BACKGROUND:Molecular testing in NSCLC is essential for treatment selection, yet routine implementation remains inconsistent across institutions. Clinical evidence suggests that variability in testing may not be explained by patient or tumor characteristics but might be driven by institutional factors, potentially leading to adverse outcomes. We examined the extent to which variability in AGA testing is attributable to the treating institution. METHODS:We analyzed 6437 adults with stage IIIB/C or IV NSCLC enrolled in the prospective German real-world registry CRISP (2016-2022). Logistic mixed-effects models with AGA testing as the primary outcome were used to determine institutional variability across 171 institutions. Models included patient, tumor, and treatment-related fixed effects with institutions as random effects. Intraclass correlations (ICC) quantified institutional variability unexplained by other covariates. Institution type was tested in secondary analysis, and overall survival in exploratory analysis. FINDINGS:AGA testing was performed in 77.9 % of patients (n = 5016). Predicted probabilities for testing use ranged from 30.5 % to 93.2 % across institutions. Institutions significantly influenced testing use (p < 0.001), accounting for 21.4 % of the total variance. Variability significantly differed by institution type and was more pronounced in subgroups, e.g., squamous histology (ICC 29.5 %) and KRAS testing (ICC 34.4 %). Absence of AGA testing was independently associated with inferior survival (HRadj 1.11, 95 % CI 1.01-1.23, p = 0.029). INTERPRETATION:Substantial institutional variability exists in AGA testing for NSCLC, which was unexplained by patient or tumor characteristics. This objective evaluation of institution-based variability in testing may emphasize the importance of practice patterns on patient care and may therefore provide an avenue for change.

Background and Purpose:The multicenter precision oncology registry INFINITY investigated biomarker-driven therapy and outcomes in patients with advanced malignancies not eligible for standard therapy in routine clinical care in Germany. Although programmed cell death (ligand) 1 (PD-(L)1) antibodies have changed the treatment landscape of several malignancies and PD-(L)1 expression level is predictive and therefore often used for treatment selection, existing predictive biomarkers are insufficient to identify patients who will benefit from PD-(L)1 inhibitor-based therapy. This project aimed to identify genomic tumor profiles predicting benefit from anti-PD-(L)1 therapy. Patients and Methods:Patients from the INFINITY registry treated with anti-PD-(L)1 monotherapy were stratified into two cohorts using a case-control design: clinical benefit (treatment duration >182 days) and no clinical benefit (treatment duration 22-63 days). Tumor tissue samples from the virtual biobank were requested from local pathologies and sent to the central pathology for next‑generation sequencing (NGS) using the OncomineTM Comprehensive Assay Plus panel (Thermo Fisher, NGS pan-cancer assay). Results:Of the 26 patients with clinical benefit and 24 patients without clinical benefit, NGS-based genetic tumor profiles were available for 11 and 8 patients, respectively. Only patients with clinical benefit from anti-PD-(L)1 therapy showed genetic alterations in KEAP1, PIK3CA and MRE11. Conclusion:Our analysis revealed a set of three genes (KEAP1, PIK3CA and MRE11) exclusively mutated in patients with clinical benefit from PD-(L)1-inhibitor therapy, possibly representing promising biomarker candidates. Given the small sample size and the heterogeneous tumor types included, these findings are exploratory, and validation in larger, preferably tumor-type-specific cohorts is required before any predictive value can be attributed to these genomic alterations.

Brain metastases (BM) from non-small cell lung cancer (NSCLC) are a relevant cause of morbidity and mortality. This study aims to identify a population at high risk for BM in order to inform personalized follow-up strategies in the future. We have therefore developed and validated a point-based risk classifier for the risk of BM1 in patients with metastatic non-oncogene-addicted NSCLC without BM at disease onset. A total of 3139 patients were included from the German CRISP lung cancer registry and randomly assigned to a derivation and validation set (2:1). In the derivation set, a Fine and Gray model was developed considering BM and death competing risks. A point-based risk classifier was derived and evaluated in the validation set. Of the baseline variables included in the risk model, ≥4 versus 0 extrathoracic metastatic sites (hazard ratio [HR], 2.69; 95% CI, 1.45-5.00), N3 vs. N0 disease (2.29; 1.41-3.72), and age < 65 vs. ≥75 years (2.03; 1.39-2.98) were the strongest predictors of BM development. Using the risk classifier, high-risk patients in the derivation set had a cumulative incidence of BM of 23.7% (95% CI, 16.7-30.1) at 18 months compared to 10.3% (8.9-11.7) in low-risk patients (HR, 2.44; 95% CI, 1.87-3.19). In the validation set, the cumulative incidence of BM at 18 months was 14.7% (11.5-17.8) and 8.9% (6.2-11.6) in the high-risk and low-risk groups, respectively (HR, 1.54; 95% CI, 1.08-2.20). In conclusion, our point-based risk classifier is able to identify NSCLC patients at high risk for BM development that may benefit from intensified brain surveillance.

There are no clear guidelines regarding the optimal treatment sequence for advanced pancreatic cancer, as head-to-head phase III randomised trials are missing. We assess real-world effectiveness of three common sequential treatment strategies by emulating a hypothetical randomised trial. This analysis included 1551 patients with advanced pancreatic cancer from the prospective, clinical cohort study Tumour Registry Pancreatic Cancer receiving FOLFIRINOX (n = 613) or gemcitabine/nab-paclitaxel (GEMNAB; n = 938) as palliative first-line treatment. We used marginal structural modelling to compare overall survival (OS) and time to deterioration (TTD) of health-related quality of life (HRQoL) between three common first- to second-line treatment sequences, adjusting for time-varying potential confounding. The sequences were: FOLFIRINOX -> GEMNAB, GEMNAB -> FOLFOX/OFF and GEMNAB -> nanoliposomal irinotecan (NALIRI) + 5-fluorouracil. Outcome was also calculated stratified by patients' prognostic risk according to the Pancreatic Cancer Score. Median OS and TTD of HRQoL independent of risk were 10.7 [8.9, 11.9] and 6.4 [4.8, 7.7] months for FOLFIRINOX -> GEMNAB, 8.4 [7.4, 9.7] and 5.8 [4.6, 7.1] months for GEMNAB -> FOLFOX/OFF and 8.9 [7.8, 10.4] and 4.6 [4.1, 6.1] months for GEMNAB -> NALIRI+5-fluorouracil. Compared to FOLFIRINOX -> GEMNAB, OS and TTD were worse for poor-risk patients with GEMNAB -> FOLFOX/OFF (OS: HR 2.09 [1.47, 2.98]; TTD: HR 1.97 [1.19, 3.27]) and those with GEMNAB -> NALIRI+5-fluorouracil (OS: HR 1.35, [0.76, 2.39]; TTD: HR 2.62 [1.56, 4.42]). Brackets denote 95%-confidence intervals. The estimated real-world effectiveness of the three treatment sequences evaluated were largely comparable. Poor-risk patients might benefit from intensified treatment with FOLFIRINOX -> GEMNAB in terms of clinical and patient-reported outcomes. Future randomised trials on sequential treatments in advanced pancreatic cancer are warranted.

There is no prospective, randomised head‐to‐head trial comparing first‐line FOLFIRINOX and gemcitabine/nab‐paclitaxel in advanced pancreatic cancer. We assess real‐world effectiveness and quality of life (QoL) of both regimens using a new prognostic score. This analysis includes 1540 patients with advanced pancreatic cancer from the prospective, clinical cohort study Tumour Registry Pancreatic Cancer separated into learning (n = 1027) and validation sample (n = 513). The Pancreatic Cancer Score (PCS) was developed using multivariate Cox regression. We compared overall survival (OS) and time to deterioration (TTD) for longitudinal QoL between first‐line FOLFIRINOX (n = 407) and gemcitabine/nab‐paclitaxel (n = 655) according to patients' prognostic risk, after inverse probability of treatment weighting (IPTW) by propensity score analysis. The PCS includes nine independent prognostic factors for survival: female sex, BMI ≥24/unknown, ECOG performance status ≥1, Charlson comorbidity index ≥1, tumour staging IV/unknown at primary diagnosis, liver metastases, bilirubin >1.5× upper limit of normal (ULN), leukocytes >ULN and neutrophil‐to‐lymphocyte ratio ≥4. Median OS of the validation sample was 11.4 (95% confidence interval [CI]: 10.4‐14.4), 8.5 (95% CI: 6.8‐9.6) and 5.9 months (95% CI: 4.0‐7.4) for favourable‐ (0‐3 risk factors), intermediate‐ (4‐5 factors) and poor‐risk group (6‐9 factors), respectively. After IPTW, only poor‐risk patients had significantly longer median OS and TTD of overall QoL with FOLFIRINOX (OS: 6.9 months, 95% CI: 3.9‐13.3; TTD: 10.6 months, 95% CI: 2.0‐14.1) vs gemcitabine/nab‐paclitaxel (OS: 4.0 months, 95% CI: 2.8‐4.8; TTD: 4.1 months, 95% CI: 2.4‐4.5). Our novel PCS may facilitate treatment decisions in clinical routine of advanced pancreatic cancer, since only poor‐risk, but not favourable‐risk patients, seem to benefit from intensified treatment with FOLFIRINOX.

The authors regret that there was an error in affiliation (b). The correct affiliation is now listed above. The authors would like to apologise for any inconvenience caused. Biomarker testing in non-small cell lung cancer in routine care: Analysis of the first 3,717 patients in the German prospective, observational, nation-wide CRISP Registry (AIO-TRK-0315)Lung CancerVol. 152PreviewLung cancer belongs to the three most frequently diagnosed cancers in Germany and accounts for 24 % and 16 % of the cancer-related deaths in men and women, respectively [1]. With 80 % of all lung cancer diagnoses, non-small cell lung cancer (NSCLC) is the most common histologic subtype, the majority of these being adenocarcinomas (46 % in women, 36 % in men) or squamous-cell carcinomas (15 % in women, 29 % in men) [2]. The course of disease in NSCLC is highly heterogeneous, with prognosis as well as therapeutic options depending on the molecular biology of the tumor. Full-Text PDF Open Access

OBJECTIVES:An increasing number of treatment-determining biomarkers has been identified in non-small cell lung cancer (NSCLC) and molecular testing is recommended to enable optimal individualized treatment. However, data on implementation of these recommendations in the "real-world" setting are scarce. This study presents comprehensive details on the frequency, methodology and results of biomarker testing of advanced NSCLC in Germany.PATIENTS AND METHODS:This analysis included 3,717 patients with advanced NSCLC (2,921 non-squamous; 796 squamous), recruited into the CRISP registry at start of systemic therapy by 150 German sites between December 2015 and June 2019. Evaluated were the molecular biomarkers EGFR, ALK, ROS1, BRAF, KRAS, MET, TP53, RET, HER2, as well as expression of PD-L1.RESULTS:In total, 90.5 % of the patients were tested for biomarkers. Testing rates were 92.2 % (non-squamous), 70.7 % (squamous) and increased from 83.2 % in 2015/16 to 94.2% in 2019. Overall testing rates for EGFR, ALK, ROS1, and BRAF were 72.5 %, 74.5 %, 66.1 %, and 53.0 %, respectively (non-squamous). Testing rates for PD-L1 expression were 64.5 % (non-squamous), and 58.5 % (squamous). The most common testing methods were immunohistochemistry (68.5 % non-squamous, 58.3 % squamous), and next-generation sequencing (38.7 % non-squamous, 14.4 % squamous). Reasons for not testing were insufficient tumor material or lack of guideline recommendations (squamous). No alteration was found in 37.8 % (non-squamous), and 57.9 % (squamous), respectively. Most common alterations in non-squamous tumors (all patients/all patients tested for the respective biomarker): KRAS (17.3 %/39.2 %), TP53 (14.1 %/51.4 %), and EGFR (11.0 %/15.1 %); in squamous tumors: TP53 (7.0 %/69.1 %), MET (1.5 %/11.1 %), and EGFR (1.1 %/4.4 %). Median PFS (non-squamous) was 8.7 months (95 % CI 7.4-10.4) with druggable EGFR mutation, and 8.0 months (95 % CI 3.9-9.2) with druggable ALK alterations.CONCLUSION:Testing rates in Germany are high nationwide and acceptable in international comparison, but still leave out a significant portion of patients, who could potentially benefit. Thus, specific measures are needed to increase implementation.

Abstract Background Gemcitabine/erlotinib treatment offers limited benefit in unselected patients with pancreatic ductal adenocarcinoma (PDAC). Development of skin rash has been associated with favorable outcomes in patients treated with gemcitabine/erlotinib. This study aimed to extend knowledge on the effectiveness of gemcitabine/erlotinib in metastatic PDAC in the context of clinical practice and with focus on skin rash. Methods This multicenter, non-interventional study enrolled 376 patients with metastatic PDAC receiving gemcitabine/erlotinib. The primary endpoint was overall survival (OS) in patients with skin rash versus no skin rash. Secondary endpoints included progression-free survival (PFS), treatment satisfaction and safety. All data were analyzed using descriptive statistics. Survival time and time to disease progression were estimated using the Kaplan-Meier method. Effectiveness endpoints were analyzed for subgroups by skin rash grade (no rash, rash grade 1, rash grade ≥ 2), duration of erlotinib treatment (≤8 weeks, > 8 weeks), Eastern Cooperative Oncology Group (ECOG) performance status at baseline (0–1, 2) and age (≤65 years, > 65 years). Results Within the full analysis set (FAS; N = 270), 48 patients (17.8%) developed grade 1 rash, 51 patients (18.9%) grade ≥ 2 rash, while 171 patients (63.3%) did not develop a rash. Median OS of all patients was 9.11 months with an OS of 9.93 months in rash-positive and 8.68 months in rash-negative patients. Median PFS was 5.06 months for rash-positive and 4.11 months for rash-negative patients. PFS was longer in patients with rash grade ≥ 2 and in older patients (> 65 years). Examination using a multivariate Cox proportional model revealed that an age > 65 years was associated with longer OS (hazard ratio 0.640; p = 0.0327) and PFS (hazard ratio 0.642; p = 0.0026). Out of the 338 patients in the SAF, 310 patients (91.7%) experienced at least one AE, and 176 patients (52.1%) experienced skin-related side effects, all of which were CTC grade 1 to 3. Conclusions Comparing rash-positive with rash-negative patients showed no significant difference in survival. While patients with rash grade ≥ 2 and older patients (independent of skin reactions) showed longer PFS, this did not translate into prolonged OS. The study did not reveal new safety signals. Trial registration ClinicalTrials.gov Identifier: NCT01782690, retrospectively registered on 4 February 2013.