PURPOSE: Small-cell lung cancer (SCLC) is an aggressive malignancy with limited treatments. Delta-like ligand 3 (DLL3) is aberrantly expressed in most SCLC. Tarlatamab (AMG 757), a bispecific T-cell engager molecule, binds both DLL3 and CD3 leading to T-cellb–mediated tumor lysis. Herein, we report phase I results of tarlatamab in patients with SCLC. PATIENTS AND METHODS: This study evaluated tarlatamab in patients with relapsed/refractory SCLC. The primary end point was safety. Secondary end points included antitumor activity by modified RECIST 1.1, overall survival, and pharmacokinetics. RESULTS: By July 19, 2022, 107 patients received tarlatamab in dose exploration (0.003 to 100 mg; n = 73) and expansion (100 mg; n = 34) cohorts. Median prior lines of anticancer therapy were 2 (range, 1-6); 49.5% received antiprogrammed death-1/programmed death ligand-1 therapy. Any-grade treatment-related adverse events occurred in 97 patients (90.7%) and grade b % 3 in 33 patients (30.8%). One patient (1%) had grade 5 pneumonitis. Cytokine release syndrome was the most common treatment-related adverse event, occurring in 56 patients (52%) including grade 3 in one patient (1%). Maximum tolerated dose was not reached. Objective response rate was 23.4% (95% CI, 15.7 to 32.5) including two complete and 23 partial responses. The median duration of response was 12.3 months (95% CI, 6.6 to 14.9). The disease control rate was 51.4% (95% CI, 41.5 to 61.2). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.1 to 5.4) and 13.2 months (95% CI, 10.5 to not reached), respectively. Exploratory analysis suggests that selecting for increased DLL3 expression can result in increased clinical benefit. CONCLUSION: In patients with heavily pretreated SCLC, tarlatamab demonstrated manageable safety with encouraging response durability. Further evaluation of this promising molecule is ongoing. [Media: see text]

Non-small cell lung cancer (NSCLC) accounts for up to 85% of all lung cancers. The last few years have seen the development of a new staging system, diagnostic procedures such as liquid biopsy, treatments like immunotherapy, as well as deeper molecular knowledge; so, more options can be offered to patients with driver mutations. Groups with specific treatments account for around 25% and demonstrate significant increases in overall survival, and in some subgroups, it is important to evaluate each treatment alternative in accordance with scientific evidence, and even more so with immunotherapy. New treatments similarly mean that we must reconsider what should be done in oligometastatic disease where local treatment attains greater value.

In recent years, immunotherapy has revolutionized and changed the standard of care in patients with advanced non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors, fundamentally those that act by blocking the programmed cell death receptor-1 (PD-1) and its ligand the programmed cell death ligand-1 (PD-L1) have emerged as novel treatment strategies in NSCLC, demonstrating undoubted superiority over chemotherapy in terms of efficacy. Several of these immune checkpoint modulators have recently gained regulatory approval for the treatment of advanced NSCLC, such as nivolumab, atezolizumab and pembrolizumab in first-line (only the latter) and second-line settings, and more recently, durvalumab as maintenance after chemoradiotherapy in locally advanced disease. There is consensus that PD-L1 expression on tumor cells predicts responsiveness to PD-1 inhibitors in several tumor types. Hence PD-L1 expression evaluated by immunohistochemistry (IHC) is currently used as a clinical decision-making tool to support the use of checkpoint inhibitors in NSCLC patients. However, the value of PD-L1 as the ‘definitive’ biomarker is controversial as its testing is puzzled by multiple unsolved issues such as the use of different staining platforms and antibodies, the type of cells in which PD-L1 is assessed (tumor versus immune cells), thresholds used for PD-L1-positivity, or the source and timing for sample collection. Therefore, newer biomarkers such as tumor mutation burden and neoantigens as well as biomarkers reflecting host environment (microbiome) or tumor inflamed microenvironment (gene expression signatures) are being explored as more reliable and accurate alternatives to IHC for guiding treatment selection with checkpoint inhibitors in NSCLC.

This study sought to assess the real incidence of pN2 among patients with non-small-cell lung cancer (NSCLC) (cN0) with negative mediastinal uptake of 2-deoxy-2-(18F)-fluoro-o-glucose (FDG). During 30 consecutive months (January 2007-May 2009), all patients with NSCLC scheduled for surgery in our unit had a preoperative FDG-positron emission tomography (PET)/computed tomography (CT) in our institution, after a dedicated chest CT (n=259). Only patients with both FDG-PET/CT and negative dedicated chest CT scan (N1 and N2 nodes <1cm) were prospectively included (n=125). Patients with cN1/cN2/cN3 and patients who had undergone preoperative chemo-radiotherapy were excluded. No invasive surgical staging was carried out in this group and curative resection plus systematic mediastinal dissection was performed except in the event of unexpected oncological contraindication. All variables were collected prospectively and, when pathological information was obtained, all the cases were carefully reviewed. Mediastinal assessment by FDG-PET/CT, negative predictive value (NPV) was 85.6%, confidence interval (CI): [77-91]; false negatives (FNs) for mediastinal lymph nodes involvement was 14.4% (18 cases). The pN2 stations most frequently involved were: 4R (six cases), seven (six cases) and five (five cases). Multiple-level pN2 occurred in six (4.8%) cases. Occult (pN2) lymph nodes were more frequent in women (p<0.01), adenocarcinoma (p<0.05) and pN1 (p<0.05). Pathological N2 prevalence for pN1 was 34 (27.7%). Considering pathological staging as the gold standard, the agreement was 70% and 47.5% for stage IA and IB (Kappa's index: 0.72 and 0.76) and, in all patients, 47% (Kappa's index: 0.27). In general, down-staging is more frequent than up-staging. Mediastinal staging of NSCLC by FDG-PET/CT showed a considerable incidence of FNs. NPV is lower than previously reported and the preoperative mediastinal staging by 18FDG-PET/CT may jeopardise the accurate treatment for early stage NSCLC patients.