Wilfried Ernst Erich Eberhardt

Background/Objectives: Following findings of the PACIFIC trial, consolidation therapy with durvalumab was established as standard of care for patients with unresectable, stage III non-small cell lung cancer (NSCLC) and no disease progression after chemoradiotherapy (CRT). This study evaluated real-world effectiveness of durvalumab consolidation in clinical routine in Germany. Methods: Patients with unresectable, stage III NSCLC enrolled in the prospective, multicenter CRISP registry (August 2018–June 2023) were classified into two subgroups: treated with/without durvalumab consolidation therapy. Following stabilized inverse probability of treatment weighting, progression-free survival (PFS) and overall survival (OS) were assessed. Results: This analysis included 231 patients, 124 with and 107 without durvalumab consolidation therapy. In the two subgroups (with/without durvalumab), median age was 67.2/64.6 years, 51.6%/47.7% were female, and 83.1%/86.0% had Eastern Cooperative Oncology Group performance status ≤1. Most patients (87%) received concurrent CRT. In the weighted analysis, median PFS was significantly longer with durvalumab consolidation (18.6 months, 95% CI [12.8, 24.5] vs. 7.5 months, 95% CI [5.5, 8.4]; HR 0.52, 95% CI [0.37, 0.73]); median OS was numerically longer but did not reach statistical significance (34.4 months, 95% CI [25.4, not available/not reached] vs. 27.5 months, 95% CI [17.4, 59.6]; HR 0.67, 95% CI [0.44, 1.02]). Conclusions: This real-world study confirmed significant PFS improvements with durvalumab consolidation in unresectable, stage III NSCLC, with effect sizes comparable to PACIFIC. Although OS differences were not statistically significant, these findings provide valuable real-world evidence supporting the effectiveness of durvalumab consolidation in routine clinical practice.

Background: Checkpoint inhibitors (CPIs) improve the survival in advanced NSCLC and ES-SCLC, but reproducibility of randomized trial results in routine practice remains unclear. Target trial emulation enables approximation of randomized trial designs using observational data while reducing common biases. Methods: Using the Baden-Württemberg Cancer Registry, we emulated four pivotal trials: KEYNOTE-189 (eKN189), KEYNOTE-407 (eKN407), IMpower133 (eIMP133), and PACIFIC (ePACIFIC). The eligibility criteria, treatment strategies, and outcomes were aligned with the original trials as closely as possible within registry constraints. Time-zero was defined as the treatment initiation for systemic therapy cohorts (eKN189, eKN407, eIMP133) and as completion of chemoradiotherapy for ePACIFIC. The treatment groups were balanced using propensity-score-based inverse probability weighting. The outcomes included the overall survival (OS) and the objective response rate (ORR). Results: A total of 4015 patients were included (eKN189: 1762; eKN407: 467; eIMP133: 1190; ePACIFIC: 595). After weighting, the baseline covariates were well balanced. ICI-based regimens were associated with an improved survival: eKN189: HR—0.59 (95% CI: 0.52–0.66), 5-year OS—22.7% vs. 4.7%; eKN407: HR—0.69 (95% CI: 0.54–0.89), 5-year OS—11.8% vs. 6.6%; eIMP133: HR—0.7 (95% CI: 0.62–0.79), 5-year OS—12.8% vs. 5.3%; ePACIFIC: HR—0.51 (95% CI: 0.39–0.66), 5-year OS—47.3% vs. 23.4%. The OS curves demonstrated long-term plateaus across CPI-containing arms. The ORRs were consistently higher with CPI-containing regimens (eKN189: 41.6% vs. 29.6%; eKN407: 44.8% vs. 31.5%; eIMP133: 51.7% vs. 43.1%; ePACIFIC: 56.6% vs. 47.1%). Conclusions: This registry-based target trial emulation reproduced the survival patterns observed in four landmark lung cancer RCTs within trial-like real-world populations, supporting the external validity of pivotal immunotherapy trials while reinforcing the role of high-quality registries as a powerful complement to randomized trials in oncology.

Oligometastatic (OMD) non‐small cell lung cancer (NSCLC) is a distinct but heterogeneous entity. Current guidelines recommend systemic therapy and consolidation with local ablative therapy (LAT). However, evidence regarding the optimal choice of multimodal treatment approaches is lacking, in particular with respect to the integration of immunotherapy. This real‐world study identified 218 patients with OMD NSCLC (2004–2023, prespecified criteria: ≤5 metastases in ≤2 organ systems) from three major German comprehensive cancer centers. Most patients had one (72.5%) or two (17.4%) metastatic lesions in a single (89.9%) organ system. Overall survival (OS) was significantly longer with a single metastatic lesion (HR 0.54, p = .003), and female gender (HR 0.4, p < .001). Median OS of the full cohort was 27.8 months, with 29% survival at 5 years. Patients who had completed LAT to all NSCLC sites, typically excluding patients with early progression, had a median OS of 34.4 months (37.7% 5‐year OS rate) with a median recurrence‐free survival (RFS) of 10.9 months (13.3% at 5 years). In those patients, systemic treatment as part of first‐line therapy was associated with doubling of RFS (12.3 vs. 6.4 months, p < .001). Despite limited follow‐up of patients receiving chemo‐immunotherapy (EU approval 2018/2019), RFS was greatly improved by adding checkpoint inhibitors to chemotherapy (HR 0.44, p = .008, 2‐year RFS 51.4% vs. 15.1%). In conclusion, patients with OMD NSCLC benefitted from multimodality approaches integrating systemic therapy and local ablation of all cancer sites. A substantial proportion of patients achieved extended OS, suggesting a potential for cure that can be further augmented with the addition of immunotherapy.

Over 40% stage‐III non‐small‐cell lung cancer (NSCLC) patients (pts) experience 5‐year survival following multimodality treatment. Nevertheless, little is known about relevant late toxicities and quality‐of‐life (QoL) in the further long‐term follow‐up. Therefore, we invited pts from our randomized phase‐III trial (Eberhardt et al., Journal of Clinical Oncology 2015) after 10 years from diagnosis to participate within a structured survivorship program (SSP) including follow‐up imaging, laboratory parameters, cardio‐pulmonary investigations, long‐term toxicity evaluations and QoL questionnaires. Of 246 pts initially accrued, 161 were considered potentially resectable following the induction therapy and were randomized (80 to arm A: definitive chemoradiation; 81 to arm B: definitive surgery; 85 not randomized for different reasons; group C). 31 from 37 pts still alive after 10 years agreed to the SSP (13 in A; 12 in B; 6 in C). Clinically relevant long‐term toxicities (grade 3 and 4) were rarely observed with no signal favoring any of the randomization arms. Furthermore, available data from the global QoL analysis did not show a signal favoring any definitive locoregional approach (Mean QoL in SSP A pts: 56.41/100, B pts: 64.39/100) and no late decline in comparison to baseline and early 1‐year follow‐up. This is the first comprehensive SSP of very late survival follow‐up reported in stage‐III NSCLC treated within a randomized multimodality trial and it may serve as important baseline information for physicians and pts deciding for a locoregional treatment option.

Pleural mesothelioma (PM) is a very aggressive malignancy with a poor prognosis. Most patients receive systemic treatment only; however, some patients may benefit from multimodality treatment. A precise staging of patients undergoing multimodal treatment is mandatory. We investigated the pattern of metastasis in a cohort of patients screened for multimodal treatment to define the extent of staging examinations. Additionally, we investigated the occurrence of metastasis during follow-up. We investigated a single-center experience of 545 patients newly diagnosed and/or treated with PM between the years 2010 and 2022. Patients who were treated naïvely and had a whole set of imaging of the brain were included and further analyzed. A total of 54% of all patients with cerebral imaging had an available ¹⁸FDG-PET CT scan. We also recorded metastasis during treatment follow-up. There were 110 patients who had a whole set of imaging (CT = 89% and MRI = 11%) of the brain, and 54% of all patients with cerebral imaging had an available ¹⁸FDG-PET CT scan. We identified four patients with cerebral metastasis at the time of first diagnosis, which means that 5.4% of the cohort had cerebral metastasis and 13.3% of all patients in the subgroup with complete data of ¹⁸FDG-PET CT had distant non-cerebral metastasis. During the longitudinal follow-up, we found 11 patients with newly diagnosed metastases after a median time of 1.6 years (range: 2 months to 3.3 years) after first diagnosis without metastases. Distant metastases are more frequent in mesothelioma patients than previously thought. This implies that extensive staging is needed for patients selected for multimodal treatment, including brain imaging and ¹⁸FDG-PET CT.