poor prognosis. Prognostic and predictive biomarkers could improve treatment strategies in these patients. Programmed death ligand 1 (PD-L1), integrin-linked kinase (ILK) and breast cancer gene 1-associated protein (BAP-1) have been proposed to predict outcomes in PM, but existing data are limited and controversial. Design and Methods: This single-center, retrospective study analyzed data on expression patterns and the prognostic role of PD-L1, ILK and BAP-1 in consecutive patients diagnosed with PM. Results: Of all patients (n = 52) included, more than half showed a positive PD-L1 expression (52% TPS ≥ 1%, 65% CPS ≥ 1), 69% showed a BAP-1 loss and 80% an ILK ≥ 50%. Positive PD-L1 expression was more frequent in the non-epithelioid subtype (p = 0.045). ILK intensity (p = 0.032) and positive PD-L1 (p = 0.034) were associated with more advanced tumor stages. The median overall survival (OS) was 16.9 (95% CI 13.1–25.2) months. Multimodality therapy (MMT) including surgery and early stage were independent prognostic factors for longer OS (MMT: HR 0.347, 95% CI 0.13–0.90, p = 0.029; advanced stage: HR 4.989; 95% CI 1.64–15.13, p = 0.005). Patients with an expression of PD-L1 TPS ≥ 1% or BAP-1 positivity showed numerically worse survival with a median OS of 15.3 (11.5; 24.4) vs. 20.0 (11.2; 34.9) and 11.3 (5.6; 31.0) vs. 20.0 (15.2; 28.1) months, respectively. Furthermore, PD-L1 was associated with worse survival in patients receiving MMT (PD-L1 TPS ≥ 1%: 15.8 (12.1–25.4) vs. 31.3 (17.4–95.4) p = 0.053). ILK expression ≥50% did not influence survival. The combinations of CPS ≥ 1% with BAP-1 positivity or ILK expression ≥50% were associated with worse survival (p = 0.045, p = 0.019). Conclusions: In this real-world analysis, expressions of PD-L1 and BAP-1 were associated with worse survival in patients with PM. ILK showed no prognostic value. Further studies with larger cohorts are needed to identify prognostic and predictive biomarkers facilitating optimized individual treatment decision in this rare type of cancer.

Background: Adenosquamous carcinoma of the lung (ASC) is a rare non-small-cell lung cancer (NSCLC) subtype combining components of squamous cell carcinoma (SCC) and adenocarcinoma (AC). Data on ASC, particularly in Caucasian populations, are limited. Methods: We reviewed clinicopathological and radiological characteristics of ASC patients diagnosed between 1996 and 2023. Patients were classified into AC-predominant ASC (AC-ASC) and SCC-predominant ASC (SCC-ASC) groups for analysis. Results: Among the 66 patients included, the median overall survival was 41.7 (95% CI, 25.0–54.4), while it was 48.1 (95% CI, 27.3–88.0) in patients treated with curative surgery (n = 44) and 15.3 (95% CI, 6.5–42.6) months for palliative patients (n = 22). The five-year survival rates were 39% and 26%, respectively. Recurrence occurred in 43% of stage I patients and was associated with worse survival (HR 3.303 (95% CI, 1.10–9.89) p = 0.033). AC-ASCs (n = 17) more frequently showed air-bronchogram (p = 0.002) and pleural effusions (p = 0.054) compared to SCC-ASCs (n = 26). SCC-ASCs exhibited more vascular invasion (p = 0.006) and PD-L1 values between 1 and 49% (TPS) (p = 0.032). The subtype did not influence survival. EGFR and ALK alterations were found in 17% and 2% of patients, respectively. Conclusions: Despite early-stage disease, ASC patients had a high recurrence rate, associated with worse survival. Clinicopathologic differences between AC-ASCs and SCC-ASCs did not influence survival.

About 15% of patients with non-small cell lung cancer (NSCLC) harbor the Kirsten rat sarcoma homolog G12C mutation (KRAS^G12C). Selective KRAS^G12C inhibitors offer new treatment opportunities, but little is known about the prevalence, characteristics, and outcomes of standard-of-care treatment (SOC) in this population. We retrospectively assessed the clinicopathological features of patients with KRAS^G12C-mutated advanced NSCLC and responses to SOC at two high-volume centers in Austria. Out of 2495 NSCLC patients tested, we identified 174 patients with advanced-stage disease carrying a KRAS^G12C mutation. Most patients were ≥65 years old (55%), heavy smokers (55%), and presented with comorbidities. The most frequent co-alteration was TP53 (18%). PD-L1 expression was high (TPS ≥ 50%) in 31%, very high (TPS ≥ 90%) in 11%, and negative in 31% of patients. A total of 138 patients (79%) received oncologic systemic treatment. The most common first-line therapy (1 L) was anti-PD-1/PD-L1 plus platinum-based chemotherapy. Median overall survival measured from 1 L treatment was 15.3 months (95% CI, 8.6–21.9), 9.4 (95% CI, 5.3–13.5) from 2 L treatment, and 8.4 (95% CI, 1.7–15.1) from 3 L treatment. The time-to-next-treatment was 8.4 (95% CI, 5.2–11.6) from 1 L and 6.1 (95% CI, 2.7–9.7) months from 2 L to 3 L. These poor outcomes underscore the need for the implementation of new treatment options and for specific molecular testing.

Malignant pleural mesothelioma (MPM) is a rare pleural cancer associated with asbestos exposure. According to current evidence, the combination of chemotherapy, surgery and radiotherapy improves patients’ survival. However, the optimal sequence and weighting of the respective treatment modalities is unclear. In anticipation of the upcoming results of the MARS-2 trial, we sought to determine the relative impact of the respective treatment modalities on complications and overall survival in our own consecutive institutional series of 112 patients. Fifty-seven patients (51%) underwent multimodality therapy with curative intent, while 55 patients (49%) were treated with palliative intent. The median overall survival (OS) of the entire cohort was 16.9 months (95% CI: 13.4–20.4) after diagnosis; 5-year survival was 29% for patients who underwent lung-preserving surgery. In univariate analysis, surgical treatment (p < 0.001), multimodality therapy (p < 0.001), epithelioid subtype (p < 0.001), early tumor stage (p = 0.02) and the absence of arterial hypertension (p = 0.034) were found to be prognostic factors for OS. In multivariate analysis, epithelioid subtype was associated with a survival benefit, whereas the occurrence of complications was associated with worse OS. Multimodality therapy including surgery significantly prolonged the OS of MPM patients compared with multimodal therapy without surgery.

In clinical practice, patients with anaplastic lymphoma kinase (ALK)-rearrangement–positive non–small-cell lung cancer commonly receive sequential treatment with ALK tyrosine kinase inhibitors. The third-generation agent lorlatinib has been shown to inhibit a wide range of ALK resistance mutations and thus offers potential benefit in later lines, although real-world data are lacking. This multicenter study retrospectively investigated later-line, real-world use of lorlatinib in patients with advanced ALK- or ROS1-positive lung cancer. Fifty-one patients registered in a compassionate use program in Austria, who received second- or later-line lorlatinib between January 2016 and May 2020, were included in this retrospective real-world data analysis. Median follow-up was 25.3 months. Median time of lorlatinib treatment was 4.4 months for ALK-positive and 12.2 months for ROS-positive patients. ALK-positive patients showed a response rate of 43.2%, while 85.7% percent of the ROS1-positive patients were considered responders. Median overall survival from lorlatinib initiation was 10.2 and 20.0 months for the ALK- and ROS1-positive groups, respectively. In the ALK-positive group, lorlatinib proved efficacy after both brigatinib and alectinib. Lorlatinib treatment was well tolerated. Later-line lorlatinib treatment can induce sustained responses in patients with advanced ALK- and ROS1-positive lung cancer.