Mutation-tailored treatment selection in non-small cell lung cancer patients in daily clinical practice

Objectives: The number of targeted drugs in non-small cell lung cancer (NSCLC) is ever-expanding and requires testing of an increasing number of predictive biomarkers. We present a comprehensive real-world evaluation of molecular testing and treatment selection in stage IV NSCLC patients in the Netherlands from 2017 to 2019. Materials and methods: Molecular pathology reports of NSCLC patients were collected from the Dutch Pathology Registry in time intervals between Oct-2017 and April-2019 (N = 5,038 patients) to study diagnostic yield. Linkage between the Dutch Pathology Registry and the Netherlands Cancer Registry enabled studying molecular testing rates for stage IV NSCLC initially diagnosed in 2017-Q4 (N = 1,193) and application of targeted therapy in stage IV NSCLC patients with potentially druggable alterations reported between Oct-2017 and June-2018 (N = 401). Results: Predictive molecular testing was performed in 85.0% of adenocarcinomas, 60.4% of NSCLC-not otherwise specified (NOS) and 17.4% of squamous cell carcinomas. Testing rates were highest for EGFR and ALK (adenocarcinoma: 82.7% and 80.7%, respectively). Incidence of molecular driver alterations (i.e. EGFR, KRAS, ALK, ROS1, BRAF, MET, ERBB2, FGFR1) was 61.1% for adenocarcinomas, 42.3% for NSCLC-NOS, and 24.7% for squamous cell carcinomas. Therapeutically relevant alterations were detected at a higher frequency by NGS- versus non-NGS-approaches (adenocarcinoma: 62.4% versus 56.5%, respectively (P = 0.004)) due to a lower failure rate, more comprehensive testing and higher sensitivity. Uptake of treatment with a registered targeted therapy in eligible patients varied per actionable target, i.e. EGFR: 85.8%, ALK: 74.7%, ROS1: 33.7%, BRAF: 51.5%. Treatment with agents in clinical studies/compassionate use was lower, i.e. MET: 22.8%, HER2: 18.9%, RET: 6.7%. Conclusion: Real-world data show NGS-based approaches to be superior to non-NGS. Uptake of molecular testing and the corresponding targeted treatments was less than expected based on guidelines and even more so for trials, off-label use and compassionate use, indicating less than optimal access to rational treatment options

Age-related treatment patterns for stage I NSCLC in three European countries

Introduction: Surgery is the preferred treatment for patients with early-stage non-small cell lung cancer (NSCLC) while stereotactic body radiation therapy (SBRT) may be applied in patients with major comorbidity or high age. We evaluated the association between age and treatment utilization for early-stage NSCLC in patients diagnosed in 2015–2016 in three European countries. Patients and methods: Information was retrieved from population-based registries in England, Norway and the Netherlands. Treatment patterns and two-year overall survival rates for 105,124 patients with clinical stage I were analysed by age-group. Results: Surgical resection rates were higher in Norway (55%) and England (53%) than in the Netherlands (47%), and decreased with increasing age. SBRT use was highest in the Netherlands (41%), followed by Norway (29%) and England (12%). In the Netherlands, SBRT was the prevailing treatment in patients aged 70 years or older. In octogenarians, the proportion not receiving curative intent treatment was 53% in England, versus 35% in Norway and 22% in the Netherlands. Two-year survival rates were better for surgery than for SBRT and slightly better in Norway. Conclusion: In patients aged 70 years or older, the proportion not receiving any curative treatment remains substantial, and differs significantly between countries. Measures to address these disparities are needed

Real-world treatment patterns and survival of patients with ROS1 rearranged stage IV non-squamous NSCLC in the Netherlands

Introduction: Rearrangement of c-ros oncogene 1 (ROS1) is a rare gene alteration in patients with stage IV non-squamous non-small cell lung cancer (NSCLC). Molecular testing for ROS1 is recommended to enable primary treatment with tyrosine kinase inhibitors (TKI). Aim of this study was to describe real-world treatment patterns and survival for patients with ROS1 in the Netherlands. Methods: All non-squamous NSCLC stage IV patients, diagnosed 2015–2019, were identified from the population-based Netherlands Cancer Registry (N = 19,871). For patients with ROS1 rearrangements (ROS1+ ) who received first line TKI, additional information about progression and second-line treatment was retrieved by active follow-up. Overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier estimators. Results: A total of 67 patients (0.43%) were diagnosed with a ROS1+ NSCLC. Systemic treatment was administered in 75% which was most often TKI (n = 34) followed by chemotherapy (n = 14). Two-year OS for patients receiving upfront TKI versus other systemic treatment was 53% (95% CI 35–68) and 50% (95% CI 25–71), respectively. For patients receiving TKI, median OS was 24.3 months. Survival was inferior in case of brain metastasis (BM) at diagnosis (5.2 months). One in five patients receiving TKI as a first line treatment had BM at diagnosis, of the remaining 22 another 9 developed BM during follow up. PFS was also inferior for patients with BM at diagnosis with a median PFS of 4.3 months versus 9.0 without BM. Conclusion: In this real-world population of ROS1+ NSCLC patients, only half received primary treatment with TKI. Overall survival and PFS during TKI were disappointing, mainly related to brain metastasis. TKI treatment with agents that have intra-cranial activity may be beneficial in this patient population and our results confirm the importance of performing an MRI of the brain as part of the standard diagnostic work up in patients with ROS1+ NSCLC

Prognostic Implication of KRAS G12C Mutation in a Real-World KRAS-Mutated Stage IV NSCLC Cohort Treated With Immunotherapy in The Netherlands

Introduction: With the approval of G12C inhibitors as the second line of treatment for KRAS G12C-mutated NSCLC, and the expanding research regarding targeting KRAS, it is key to understand the prognostic implication of KRAS G12C in the current first line of treatment. We compared overall survival (OS) of patients with stage IV KRAS G12C-mutated NSCLC to those with a KRAS non-G12C mutation in a first-line setting of (chemo)immunotherapy. Methods: This nationwide population-based study used real-world data from The Netherlands Cancer Registry. We selected patients with stage IV KRAS-mutated lung adenocarcinoma diagnosed in 2019 to 2020 who received first-line (chemo-)immunotherapy. Primary outcome was OS. Results: From 28,120 registered patients with lung cancer, 1185 were selected with a KRAS mutation, of which 494 had a KRAS G12C mutation. Median OS was 15.5 months (95% confidence interval [CI]: 13.6–18.4) for KRAS G12C versus 14.0 months (95% CI:11.2–15.7) for KRAS non-G12C (p = 0.67). In multivariable analysis, KRAS subtype was not associated with OS (hazard ratio = 0.95, 95% CI: 0.82–1.10). For the subgroup with programmed death-ligand 1 at 0% to 49% who received chemoimmunotherapy, median OS was 13.3 months (95% CI: 10.5–15.2) for G12C and 9.8 months (95% CI: 8.6–11.3) for non-G12C (p = 0.48). For the subgroup with programmed death-ligand 1 more than or equal to 50% who received monoimmunotherapy, the median OS was 22.0 months (95% CI: 18.4–27.3) for G12C and 18.9 months (95% CI: 14.9–25.2) for non-G12C (p = 0.36). Conclusions: There was no influence of KRAS subtype (G12C versus non-G12C) on OS in patients with KRAS-mutated stage IV NSCLC treated with first-line (chemo)immunotherapy

Weinig lokaal recidieven na mammachirurgie: goede kwaliteit van de Nederlandse borstkankerzorg

Doel: Het beschrijven van het percentage lokaal recidief binnen 5 jaar na operatie van mammacarcinoom als prestatie-indicator van de Nederlandse ziekenhuizen. Opzet: Beschrijvend, cohortonderzoek. Methode: Alle vrouwen bij wie in 2003 een eerste invasief mammacarcinoom was gediagnosticeerd en die in opzet curatief waren geopereerd (met of zonder radiotherapie), werden geselecteerd uit de Nederlandse kankerregistratie (NKR). Registratiemedewerkers van de NKR verzamelden gegevens over het optreden van recidieven binnen 5 jaar bij deze patiënten aan de hand van een gestandaardiseerd protocol. Recidiefpercentages werden bepaald per ziekenhuis met de kaplan-meier-methode en weergegeven in ‘forest’-plots en ‘funnel’-plots. Resultaten: In 2003 werden 9898 patiënten in 99 Nederlandse ziekenhuizen gediagnosticeerd en curatief behandeld voor een eerste mammacarcinoom. 266 patiënten kregen een lokaal recidief binnen 5 jaar. Het 5-jaarsrecidiefpercentage was 3,03 (95%-BI: 2,69-3,41). Na een borstsparende operatie was het 5-jaarsrecidiefpercentage 2,63 (95%-BI: 2,21-3,12); na borstamputatie was dit 3,50% (95%-BI: 2,97-4,13). Er was een grote variatie in recidiefpercentage tussen ziekenhuizen (0-17%). De aantallen behandelde patiënten waren in de meeste ziekenhuizen echter te laag om betrouwbare schattingen te geven. Conclusie: Het percentage lokale recidieven na chirurgische behandeling voor mammacarcinoom lag in Nederland onder de norm van 5% binnen 5 jaar. Het is niet mogelijk om op basis van deze indicator een uitspraak te doen over verschillen in de kwaliteit van zorg tussen ziekenhuizen door de lage gemiddelde recidiefkans en het relatief lage aantal patiënten met een lokaal recidief per ziekenhuis

Landelijke variatie in moleculaire diagnostiek bij gemetastaseerde longkanker

OBJECTIVE: The objective of this study is to determine at a national level whether patients with metastatic non-small cell lung cancer (NSCLC) are adequately tested for EGFR mutations and ALK rearrangement, because targeted therapy is tailored to the results of molecular diagnostics. DESIGN: Retrospective cohort study. METHOD: Data from all patients with metastatic non-squamous NSCLC diagnosed in 2013 or 2015 were identified from the Netherlands Cancer Registry, and coupled with data from the Netherlands national pathology registry (PALGA). Using information extracted from PALGA we determined what percentage of the tumours were tested for EGFR or KRAS mutations and ALK rearrangement, identified the variables that were associated with the performance of molecular diagnostics and investigated the differences between 48 laboratories. RESULTS: A total of 6,619 patients were included (2013: n = 3,195; 2015: n = 3,424). In 2013, EGFR or KRAS testing was performed on 73.1% of the tumours (variation between laboratories 30.6-91.7%); in 2015 this was 78.9% (variation 40.0-91.0%). In 2013 49.5% of the tumours without EGFR or KRAS mutations underwent ALK testing (variation between laboratories 6.3-100%) and in 2015 ALK testing was performed on 77.4% (32.5-100%). In 2015, 6 and 7 laboratories tested significantly fewer EGFR and ALK tests, respectively, than the national average. CONCLUSION: In 2013, molecular testing for EGFR and KRAS mutations and, in particular, for ALK rearrangement was suboptimal. EGFR and ALK testing was performed significantly more often in 2015. Despite this increase, there is room for improvement in a number of laboratories and hospitals, considering that some patients were possibly wrongly not eligible for targeted therapy

Landelijke variatie in moleculaire diagnostiek bij gemetastaseerde longkanker

OBJECTIVE: The objective of this study is to determine at a national level whether patients with metastatic non-small cell lung cancer (NSCLC) are adequately tested for EGFR mutations and ALK rearrangement, because targeted therapy is tailored to the results of molecular diagnostics. DESIGN: Retrospective cohort study. METHOD: Data from all patients with metastatic non-squamous NSCLC diagnosed in 2013 or 2015 were identified from the Netherlands Cancer Registry, and coupled with data from the Netherlands national pathology registry (PALGA). Using information extracted from PALGA we determined what percentage of the tumours were tested for EGFR or KRAS mutations and ALK rearrangement, identified the variables that were associated with the performance of molecular diagnostics and investigated the differences between 48 laboratories. RESULTS: A total of 6,619 patients were included (2013: n = 3,195; 2015: n = 3,424). In 2013, EGFR or KRAS testing was performed on 73.1% of the tumours (variation between laboratories 30.6-91.7%); in 2015 this was 78.9% (variation 40.0-91.0%). In 2013 49.5% of the tumours without EGFR or KRAS mutations underwent ALK testing (variation between laboratories 6.3-100%) and in 2015 ALK testing was performed on 77.4% (32.5-100%). In 2015, 6 and 7 laboratories tested significantly fewer EGFR and ALK tests, respectively, than the national average. CONCLUSION: In 2013, molecular testing for EGFR and KRAS mutations and, in particular, for ALK rearrangement was suboptimal. EGFR and ALK testing was performed significantly more often in 2015. Despite this increase, there is room for improvement in a number of laboratories and hospitals, considering that some patients were possibly wrongly not eligible for targeted therapy