Neuroendocrine carcinomas (NECs) are poorly differentiated and highly aggressive epithelial neuroendocrine neoplasms. The most common primary site is the lung, but they may arise in every organ. Approximately 37% of extrapulmonary NECs (EP-NECs) occur in the gastroenteropancreatic (GEP) tract, followed by the genitourinary (GU) system and gynecological tract. As a result of their rarity, there is scant evidence to guide treatment recommendations, and a multidisciplinary approach is essential for the management of such patients. Platinum-based chemotherapy currently represents the standard of care for EP-NECs of any site, mirroring the management of small-cell lung cancer (SCLC), but further approaches are still under investigation. Indeed, ongoing trials evaluating targeted therapies, immune checkpoint inhibitors (ICIs), and radionuclide therapy could provide potentially breakthrough therapeutic options. Given the relative dearth of evidence-based literature on these orphan diseases, the aim of this review is to provide an overview of the pathology and current treatment options, as well as to shed light on the most pressing unmet needs in the field.

Background: Docetaxel is the standard of care for advanced non-small cell lung cancer (NSCLC) after platinum-based chemotherapy and/or immunotherapy but is associated with modest clinical outcomes and considerable toxicity. Sacituzumab govitecan and datopotamab deruxtecan are trophoblast cell surface antigen (TROP)-2-directed antibody–drug conjugates (ADCs) that showed encouraging activity in pretreated patients with advanced NSCLC. This systematic review and pooled analysis aims to comprehensively assess the efficacy and safety of anti-TROP-2 ADCs compared to docetaxel in pretreated patients with advanced NSCLC. Methods: A systematic search through PubMed and EMBASE before 31 January 2025 was performed to identify eligible studies. Randomized controlled phase III trials comparing an anti-TROP-2 regimen to docetaxel in patients with pretreated advanced NSCLC were included. Overall survival (OS), progression-free survival (PFS), and grade ≥ 3 treatment-related adverse events (TRAEs) were extracted from the identified trials. A pooled analysis of reconstructed patient data and meta-analysis employing the random-effect model were used to summarize the efficacy and safety outcomes. Results: Across the two trials included, 1207 patients were enrolled, 598 in the TROP-2 ADC arm and 609 in the docetaxel arm. Anti-TROP-2 treatment did not produce significant improvements in OS (HR: 0.90; 95% CI, 0.78–1.03; P = 0.13) and PFS (HR: 0.84; 95% CI, 0.68–1.02; P = 0.08), compared to docetaxel, even in patients with a nonsquamous histology (OS HR: 0.86; 95% CI, 0.73–1.01; P = 0.06; PFS HR: 0.76; 95% CI, 0.52–1.12; P = 0.17). Across the subgroup analyses, a statistically significant improvement in OS was observed in patients with actionable genomic alterations (AGAs) (HR: 0.63; 95% CI, 0.41–0.95; P = 0.03). Compared to docetaxel, the anti-TROP-2 regimen demonstrated a lower risk of developing grade ≥ 3 TRAEs (RR: 0.76; 95% CI, 0.55–1.05; P = 0.09). Conclusions: The anti-TROP-2 regimen showed a better safety profile but failed to demonstrate a relevant clinical improvement over docetaxel. Anti-TROP-2 ADCs could find a role in the management of patients with AGAs.

Purpose: With rapidly expanding treatment options for patients with epidermal growth factor receptor (EGFR)–mutated non–small cell lung cancer (NSCLC), identifying biomarkers that may assist in treatment selection is critical. The impact of EGFR amplification (EGFRAMP) on outcomes to osimertinib is currently unknown. Experimental Design: Patients with metastatic EGFR-mutated NSCLC who received first-line osimertinib and had undergone baseline next-generation sequencing (NGS) that included assessment of EGFRAMP were included. EGFRAMP was defined as an EGFR copy number (CN) ≥6. Results: Among 473 patients, 81 (17.1%) had EGFRAMP. Compared with patients with non-amplified EGFR (EGFRNon-AMP; n = 392), they frequently had TP53 comutations (80% vs. 55.4%, P < 0.001) and brain (50.6% vs. 34.3%, P = 0.008), liver (25.9% vs. 13.5%, P = 0.009), and bone (65.4% vs. 51.3%, P = 0.028) metastases. When treated with osimertinib, patients with EGFRAMP achieved a similar objective response rate (88% vs. 83%, P = 0.23) but shorter median progression-free survival [PFS; 11.6 vs. 19 months, hazard ratio (HR), 1.77; P < 0.0001] and overall survival (OS; 34 vs. 40.1 months; HR, 1.40; P = 0.040). EGFRAMP was consistently associated with worse PFS regardless of TP53 comutations; however, EGFRAMP was associated with worse PFS and OS in patients with EGFR exon 19 deletion, but not in those with EGFR L858R. Within EGFRAMP cases, a higher EGFR CN and the amplification of the mutant allele, as opposed to wild-type amplification, correlated with inferior outcomes. Among patients reassessed with NGS after osimertinib resistance (n = 113), those with baseline EGFRAMP more frequently showed acquired MET alterations (29% vs. 12%, P = 0.04). Conclusions: EGFR AMP correlates with distinct characteristics and worse outcomes to osimertinib monotherapy among patients with EGFR-mutated NSCLC.