Factors affecting outcome in resected EGFR-mutated lung cancer.

INTRODUCTION: Long-term data on disease trajectory of EGFR-mutated early-stage non-small cell lung cancer (NSCLC) is still limited. This is relevant in the context of the recently approved introduction of adjuvant EGFR-targeting therapy, specifically osimertinib in resected stage II-III EGFR-mutated NSCLC. METHODS: Long-term data on patients with resected adenocarcinoma of the lung and known EGFR-status were analysed with focus on site of relapse and detailed cause of death. Patients resected in the period 2006 to 2018 were included. RESULTS: Of 503 patients (286 (57%) females, median age 67.3 years), 62 (12%) harboured an EGFR-mutation, 286 (57%) were in stage I. After a median follow-up of 8.0 years, 241 (48%) patients relapsed. Recurrence occurred in 30% and 53% of EGFR-positive stage IA and IB patients, respectively. Median overall survival was longer in EGFR-mutated versus non-mutated patients (128 versus 88 months). The recurrence rate, time to recurrence and rate of brain metastases was not different between EGFR-mutated and non-mutated groups. Median time from recurrence to death was longer in EGFR-mutated patients (31 months) compared with non-mutated patients (15 months). More patients without EGFR-mutation succumbed to non-cancer related death (18%) compared to patients with EGFR-mutations (8%). CONCLUSIONS: The recurrence pattern in EGFR-mutated and non-mutated NSCLC-patients is similar and the rate is high in early stages. Time from recurrence to death and overall survival is longer in the EGFR-mutated group, due to lower risk of non-lung cancer deaths, and efficient treatment upon relapse.

Epidemiology and outcome of peritoneal and pleural mesothelioma subtypes in Norway. A 20 year nation-wide study.

BACKGROUND: Mesothelioma of the pleural or peritoneal cavities is one of the deadliest cancer types. The incidence of pleural subtypes has decreased over time due to decrease in asbestos exposure, and the current treatment landscape is changing due to introduction of novel therapies. In this study we have analysed contemporary epidemiological data of mesothelioma on a national level before the advent of immunotherapy. MATERIAL AND METHODS: Complete national data on 1509 pleural and peritoneal malignant mesothelioma from the Cancer Registry of Norway from 2000 to 2019 are presented. Age standardised incidence and median survival were calculated. RESULTS: The age-standardised incidence of pleural mesothelioma among males has decreased from 1.7 per 100 000 in 2000-2004 to 1.1 in 2015-2019, whereas the incidence for females has been stable, lower than 0.3 per 100 000 throughout the period. Incidence of peritoneal mesotheliomas remained low, below 0.08 per 100 000. The female to male ratio among pleural mesotheliomas was 1:7 with no differences among morphological subtypes, whereas this ratio was 1:1.2 in peritoneal mesotheliomas. Median age at diagnosis for pleural mesothelioma was 73 years and 76 years for females and males respectively in the last 5-year period, and 67 years for peritoneal mesotheliomas of both sexes. Median survival among pleural mesotheliomas has been stable, with significantly worse prognosis among sarcomatoid subtype (5.4 months) compared to epithelioid subtype (15.8 months). Peritoneal mesothelioma of the epithelioid subtype, representing 38% of cases, had a median survival of 43.3 months, contrasting the non-epithelioid subtype of 5.1 months. DISCUSSION: Mesothelioma is still a significant disease with a dismal prognosis. Improvement in treatment is warranted.

Intracranial effect of osimertinib in relapsed EGFR-mutated T790M-positive and -negative non-small cell lung cancer patients: results from a phase II study.

INTRODUCTION: Osimertinib is effective for relapsed T790M-positive patients with brain metastases. The high brain permeability suggests that also such patients without T790M could benefit. Therefore, we evaluated the effect of osimertinib on brain metastases in both T790M-positive and -negative patients. METHODS: The TREM-study was an investigator-initiated phase II, single-arm, multi-institutional clinical trial conducted in Northern Europe. Patients with resistance to prior EGFR-TKIs received osimertinib until radiological progression, unacceptable toxicity or death. Baseline brain scans were performed in patients with known or suspected brain metastases and repeated every 8-12 weeks. We assessed intracranial efficacy in patients with baseline brain metastases. RESULTS: Brain metastases were detected in 48/199 patients at baseline. Of these, 63% were T790M-positive, 27% -negative and 10% had unknown T790M-status. The majority (73%) of the patients had received prior whole brain radiotherapy and additionally 8% had received stereotactic radiosurgery (SRS). Brain scans were available for review for 42 patients. The intracranial progression free survival was 39.7 versus 3.5 months for T790M + and T790M- patients, respectively (p < 0.001). The overall intracranial disease control rate (iDCR) was 81%, and for T790M + and T790M- patients the DCR was 89% versus 55%, respectively. The estimated risk of CNS progression was 0.8% at 6 months and 6% at 12 months for T790M-positive patients, and 14% and 17% at 6 and 12 months, respectively, for the T790M-negative. CONCLUSION: This subgroup analysis confirms CNS efficacy of osimertinib in patients with the T790M resistance mutation, while other treatment options should be considered for EGFR-TKI relapsed T790M-negative patients with brain metastases.

Lung cancer treated abroad with receptor tyrosine kinase inhibitor. / Lungekreft behandlet med reseptortyrosin=kinasehemmer i utlandet.

BACKGROUND: Activating RET fusions are oncogenic drivers in multiple cancers and are identified in 1-2 % of non-small cell lung cancers (NSCLC). Selpercatinib and pralsetinib are tyrosine kinase inhibitors selectively targeting RET and with clinical activity in RET-positive NSCLC. CASE PRESENTATION: A male never-smoker in his forties was diagnosed with advanced lung adenocarcinoma. With negative tests for EGFR mutations, ROS1 and ALK rearrangements, he was treated with a combination of chemotherapy and an immune checkpoint inhibitor. Upon progression a rebiopsy analysed by next generation sequencing (NGS) revealed a KIF5B-RET fusion. He received treatment with pralsetinib through a compassionate use programme, with relief of symptoms within weeks, and radiological partial response after two months of treatment. He has not experienced side effects after six months of treatment. INTERPRETATION: Precision medicine is dependent on diagnostic methods such as NGS to identify patients who might benefit from targeted therapies. Selective inhibitors of molecular oncogenic drivers are usually effective and well tolerated.

Real-World Data on EGFR and ALK Testing and TKI Usage in Norway-A Nation-Wide Population Study.

Clinical studies have shown the efficacy of EGFR- and ALK-directed therapies in non-small cell lung cancer (NSCLC). Real-world data on, e.g., testing patterns, uptake, and duration of treatment are scarce. Reflex EGFR and ALK testing of non-squamous NSCLCs were implemented in Norwegian guidelines in 2010 and 2013, respectively. We present a complete national registry data on incidence, pathology procedures, and drug prescription in the period of 2013 to 2020. Test rates for both EGFR and ALK increased over time and were 85% and 89%, respectively, at the end of the study period, independent of age up to 85 years. The positivity rate for EGFR was higher among females and young patients, whereas no sex difference was observed for ALK. EGFR-treated patients were older than ALK-treated patients (71 vs. 63 years at start, p < 0.001). Male ALK-treated patients were significantly younger than females at the start of treatment (58 vs. 65 years, p = 0.019). The time from the first dispensation to the last dispensation of TKI (as a surrogate for progression-free survival) was shorter for EGFR- than for ALK-TKI, and survival for both EGFR- and ALK-positive patients was substantially longer than for non-mutated patients. We found a high adherence to molecular testing guidelines, good concordance of mutation positivity and treatment, and the real-world replication of findings in clinical trials, indicating that the relevant patients are provided substantially life-prolonging therapy.

"Evaluation of ROS1 expression and rearrangements in a large cohort of early-stage lung cancer".

BACKGROUND: ROS1 fusion is an infrequent, but attractive target for therapy in patients with metastatic non- small-cell lung cancer. In studies on mainly late-stage disease, the prevalence of ROS1 fusions is about 1-3%. In early-stage lung cancer ROS1 might also provide a fruitful target for neoadjuvant or adjuvant therapy. In the present study, we investigated the prevalence of ROS1 fusion in a Norwegian cohort of early-stage lung cancer. We also explored whether positive ROS1 immunohistochemical (IHC) stain was associated with certain mutations, clinical characteristics and outcomes. METHODS: The study was performed using biobank material from 921 lung cancer patients including 542 patients with adenocarcinoma surgically resected during 2006-2018. Initially, we screened the samples with two different IHC clones (D4D6 and SP384) targeting ROS1. All samples that showed more than weak or focal staining, as well as a subgroup of negative samples, were analyzed with ROS1 fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) with a comprehensive NGS DNA and RNA panel. Positive ROS1-fusion was defined as those samples positive in at least two of the three methods (IHC, FISH, NGS). RESULTS: Fifty cases were IHC positive. Of these, three samples were both NGS and FISH-positive and considered positive for ROS1 fusion. Two more samples were FISH positive only, and whilst IHC and NGS were negative. These were also negative with Reverse Transcription quantitative real time Polymerase Chain Reaction (RT-qPCR). The prevalence of ROS1 fusion in adenocarcinomas was 0.6%. All cases with ROS1 fusion had TP53 mutations. IHC-positivity was associated with adenocarcinoma. Among SP384-IHC positive cases we also found an association with never smoking status. There was no association between positive IHC and overall survival, time to relapse, age, stage, sex or pack-year of smoking. CONCLUSIONS: ROS1 seems to be less frequent in early-stage disease than in advanced stages. IHC is a sensitive, but less specific method and the results need to be confirmed with another method like FISH or NGS.

Elevated expression of miR-494-3p is associated with resistance to osimertinib in EGFR T790M-positive non-small cell lung cancer.

Background: Non-small cell lung cancer (NSCLC) harboring activating mutations in the gene encoding epidermal growth factor receptor (EGFR) is amenable for targeted therapy with tyrosine kinase inhibitors (TKIs). Eventually, resistance to TKI-therapy occurs resulting in disease progression. A substantial fraction of resistance mechanisms is unknown and may involve alterations in the RNA or protein landscape. MicroRNAs (miRNAs) have been frequently suggested to play roles in various forms of cancer including NSCLC. However, a role of miRNAs in acquired resistance to EGFR TKIs remains elusive. In this work, we aimed to investigate the potential involvement of miRNAs in acquired resistance to the third-generation EGFR TKI osimertinib in NSCLC. Methods: We combined miRNA expression profiling with miRNA-inhibitory screening to identify miRNAs involved in conferring resistance to osimertinib. Finally, we validated our top miRNA candidate by profiling longitudinal plasma exosomal RNA from patients receiving osimertinib as second-line therapy in a clinical trial. Results: Various miRNAs displayed differential expression in parental versus osimertinib-refractory NSCLC cells. miRNA-inhibitory screening revealed miR-494-3p to partially confer resistance to osimertinib in vitro. Expression of miR-494-3p was significantly elevated in plasma sampled at disease progression compared to plasma sampled at treatment baseline in a cohort of 21 EGFR T790M-mutation positive NSCLC patients receiving osimertinib. Conclusions: Our results highlight the need for further therapeutic exploration of miR-494-3p in in vivo models of EGFR-mutant NSCLC.

Osimertinib in non-small cell lung cancer with uncommon EGFR-mutations: a post-hoc subgroup analysis with pooled data from two phase II clinical trials.

Background: Osimertinib is standard of care for EGFR-mutated non-small cell lung cancer (NSCLC) patients. The efficacy of the drug in patients with mutations other than the common deletion in exon 19 and L858R in exon 21 is largely unknown. Methods: We identified patients with uncommon EGFR-mutations from two prospective clinical phase II, single-arm studies for previously treated patients and untreated patients, respectively, and pooled data for this analysis. All patients received treatment with osimertinib 80 mg daily until radiological progression or death. The primary endpoint of both trials was objective response rate (ORR), with progression-free survival (PFS), overall survival (OS) and intracranial efficacy as key secondary endpoints. Circulating tumour DNA (ctDNA) was analysed before and two weeks after treatment initiation in the first line cohort. Results: Of 299 enrolled patients in the two trials, 21 patients with uncommon mutations were identified; 12 patients had a single mutation (G719X or L861Q), one patient had L861Q and an exon 20 insertion, and 8 patients had compound mutations with G719X and either L861Q or S768I. Three of the 10 pretreated patients had the T790M resistance mutation. ORR was 47.6% and disease control rate (DCR) 85.7%. The median duration of response (DoR) was 7.9 months. Among 11 patients treated with osimertinib in first line, ORR was 63.6% vs. 30.0% of 10 previously treated patients. The median PFS was 5.5 months in both groups. Patients with G719X-compound mutations had a higher response rate (62.5% vs. 38.5%), a longer median PFS (13.7 vs. 3.5 months) and median OS (29.3 vs. 7.5 months) than patients with other mutations. Most first line treated patients (81.8%) displayed a reduction in ctDNA after two weeks of treatment. Conclusions: Osimertinib demonstrates activity in patients with uncommon EGFR-mutations, and especially for G719X-compound mutations.

Plasma RNA profiling unveils transcriptional signatures associated with resistance to osimertinib in EGFR T790M positive non-small cell lung cancer patients.

Background: Targeted therapy with tyrosine kinases inhibitors (TKIs) against epidermal growth factor receptor (EGFR) is part of routine clinical practice for EGFR mutant advanced non-small cell lung cancer (NSCLC) patients. These patients eventually develop resistance, frequently accompanied by a gatekeeper mutation, T790M. Osimertinib is a third-generation EGFR TKI displaying potency to the T790M resistance mutation. Here we aimed to analyze if exosomal RNAs, isolated from longitudinally sampled plasma of osimertinib-treated EGFR T790M NSCLC patients, could provide biomarkers of acquired resistance to osimertinib. Methods: Plasma was collected at baseline and progression of disease from 20 patients treated with osimertinib in the multicenter phase II study TKI in Relapsed EGFR-mutated non-small cell lung cancer patients (TREM). Plasma was centrifuged at 16,000 g followed by exosomal RNA extraction using Qiagen exoRNeasy kit. RNA was subjected to transcriptomics analysis with Clariom D. Results: Transcriptome profiling revealed differential expression [log2(fold-change) >0.25, false discovery rate (FDR) P<0.15, and P(interaction) >0.05] of 128 transcripts. We applied network enrichment analysis (NEA) at the pathway level in a large collection of functional gene sets. This overall enrichment analysis revealed alterations in pathways related to EGFR and PI3K as well as to syndecan and glypican pathways (NEA FDR <3×10-10). When applied to the 40 individual, sample-specific gene sets, the NEA detected 16 immune-related gene sets (FDR <0.25, P(interaction) >0.05 and NEA z-score exceeding 3 in at least one sample). Conclusions: Our study demonstrates a potential usability of plasma-derived exosomal RNAs to characterize molecular phenotypes of emerging osimertinib resistance. Furthermore, it highlights the involvement of multiple RNA species in shaping the transcriptome landscape of osimertinib-refractory NSCLC patients.

Osimertinib in T790M-positive and -negative patients with EGFR-mutated advanced non-small cell lung cancer (the TREM-study).

OBJECTIVES: In non-small cell lung cancer patients with acquired resistance to first- or second-generation EGFR-TKIs, osimertinib is approved in the presence of the T790 M resistance mutation. We assessed the efficacy of osimertinib in both T790M-positive and T790M-negative patients. MATERIALS AND METHODS: The TREM-study is an investigator-initiated, multi-centre, single-arm, phase 2 clinical trial conducted in five Northern European countries. Patients with progression on at least one previous EGFR-TKI were assigned to treatment with 80 mg of osimertinib daily until radiological progression or death. Patients were included regardless of the presence of T790 M. The primary endpoint was objective response rate (ORR). RESULTS: Of 199 included patients, 120 (60 %) were T790M-positive, 52 (26 %) were T790M-negative and 27 (14 %) had unknown T790M-status. 24 % had brain metastases and 15 % had an ECOG performance status of 2. Overall ORR was 48 % (95 % CI, 41 %-55 %), 60 % (51 %-69 %) for T790M-positive patients and 28 % (15 %-41 %) for T790M-negative patients, p < 0.001. ORR for patients with co-occurring del19 vs L858R was 61 % vs 32 %, p = 0.001. Duration of response was similar between the T790M-positive and -negative groups (11.8 vs 10.7 months, p = 0.229). Overall median progression-free survival (PFS) was 8.9 months (95 % CI, 7.4-10.5), and 10.8 vs 5.1 months for T790M-positive vs -negative patients (HR 0.62, p = 0.007). Median overall survival (OS) was 17.9 months (95 % CI, 14.4-21.3). For T790M-positive vs -negative median OS was 22.5 vs 13.4 months, (HR 0.55, p = 0.002). CONCLUSIONS: This study confirms the efficacy of osimertinib for T790M-positive patients. There was also clinically significant activity of osimertinib in a proportion of T790M-negative patients. CLINICAL TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov (NCT02504346).