Search Results (48)

Background: The treatment options for HER2-negative metastatic breast cancer include targeted therapies, cytotoxic chemotherapies, and immunotherapy. However, limited specificity and inevitable resistance highlight the need for novel agents. Antibody–drug conjugates (ADCs), such as trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG), represent a breakthrough by selectively delivering cytotoxic agents to tumor cells, potentially improving the therapeutic index. Despite demonstrated efficacy, ADCs present toxicity profiles similar to conventional chemotherapy, alongside unique adverse events. In clinical practice, oncologists may face scenarios where both T-DXd and SG are treatment options in HER2-negative mBC. To enable shared decision-making, it is crucial to present a comprehensive overview that includes both efficacy data and detailed toxicity profiles. Our objective was to provide a pooled and informative synthesis of toxicities from pivotal studies, including graphical representations, to support informed, patient-centered medical decisions. Methods: We reviewed safety data from phase 3 clinical trials in HER2-negative mBC: DESTINY-Breast04/DESTINY-Breast06 for T-DXd and ASCENT/TROPICS-02 for SG. Adverse event (AE) profiles, including frequency and severity, were extracted, and weighted means were calculated. Emerging ADCs such as datopotamab deruxtecan and patritumab deruxtecan were considered to contextualize future therapeutic decisions. Results: Tables, bar plots and radar plots were generated. T-DXd demonstrated high rates of nausea (69.2%), fatigue (47.2%), and neutropenia (35.6%), with 52.7% experiencing grade ≥ 3 AEs. Notably, pneumonitis occurred in 10.7%, with grade ≥ 3 in 2.6%. SG showed a distinct AE profile, with higher incidences of neutropenia (67.1%), with grade ≥ 3 in 51.3%, and diarrhea (60.8%). Conclusions: The choice between ADCs in HER2-negative metastatic BC when both T-DXd and SG are treatment options should consider toxicity profiles to optimize patient-centered treatment strategies. Tailoring ADC selection based on individual tolerance and preferences is critical for shared decision-making, and future research should focus on assessing the utility and acceptability of such clinical tools to guide treatment selection. Full article

Background: Small cell lung cancer (SCLC) remains a highly aggressive malignancy with a poor prognosis. Despite multimodal standard therapies, most patients relapse within months, and second-line treatment options such as topotecan offer only limited benefit. Novel therapeutic strategies are therefore urgently needed. Methods: This narrative review is based on a selective literature search conducted via PubMed and ClinicalTrials.gov (last updated June 2025). Results: Emerging treatment strategies include bispecific T-cell engagers (e.g., tarlatamab), antibody-drug conjugates (ADCs) such as sacituzumab govitecan, DS-7300, and ZL-1310, as well as targeted therapies. Among these, tarlatamab has demonstrated improved survival outcomes with an acceptable safety profile and is poised to become the new second-line standard. In contrast, ADCs and targeted agents have shown only modest efficacy and have yet to deliver meaningful survival benefits, often accompanied by increased toxicity. Additionally, the identification of molecular subtypes of SCLC has revealed subtype-specific differences in treatment response. However, clinical translation is challenged by intratumoral heterogeneity, plasticity, and the lack of standardized diagnostic assays. Conclusions: While tarlatamab represents a major therapeutic advancement, other agents remain in early clinical development and require validation in large, randomized trials. The clinical implementation of molecular subtyping remains limited, though it holds promise for future personalized treatment approaches. Despite recent progress, SCLC continues to pose substantial therapeutic challenges, emphasizing the need for improved treatment strategies and validated predictive biomarkers. Full article

Background: The patient-reported outcomes (PROs) of sacituzumab govitecan (SG) were compared with chemotherapy using two phase 3 trials (TROPiCS-02, EVER-132-002) involving patients with HR+/HER2− locally recurrent inoperable or metastatic breast cancer. Methods: A meta-analysis was performed to compare change from baseline (CFB) scores and time-to-deterioration (TTD) between SG and chemotherapy using EORTC QLQ-C30 and EQ-5D-5L VAS in the overall, prior CDK4/6i-treated, and fast-progressor populations. Results of CFB and TTD analyses were summarized using hazard ratio (HR) and mean difference measures. Results: Statistically significant improvement (p < 0.05) in CFB scores was observed with SG over chemotherapy in five EORTC QLQ-C30 domains: physical (mean difference: 2.64), role functioning (mean difference: 2.70), fatigue (mean difference: −2.51), pain (mean difference: −3.25) and dyspnea (mean difference: −3.27), and EQ-5D-5L VAS (mean difference: 1.58). In the overall population, longer TTD (p < 0.05) was observed with SG versus chemotherapy on six domains of EORTC QLQ-C30: GHS/QoL (HR: 0.76), physical (HR: 0.72), emotional functioning (HR: 0.73), fatigue (HR: 0.80), pain (HR: 0.82), and dyspnea (HR: 0.71). Results from EORTC QLQ-C30 domains were mostly consistent among the overall, prior CDK4/6i treated and fast-progressor populations. SG demonstrated longer TTD (p < 0.05) over chemotherapy for EQ-5D-5L-VAS across all studied populations (HR range: 0.63–0.69). PROs significantly worsened with SG in the domains of diarrhea and nausea and vomiting (commonly reported adverse events of SG, manageable by following established guidelines). Conclusions: SG significantly improved PROs versus chemotherapy for several subdomains of EORTC QLQ-C30 and EQ-5D-5L-VAS. The consistency of these results in the overall population and subgroups supports the generalizability of the meta-analytic evidence and reinforces the PRO benefits associated with SG versus chemotherapy. Full article

Background/Objectives: ADCs bring an innovative strategy to cancer treatment by conjugating powerful cytotoxic agents to the specificity of monoclonal antibodies. This review discusses recent advancements and challenges in the field of ADCs, along with future potential applications. Methods: Studies focused on the development of ADCs were reviewed. These include the effects of payload improvements, linker technologies, antibody engineering, and ADC internalization, which were particular topics of examination regarding their role in pancreatic ductal adenocarcinoma (PDAC) and triple-negative breast cancer (TNBC). The efficacy of some ADCs for pancreatic and breast cancers was compared. Results: In TNBC, ADCs such as sacituzumab govitecan and trastuzumab deruxtecan have improved progression-free survival in advanced cases. In contrast, PDAC ADC development is challenged by low antigen density and poor internalization; despite evidence of target engagement in early trials targeting mesothelin and MUC1, ADCs for PDAC have yet to achieve significant clinical efficacy or regulatory approval. Conclusions: While ADCs have significantly advanced treatment options in TNBC, PDAC remains a difficult target due to its stroma-rich microenvironment and lack of high-density, tumor-specific antigens. This article emphasizes the need for tailor-made ADC designs to enhance results in various types of cancers and provides valuable insight into future advancements in precision oncology. Full article

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. Full article

Background/Objectives: In recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), the overall prognosis is poor, and systemic treatment options remain limited. While precision therapy approaches have revolutionized treatment strategies in several tumor types, molecularly informed therapies in R/M HNSCC are rare, primarily due to the low number of actionable genetic alterations identified through next-generation sequencing (NGS) panels. There is an urgent need to establish precision therapy approaches in R/M HNSCC using innovative predictive testing. Methods: We report the case of a 43-year-old patient with recurrent oral cancer who was extensively pretreated and comprehensively characterized using both descriptive and functional testing. Results: NGS revealed no targetable alterations. A tumor tissue slice radiosensitivity assay suggested radioresistance, arguing against re-irradiation. Kinome profiling identified upregulated Src-family kinases (SFK), and SFK inhibition reduced kinase activity in vitro. Most notably, mRNA analysis demonstrated high Trop-2 overexpression, confirmed by immunohistochemistry (3+ in 100% of tumor cells). Following six cycles of the Trop-2-directed antibody–drug conjugate Sacituzumab govitecan (SG), the patient had an impressive clinical response. Conclusions: Tumor characterization beyond genetic profiling can identify novel treatment options in therapy-refractory HNSCC. This is the first report of “real-world” data on promising antitumor efficacy of SG in a heavily pretreated oral cancer patient with Trop-2 overexpression. Consistent with the findings of the Basket TROPiCS-03 study, SG appears to be a promising novel therapy option for R/M HNSCC after failure of immunotherapy and chemotherapy, particularly in patients with Trop-2 overexpression. Full article

Background/Objectives: Sacituzumab govitecan (SG) is an antibody–drug conjugate targeting Trop-2, approved for use in metastatic triple-negative breast cancer (mTNBC) and more recently in the hormone receptor-positive/HER2-negative (mHRPBC) subtype. While clinical trials have demonstrated its efficacy, real-world data—especially those involving both molecular subtypes—remain scarce. This multicenter, retrospective study aimed to evaluate real-world observational data describing the clinical outcomes, safety, and prognostic factors associated with SG treatment in patients with mTNBC or mHRPBC. Methods: A total of 68 patients treated with SG between 2022 and 2025 were included from multiple oncology centers in Turkey. Patients with mTNBC were required to have received at least one prior chemotherapy line, while mHRPBC patients had received at least two prior chemotherapy lines in addition to cyclin-dependent kinase 4 and 6 inhibitors (CDK 4/6) plus hormone therapy. The clinical outcomes—including the progression-free survival (PFS), overall survival (OS), and objective response rate (ORR)—were evaluated. Univariate and multivariate analyses were performed to identify factors influencing outcomes. Adverse events (AEs) were also documented and graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5 (NCI-CTCAE v5.0). Results: The cohort included 35 (51.5%) mTNBC and 33 (48.5%) mHRPBC patients. The median PFS was 6.1 months, and the median OS was 12.5 months, with no significant differences between subtypes. The ORR was 52.9%, with a complete response observed in 10.3% of patients. A high Eastern Cooperative Oncology Group Performance Status (ECOG PS) and liver metastasis were independent predictors of poorer PFS and OS. Prior immunotherapy did not negatively impact SG’s efficacy. SG was generally well tolerated; the most common AEs were alopecia, anemia, neutropenia, and diarrhea. Treatment discontinuation due to AEs was rare (2.9%). Conclusions: SG was associated with similar clinical outcomes and tolerability in both the mTNBC and mHRPBC subtypes. Although the real-world PFS and OS outcomes mirror those seen in clinical trials, the absence of a control group means that these findings should be interpreted descriptively rather than as confirmation of treatment efficacy. Importantly, this study provides one of the first real-world datasets evaluating SG in the mHRPBC subgroup, highlighting its potential role beyond clinical trials. These results support SG as a valuable therapeutic option in heavily pretreated patients, warranting further prospective and biomarker-driven studies. Full article

The therapeutic landscape for small cell lung cancer (SCLC) has remained stationary for decades, with chemotherapy representing the sole treatment strategy, with a modest survival benefit. The addition of immune checkpoint inhibitors (ICIs) to standard first-line chemotherapy for SCLC was a considerable milestone. However, despite high overall response rates, this strategy failed to deliver long-term benefits for most patients, who continue to face a poor prognosis. Over the last few years, a deeper knowledge of the molecular biology of SCLC and the impressive advancements in drug development, have led to the generation of novel classes of systemic therapies that promise to revolutionize the current therapeutic scenario. Among the various therapeutic approaches in development, T-cell Engagers (TCE) and antibody-drug conjugates (ADCs) stand out due to their unique structural characteristics and mechanisms of action. These therapies represent a paradigm shift from traditional monoclonal antibody (mAb) and chemotherapy regimens, allowing direct engagement of multiple targets associated with tumor progression. In this review, we provide an overview of current drug development in SCLC, specifically focusing on these new agents, summarizing available evidence, and tracking future directions. Full article

Camptothecin and its derivatives (CPTs) are potent antineoplastic agents that exert their effects by inhibiting DNA topoisomerase I, leading to apoptosis during cell proliferation. Since their discovery in the 1960s, CPTs have faced challenges such as low water solubility, pH-dependent lactone ring instability, and severe off-target toxicities. Despite extensive research, only two CPTs, irinotecan and topotecan, have received health authority approval. Ongoing clinical trials continue to explore the use of CPTs in combination with targeted therapies and immunotherapies to expand their clinical use. Drug delivery systems, including liposomes and antibody–drug conjugates (ADCs), have significantly enhanced the therapeutic index of CPTs. Liposomal irinotecan (Onivyde^®, Ipsen, Paris, France) and two ADCs delivering CPT payloads, trastuzumab deruxtecan (Enhertu^®, Daiichi Sankyo, Tokyo, Japan) and sacituzumab govitecan (Trodelvy^®, Gilead Sciences, Inc., Foster City, CA, USA), have demonstrated substantial efficacy and safety. There is promise that novel strategies such as inverse targeting and co-dosing with anti-idiotypic distribution enhancers may expand the utility of CPT ADCs. This review highlights CPT therapies in clinical use and discusses approaches to further enhance their therapeutic selectivity. Full article

In TROPiCS-02, sacituzumab govitecan (SG) demonstrated significantly longer overall survival and progression-free survival with improved quality of life vs. chemotherapy treatment of physician’s choice (TPC) in patients with HR+/HER2− metastatic breast cancer (mBC). The safety profile was consistent with previous studies of SG. We assessed the benefit-–risk profile of SG vs. TPC by integrating patient preferences with clinical benefits using Quality-adjusted Time Without Symptoms of disease progression or Toxicity of treatment (Q-TWiST) analysis in this study population. Survival time was partitioned into three health states: TOX (grade ≥3 treatment-emergent adverse events [TEAEs] after randomization/before disease progression), REL (disease progression until death or end of follow-up), and TWiST (time without progression or grade ≥3 TEAEs). Health state utility weights were obtained from the published literature. The established threshold for clinically important Q-TWiST gain is 10%. SG demonstrated significantly improved Q-TWiST vs. TPC (mean 9.7 vs. 8.1 months; difference 1.6 months; 95% CI, 0.5–2.7; p = 0.0067), which increased with longer follow-up. Relative Q-TWiST improvement met the threshold for clinical importance at 10.8%. Time in TOX was numerically higher with SG than TPC, and the difference stabilized over time. Q-TWiST supports a positive benefit–risk profile for SG over TPC in patients with pretreated HR+/HER2− mBC. Full article

Background: Antibody–drug conjugates (ADCs) represent a novel therapeutic class that combines an antibody against a tumor-associated antigen (TAA), a payload, and a linker that binds these two components. Serious adverse events (SAEs), particularly those of grade 3 (G3) or higher, frequently contribute to the abandonment of ADCs during clinical development. Methods: In this study, we analyzed the toxicity profiles of all approved ADCs, aiming to uncover correlations between their safety profiles and the specific characteristics of their components. Results: In our analysis, dose reductions, dose delays, treatment discontinuations, and ≥G3 toxicities were not significantly different across payload types. Similarly, no association was found between the payload mechanism of action and ≥G3 toxicities, including anemia, neutropenia, febrile neutropenia, thrombocytopenia, and diarrhea. By exploring the specific toxicities of ADCs observed by organ, we identified that most were related to the payload mechanism of action, like the ≥G3 diarrhea observed in 10% of patients treated with sacituzumab govitecan (the payload SN-38 is the active metabolite of irinotecan), and very few were related to the presence of the TAA in normal tissue (presence of Nectin-4 in skin and ≥G3 rash toxicity in 14% of patients treated with enfortumab vedotin). In line with this, no major differences in ≥G3 toxicities were identified in studies with different levels of the TAA (trastuzumab deruxtecan in Destiny Breast Studies with different HER2 expression levels). Conclusions: Our analysis reveals that most ADC toxicities are driven by the payload’s effects on non-transformed tissues; however, a detailed analysis of each ADC component should be taken into consideration. Full article

New breast cancer (BC) diagnoses will soon reach 2.5–3 million/year worldwide, with 15–25% of them being triple-negative breast cancer (TNBC), the most aggressive type, characterized for lacking the main pharmacological targets: estrogen and progesterone receptors (ERs and PRs), as well as HER2 overexpression. Therefore, chemotherapy remains the almost-unique systemic treatment for TNBC. However, some targeted therapies are recommended for use in combination with chemotherapy; namely, PARP inhibitors for BRCA-mutated TNBC, the immune checkpoint inhibitors pembrolizumab and atezolizumab, as well as the antibody–drug conjugates sacituzumab govitecan and trastuzumab deruxtecan, the latter for HER2low subtypes. Regardless of the limited benefits they provide, other treatments with similar mechanisms of action are being investigated in advanced clinical stages. Further, therapies that benefit other cancers, like PI3K/Akt/mTOR pathway and CDK4/6 inhibitors, are still being investigated for TNBC, although convincing results have not been obtained. Given this scenario, it might appear innovation for TNBC treatments has become stuck. However, the huge unmet medical need drives intense research into the biology of the disease. As a result, emerging disruptive therapies are being tested in early-stage trials, designed for novel targets and applying cutting-edge advances in immunotherapy and precision oncology. Full article

Introduction: The optimal treatment of estrogen receptor-positive (ER +) metastatic breast cancer (MBC) after progression on cyclin-dependent 4/6 kinase inhibitors (CDK4/6i) is unknown. Methods: We conducted a systematic review and network meta-analysis (NMA) of phase-II/-III randomized trials of ER + MBC post CDK4/6i + ET progression. We calculated the hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS) using generic inverse variance and odds ratios (ORs) using the Mantel–Haenszel method for adverse events (AEs) with Review-Manager version-5.4. NMA was executed using WINBUGS (Microsoft Excel). Three molecular subgroups were analyzed: HER2-low, PI3K/AKT/mTOR, and the ESR1 mutation subgroup for selective estrogen receptor degrader (SERD). Results: A total of 14 studies were included. In the HER2-low group, Sacituzumab govitecan and trastuzumab deruxtecan had a similar efficacy (HR, 95% CI): PFS (0.98; 0.63–1.43) and OS (1.08; 0.76–1.55). In PI3K/AKT/mTOR-altered cases, capivasertib was superior to alpelisib PFS (0.77; 0.53–1.12), and OS (0.80; 0.48–1.35). SERDs had worse PFS and OS versus ongoing CDK 4/6i (ribociclib). Conclusion: No therapy emerged as the unequivocal choice in the post-CDK 4/6i domain in unselected subgroups. In the HER2-low population, a similar efficacy and different toxicity spectrum was seen. In AKT-altered tumors, capivasertib was less toxic than alpelisib. PROSPERO ID: CRD4202236412. Full article

Advanced triple-negative breast cancer (TNBC) has poorer outcomes due to its aggressive behavior and restricted therapeutic options. While therapies like checkpoint inhibitors and PARP inhibitors offer some benefits, chemotherapy remains ineffective beyond the first line of treatment. Antibody–drug conjugates (ADCs) like sacituzumab govitecan-hziy (SG) represent a significant advancement. SG combines SN-38, an irinotecan derivative, with a Trop-2-targeting antibody via a pH-sensitive linking moiety, achieving a good drug:antibody ratio. In a phase I-II study involving metastatic TNBC (mTNBC) individuals, SG achieved an overall response rate of 33.3% and a median response period of 7.7 months. The phase III ASCENT trial demonstrated SG’s efficacy in relapsed or refractory TNBC, improving median progression-free survival and median overall survival compared to chemotherapy. Common side effects include neutropenia, nausea, and fatigue. This article highlights the clinical potential, pharmacokinetics, safety profile, and resistance mechanisms of SG along with key ongoing clinical trials, emphasizing its role in managing refractory mTNBC, especially in third-line therapy. The review also discusses current strategies for managing adverse reactions and sequencing ADC treatments in clinical practice, along with the predicted basis of resistance. The optimal sequencing of SG relative to other ADCs, such as trastuzumab deruxtecan or T-DXd, remains an evolving question, especially as newer agents with distinct mechanisms of action and safety profiles enter the field. Further research is essential to establish evidence-based strategies for sequencing SG and addressing disease progression post-ADC therapy. Full article

Breast cancer is the most frequently diagnosed neoplasm all over the world and the second leading cause of cancer death in women. Breast cancer prognosis has significantly improved in the last years due to the advent of novel therapeutic options, both in the early and in advanced stages. However, the spread of the disease to the brain, accounting for 15–30% of the metastatic diagnoses, is challenging, and its poor prognosis represents an unmet medical need, leading to deterioration of quality of life and causing morbidity and mortality. Generally, triple-negative and HER2-positive breast cancer subtypes more frequently spread to the brain or in the leptomeningeal space. Consequently, according to international guidelines, several systemic treatments can be offered as a first option in some subsets of patients. However, a multidisciplinary approach is recommended to offer the most appropriate strategy to patients. Antibody–drug conjugates such as trastuzumab deruxtecan or sacituzumab govitecan along with small molecules have led to important achievements in the treatment of brain metastases from HER2-positive and triple-negative breast cancer. In this narrative review, we will focus on the molecular features leading to the development of brain metastases and explore the risk and the prognostic factors involved in the development of brain metastases. Finally, we will review the major achievements in the treatment landscape of brain metastases from breast cancer and novel medical approaches. Full article