Checkpoint Inhibitor Monotherapy in Potentially Trial-Eligible or Trial-Ineligible Patients With Metastatic NSCLC in the German Prospective CRISP Registry Real-World Cohort (AIO-TRK-0315).

Introduction: Patients with metastatic NSCLC (mNSCLC) treated with immune checkpoint inhibitors in clinical practice may often not meet the strict inclusion criteria of clinical trials. Our aim was to assess the trial eligibility of patients with mNSCLC treated with pembrolizumab monotherapy in real-world and to compare the outcome of "trial-ineligible" and "potentially trial-eligible" patients. Methods: Data from the prospective, clinical research platform CRISP were used to compare patient characteristics, treatment, and outcome of patients with programmed cell death-ligand 1 tumor proportion score greater than or equal to 50% tumors treated with pembrolizumab monotherapy who are deemed either "potentially trial-eligible" or "trial-ineligible" according to inclusion and exclusion criteria of the registrational studies (KEYNOTE-024 and -042). Results: Of 746 patients included, 343 patients (46.0%) were classified as "trial-ineligible" and had significantly worse outcomes compared with "potentially trial-eligible" patients (n = 403, 54.0%): median progression-free survival: 6.2 (95% confidence interval [CI]: 5.2-8.4) versus 10.3 (95% CI: 8.4-13.8) months, hazard ratio (trial-ineligible versus potentially trial-eligible) of 1.43 (95% CI: 1.19-1.72), p less than 0.001; median overall survival: 15.9 (95% CI: 11.4-20.3) versus 25.3 (95% CI: 19.8-30.4) months, hazard ratio of 1.36 (95% CI: 1.10-1.67), p equals 0.004. Conclusions: Our data reveal that a considerable proportion of patients with mNSCLC are not eligible to participate in a clinical trial and were found to have worse outcomes than potentially trial-eligible patients, whose outcomes were comparable with those obtained from pivotal clinical trials. This is of substantial clinical relevance for physicians discussing outcomes to be expected with their patients and stresses the need for real-world effectiveness analyses.

Patient-reported outcomes in advanced NSCLC before and during the COVID-19 pandemic: Real-world data from the German prospective CRISP Registry (AIO-TRK-0315).

Patients with lung cancer under treatment have been associated with a high risk of COVID-19 infection and potentially worse outcome, but real-world data on patient-reported outcomes (PROs) are rare. We assess patients' characteristics and PROs before and during the COVID-19 pandemic in an advanced non-small cell lung cancer (NSCLC) cohort in Germany. Patients with locally advanced or metastatic NSCLC from the prospective, multicentre, observational CRISP Registry (NCT02622581) were categorised as pre-pandemic (March 2019 to Feb 2020, n = 1621) and pandemic (March 2020 to Feb 2021, n = 1317). From baseline to month 15, patients' health-related quality of life (HRQoL) was assessed by FACT-L, anxiety and depression by PHQ-4. Association of pandemic status with time to deterioration (TTD) in QoL scales adjusted for potential covariates was estimated using Cox modelling. PROs were documented for 1166 patients (72%) in the pre-pandemic, 979 (74%) in the pandemic group. Almost 60% of patients were male, median age was 66 years, comorbidities occurred in 85%. Regarding HRQoL, mean-change-from-baseline plots hardly differed between both samples. Approximately 15%-21% of patients reported anxiety, about 19%-27% signs of depression. For the pandemic group, TTD was slightly, but statistically significantly, worse for the physical well-being-FACT-G subscale (HR 1.15 [95%CI 1.02-1.30]) and the anxiety-GAD-2 subscale (HR 1.14 [95%CI 1.01-1.29]). These prospectively collected real-world data provide valuable insights into PROs before and during the COVID-19 pandemic in advanced NSCLC. For the patients, the pandemic seemed to be less of a burden than the disease itself, as there was a considerable proportion of patients with anxiety and depression in both groups.

Prognostic factors in nonsmall cell lung cancer: insights from the German CRISP registry.

INTRODUCTION: Understanding prognosis, especially long-term outcome, in advanced nonsmall cell lung cancer (NSCLC) is crucial to inform patients, guide treatment and plan supportive and palliative care. METHODS: Prognostic factors influencing overall survival (OS) and progression-free survival (PFS) in 2082 patients with wild-type (WT)-NSCLC (629 M1a, 249 M1b, 1204 M1c) are reported. Patients were included in the prospective German CRISP registry recruiting in >150 centres. Analysis for pre-therapeutic factors was based on results from Cox proportional hazard models. RESULTS: Current M-descriptors of the Union for International Cancer Control-8 staging system were validated: M1a and M1b patients had significantly longer median time to events compared to M1c (OS/PFS 16.4/7.2 months, 17.8/6.7 months and 10.9/5.4 months, respectively). OS and PFS were influenced by number and location of metastatic organ systems. M1c and four or more metastatic organs involved had shorter OS and PFS than M1c with one to three organs (OS hazard ratio (HR) 1.69, p<0.001; PFS HR 1.81, p<0.001). M1b-liver metastases had shorter OS/PFS than M1b involving other organs (OS HR 2.70, p=0.006; PFS HR 2.48, p=0.007). Based on number of involved organs (orgsys) and liver metastases, two risk groups (low-risk: M1a, M1b-non-liver, M1c-1-3-orgsys-non-liver; high-risk: M1c-liver, M1b-liver, M1c-4+-orgsys) with significantly different prognoses could be amalgamated (median OS/PFS 14.3/6.5 months and 7.7/4.1 months, respectively). Other favourable factors were female gender and Eastern Cooperative Oncology Group stage 0, with age showing no impact. Those with T1- or N0-status were associated with longer OS than T2-4 or N2-3. CONCLUSION: In this large observational dataset, we further defined factors for outcome in WT-NSCLC, including increased number of involved metastatic organ systems and liver metastases, as those with overall poorer prognosis and reduced survival chance.

KRAS G12C-mutated advanced non-small cell lung cancer: A real-world cohort from the German prospective, observational, nation-wide CRISP Registry (AIO-TRK-0315).

OBJECTIVES: After decades of unsuccessful efforts in inhibiting KRAS, promising clinical data targeting the mutation subtype G12C emerge. Since little is known about outcome with standard treatment of patients with G12C mutated non-small cell lung cancer (NSCLC), we analyzed a large, representative, real-world cohort from Germany. PATIENTS AND METHODS: A total of 1039 patients with advanced KRAS-mutant or -wildtype NSCLC without druggable alterations have been recruited in the prospective, observational registry CRISP from 12/2015 to 06/2019 by 98 centers in Germany. Details on treatment, best response, and outcome were analyzed for patients with KRAS wildtype, G12C, and non-G12C mutations. RESULTS: Within the study population, 160 (15.4 %) patients presented with KRAS G12C, 251 (24.2 %) with non-G12C mutations, 628 (60.4 %) with KRAS wildtype. High PD-L1 expression (Tumor Proportion Score, TPS > 50 %) was documented for 28.0 %, 43.5 %, and 28.9 % (wildtype, G12C, non-G12C) of the tested patients; 68.8 %, 89.3 %, and 87.7 % of the patients received first-line treatment combined with an immune checkpoint-inhibitor in 2019. TPS > 50 % vs. TPS < 1 % was associated with a significantly decreased risk of mortality in a multivariate Cox model (HR 0.39, 95 % CI 0.26-0.60, p=<0.001). There were no differences in clinical outcome between KRAS wildtype, G12C or non-G12C mutations and KRAS mutational status was not prognostic in the model. CONCLUSION: Here we describe the so far largest prospectively recruited cohort of patients with advanced NSCLC and KRAS mutations, with special focus on the G12C mutation. These data constitute an extremely valuable historical control for upcoming clinical studies that employ KRAS inhibitors.

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).

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.