Michael Thomas

Neoadjuvant therapy has recently become an integral component of multimodal treatment for resectable lung cancer. However, real‐world data on perioperative morbidity and treatment adherence remain limited. This study aimed to assess the feasibility and safety of different neoadjuvant treatment approaches applied within daily clinical routine. We retrospectively analyzed patients with resectable stage II–III non‐small cell lung cancer undergoing either neoadjuvant chemoimmunotherapy or chemotherapy/chemoradiotherapy followed by curative surgical resection. Treatment groups were compared with respect to perioperative outcomes, radiologic and pathologic downstaging, and pathologic response. A total of 143 patients met the inclusion criteria, of whom 46 (32.2%) received chemoimmunotherapy and 97 (67.8%) were treated with chemotherapy prior to surgery. Adverse events leading to treatment discontinuation occurred in only two patients in the chemoimmunotherapy group and four patients in the chemotherapy group. Chemoimmunotherapy was associated with significantly higher rates of pathologic complete response (37.0% vs. 4.1%) and more pronounced nodal downstaging, with a higher proportion of patients achieving ypN0 status (76.1% vs. 34.0%). High tumoral PD‐L1 expression (≥ 50%) and squamous cell carcinoma histology were independently associated with pathologic complete response. Real‐world treatment with neoadjuvant chemoimmunotherapy was feasible and resulted in improved response rates compared with chemotherapy, without increasing perioperative morbidity. Histology and high PD‐L1 expression may serve as predictors for complete pathologic response, although the predictive value of PD‐L1 requires confirmation in larger cohorts with more complete biomarker data.

1. 1.1. Lung cancer is the second most diagnosed cancer worldwide, with approximately 2.2 million cases diagnoses in 2020, representing about 11.4% of the total cancer cases [1]. Non-small cell lun...

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.

Immune checkpoint inhibitors have shown promising results in the neoadjuvant treatment of resectable non‐small cell lung cancer. This open‐label, single‐arm, prospective, monocentric trial evaluated the efficacy and safety of neoadjuvant atezolizumab plus carboplatin/nab‐paclitaxel in patients with resectable non‐squamous non‐small cell lung cancer. Patients with previously untreated, pathologically confirmed, non‐squamous non‐small cell lung cancer in stage II, IIIA, and select IIIB (T3N2 only) were treated with atezolizumab and carboplatin/nab‐paclitaxel for 3 cycles followed by curative intent surgery. Major pathologic response (MPR) was defined as primary endpoint. 20 patients with histologically confirmed pulmonary adenocarcinoma in TNM‐stage IIA ( n = 1, 5%), stage IIB ( n = 7, 35%), and stage IIIA ( n = 12, 60%) were enrolled and treated according to the study protocol. 151 treatment‐related adverse events were recorded, and 13 patients (65%) had treatment‐related adverse events of grade 3 or higher. There were no grade 5 events. All patients underwent complete anatomical resection (R0). MPR was observed in 9 patients (45%), including 5 (25%) patients with complete pathological response. The proportion of remaining viable tumor showed a significant but weak association to the relative tumor size change in CT ( p = 0.018) and the relative change in SUV _max ( p = 0.006). In conclusion, neoadjuvant chemoimmunotherapy with atezolizumab achieved a promising MPR‐rate of 45% while being well tolerated and allowing a safe and complete surgical resection. These results strongly support the further investigation of atezolizumab as preoperative therapy in resectable non‐small cell lung cancer and underline the continued need to develop biomarkers of response.

RET fusions appear in 1%-2% of non–small cell lung cancers (NSCLCs). The results from the ARROW study (ClinicalTrials.gov identifier: NCT03037385 ) supported US Food and Drug Administration approval of pralsetinib, an oral selective RET inhibitor, for metastatic RET -altered NSCLC and RET fusion–positive thyroid cancers. ARROW was a phase I/II open-label study of pralsetinib 400 mg once daily in RET fusion–positive NSCLCs. Coprimary end points were overall response rate (ORR) and safety. Key secondary end points included duration of response, progression-free survival, and overall survival (OS). At data lock (May 20, 2024), 281 patients initiated pralsetinib (median treatment duration, 15.0 months). ORR (measurable disease patients; n = 259) was 78% (95% CI, 69 to 86) for treatment-naïve patients and 63% (95% CI, 54 to 71) for prior platinum-based chemotherapy patients. Median OS was 44.3 months (95% CI, 30.9 to 53.1), 50.1 months (95% CI, 28.3 to not reached) in treatment-naïve patients, and 39.7 months (95% CI, 27.8 to 53.2) in prior platinum patients. Common grade ≥3 treatment-related adverse events were anemia (21%), hypertension (15%), and decreased neutrophils (13%). Three treatment-related deaths occurred (pneumonia, n = 2; interstitial lung disease and rhabdomyolysis, n = 1 each). Safety was consistent with previous ARROW reports; no hypersensitivity was reported in patients receiving prior immunotherapies. Pralsetinib produced robust, durable responses with manageable safety in treatment-naïve and previously treated patients with RET fusion–positive NSCLCs, confirming previous findings with longer follow-up.

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.

Aim: MET exon 14 (MET ex14) skipping occurs in 3–4% of non-small-cell lung cancer (NSCLC) cases. Low frequency of this alteration necessitated open-label, single-arm trials to investigate MET inhibitors. Since broad MET biomarker testing was only recently introduced in many countries, there is a lack of historical real-world data from patients with MET ex14 skipping NSCLC receiving conventional therapies. Given the rarity of this population and limitations of existing real-world data sources, the MOMENT registry aims to prospectively collect uniform, comprehensive, high-quality data from patients with MET ex14 skipping advanced NSCLC treated in routine clinical practice, which can support clinical and regulatory decision making. Patients & methods: MOMENT is a multinational, non-interventional disease registry collecting data on patients with MET ex14 skipping advanced NSCLC receiving any systemic anticancer therapy. Newly diagnosed patients and those already receiving treatment are eligible. Patients with previous participation in a clinical trial can be included if they receive at least one subsequent therapy line in a routine clinical setting. Eligible systemic treatment includes all available anticancer therapies (approved, conditionally approved or provided through Early Access). Data collection includes biomarker testing results, demographics, baseline clinical characteristics, treatment details and effectiveness, safety information and imaging. Registry site inclusion is dependent on confirmation that local MET ex14 skipping detection methods are sufficient to confirm MET ex14 skipping status. MOMENT is currently active at more than 60 sites across Europe and North America and approximately 700 patients are expected to be enrolled within the next 4 years. The first patient was enrolled on 4 October 2022. After completion of data collection, MOMENT data can be shared with external parties to conduct non-interventional studies. Discussion/conclusion: The MOMENT registry collects comprehensive, high-quality real-world data from patients with MET ex14 skipping advanced NSCLC receiving systemic anticancer treatment in a routine clinical setting, to enable future studies informing regulatory decisions and optimal care for this rare population. Clinical Trial Registration: NCT05376891 ( ClinicalTrials.gov ); EUPAS47602 (EU PAS register no.)