ROS1 rearrangements in lung adenocarcinomas are defined by diffuse strong immunohistochemical expression of ROS1.

A small subset of lung adenocarcinomas harbour ROS1 gene arrangements and are amenable to tyrosine kinase inhibitor therapy. Current practice in Australia involves screening for ROS1 rearrangements in adenocarcinomas using ROS1 immunohistochemistry (IHC) followed by confirmatory molecular testing such as fluorescence in situ hybridisation (FISH), if other known genetic driver alterations are absent. The best threshold to determine ROS1 IHC positivity is not well defined, however, and this study aims to determine the optimal threshold for ROS1 IHC screening to identify ROS1-rearranged lung adenocarcinomas. A total of 177 lung adenocarcinomas tested for a ROS1 rearrangement by FISH at our institution between 2017 and 2020 due to presence of ROS1 IHC staining were included in the study. ROS1 IHC staining was assessed by scoring the staining intensity (0, 1, 2, or 3+) and multiplying by the percentage of positive cells to generate an H-score. IHC H-scores were compared with FISH. Of 177 cases, 32 (18%) were ROS1 FISH-positive and 145 (82%) were negative. FISH-positive cases had a median H-score of 300 (range 200-300; mean 290.3) and negative cases had a median H-score of 40 (range 0-300; mean 63). All FISH-positive cases showed strong and diffuse IHC positivity. Using a threshold H-score of 200, the sensitivity of identifying ROS1 rearrangements was 100% and the specificity was 95% amongst cases referred with ROS1 IHC positivity. Adenocarcinomas with a FISH-confirmed ROS1 rearrangement demonstrate diffuse, strong (2-3+) IHC staining. Cases with weak, patchy ROS1 IHC staining are not associated with ROS1 rearrangements and in these cases FISH testing is of little to no utility.

Real-world programmed death-ligand 1 prevalence rates in non-small cell lung cancer: correlation with clinicopathological features and tumour mutation status.

AIMS: The detection of programmed death-ligand 1 (PD-L1) protein expression on tumour cells by immunohistochemistry (IHC) is a predictor of response to immune checkpoint inhibitors. New immunotherapeutic options are changing the treatment paradigm for patients with advanced non-small cell lung cancer (NSCLC). The aim of this retrospective study was to investigate real-world prevalence of PD-L1 expression in NSCLC and any correlations with clinicopathological features. METHODS: We reviewed 425 NSCLC cases at a Sydney metropolitan hospital that had PD-L1 IHC (SP263 clone) expression estimated as part of routine diagnostic assessment during a 30-month period. RESULTS: Overall, 32.2% of cases were negative for PD-L1 expression (<1%), 40.3% demonstrated low expression (1%-49%) and 27.5% exhibited high protein expression (≥50%). High PD-L1 expression rates were more likely in non-lung resection cases and in KRAS mutant NSCLC as opposed to KRAS wildtype, while lower expression rates were more commonly found in EGFR mutant NSCLC compared with EGFR wildtype tumours. CONCLUSIONS: Ongoing observation and comparison of PD-L1 expression rates is an important practice for ensuring its validity as a predictive biomarker. The results from our study align with and contribute to the growing field of published real-world PD-L1 prevalence rates in NSCLC.

Retrospective Evaluation of the Use of Pembrolizumab in Malignant Mesothelioma in a Real-World Australian Population.

INTRODUCTION: We investigated the efficacy and toxicity of pembrolizumab in patients with mesothelioma from a real-world Australian population. We aimed to determine clinical factors and predictive biomarkers that could help select patients who are likely to benefit from pembrolizumab. METHOD: Patients with mesothelioma who were treated with pembrolizumab as part of the Insurance and Care New South Wales compensation scheme were included. Clinical information was collected retrospectively. Tumor biomarkers such as programmed death-ligand 1 (PD-L1), BAP1, and CD3-positive (CD3+) tumor-infiltrating lymphocytes (TILs) were examined using archival formalin-fixed paraffin-embedded tumor samples. RESULTS: A total of 98 patients were included with a median age of 70 years (range, 46-91 y); 92% were men; 76% had epithelioid subtype; 21% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0. Pembrolizumab was used as second-line or subsequent-line treatment in 94 patients and as first-line treatment in four patients. The overall response rate was 18%, and the disease control rate was 56%. The median progression-free survival (PFS) was 4.8 months (95% confidence interval: 3.6-6.2), and the median overall survival (OS) was 9.5 months (95% confidence interval: 6.6-13.7). Immune-related adverse events occurred in 27% of patients, of which nine (9%) were of grade 3 or higher. In the multivariable analysis, factors independently associated with longer PFS included baseline ECOG status of 0 (median PFS: 12 mo versus 4 mo, p < 0.01) and PD-L1 tumor proportion score of greater than or equal to 1% (median PFS: 6 mo versus 4 mo, p < 0.01). Baseline platelet count of less than or equal to 400 × 109/liter was independently associated with longer PFS and OS (median PFS: 6 mo versus 2 mo, p = 0.05; median OS: 10 mo versus 4 mo, p = 0.01), whereas lack of pretreatment dexamethasone was independently associated with OS but not PFS (median OS: 10 mo versus 3 mo, p = 0.01). The odds of response were higher for patients with baseline ECOG status of 0 (p = 0.02) and with greater than or equal to 5% CD3+ TILs in the tumor (p < 0.01). PD-L1 expression, BAP1 loss, and CD3+ TILs in the stroma were not significantly associated with the overall response rate. CONCLUSIONS: Immunotherapy is a reasonable treatment option for patients with mesothelioma. Our results are comparable to other clinical trials investigating pembrolizumab in mesothelioma in terms of response. Good performance status assessment remains the most robust predictor for patient outcomes. CD3+ TILs in the tumor may help select patients that are likely to respond to pembrolizumab, whereas factors such as PD-L1 expression, baseline platelet count, and lack of pretreatment dexamethasone may help predict survival outcomes from pembrolizumab treatment.