Introduction:Trastuzumab deruxtecan (T-DXd) has transformed treatment for HER2-expressing malignancies, yet pneumonitis remains a potentially fatal toxicity. Most pneumonitis data derive from breast cancer cohorts, but risk factors and outcomes in non-breast solid organ tumors are poorly characterized. Materials and Methods:We conducted a retrospective, single-center cohort study of adults with advanced non-breast solid organ tumors receiving T-DXd in routine clinical practice at a comprehensive cancer center (January 2019-May 2025). Pneumonitis was defined as new or worsening radiographic infiltrates not developing due to infection, disease progression, or an alternative etiology. Cumulative incidence was estimated using competing-risk methods. Fine-Gray subdistribution hazard regression identified risk factors, and extended Cox proportional hazards regression assessed the association between pneumonitis and overall survival. Results:Among 99 patients (median age, 65 years; 61% female), primary tumor sites included lung (43%), gynecologic (28%), gastrointestinal or esophageal (15%), and other (14%). Pneumonitis occurred in 11 patients (11.1%), predominantly among those with lung cancer (20.9% vs 3.6% non-lung; p = 0.009). Median time to onset was 144 days. Grade 5 pneumonitis occurred in three patients. In univariable competing-risk analysis, a higher T-DXd dose (subdistribution hazard ratio [sHR], 2.43; p = 0.001) and a short washout from prior therapy (≤14 days; sHR, 4.62; p = 0.01) were associated with pneumonitis. In the lung cancer subgroup, current smoking was associated with pneumonitis in an exploratory adjusted model (sHR, 3.55; p = 0.002). Pneumonitis was associated with a 3-fold increased mortality risk in adjusted time-varying Cox analysis (HR, 3.26; p = 0.003). Conclusion:T-DXd-associated pneumonitis disproportionately affects patients with lung cancer and confers substantial mortality risk. A higher T-DXd dose and a short interval from prior therapy may increase pneumonitis risk but require validation in larger cohorts.
Introduction:Pembrolizumab-based neoadjuvant chemoimmunotherapy following the KEYNOTE-522 regimen (NCT03036488) is a standard treatment approach for stage II and III triple-negative breast cancer (TNBC). Real-world evidence on the impact of germline BRCA status on pathologic complete response (pCR) and survival outcomes remains limited. Methods:We performed a retrospective single-center cohort study of patients with stage II-III TNBC treated with a KEYNOTE-522 regimen between January 2021 and December 2023. Only patients with documented germline BRCA status were included. The primary end point was pCR rate, defined as achievement of ypT0/is ypN0. Secondary end points included treatment delivery (completion and early discontinuation), postneoadjuvant systemic therapy patterns, recurrence-free survival (RFS), and overall survival (OS). Categorical variables were compared using Fisher's exact test, and survival outcomes were estimated using Kaplan-Meier methods and compared with log-rank tests. Results:Among 1004 patients with breast cancer screened between 2021 and 2023, 125 had TNBC. After exclusion of patients who did not receive a KEYNOTE-522 regimen, had metastatic disease, underwent definitive surgery before neoadjuvant systemic therapy, had unretrievable BRCA status, or had other missing key eligibility data, 54 patients were eligible for analysis. The final cohort included 11 patients who were BRCA+ and 43 who were BRCA-. The BRCA+ patients were younger than BRCA- patients (median 38 vs 46 years; p = 0.018). pCR was evaluable in 52 patients and was achieved in 31 of 52 patients (60%) overall; pCR was numerically higher in BRCA+ vs BRCA- patients (73% [8 of 11] vs 56% [23 of 41]; p = 0.49). Median follow-up was 25 months. Two-year RFS was 100% in BRCA+ and 75.4% in BRCA- patients (log-rank p = 0.068), whereas 2-year OS was 100% and 88%, respectively (log-rank p = 0.272). Within the BRCA+ subgroup, the prognostic significance of pCR could not be assessed because no recurrence or death events were observed during follow-up. Within the BRCA- subgroup, pCR strongly stratified prognosis, with 2-year RFS of 100% in patients achieving pCR vs 45.5% in those without pCR (log-rank p = 0.00004), and 2-year OS of 100% vs 72.7%, respectively (log-rank p = 0.018). Conclusions:Germline BRCA positivity was associated with a numerically higher pCR rate, but differences in pCR and survival by BRCA status were not statistically significant. Given the limited sample size and low event counts, these findings should be considered hypothesis-generating. Recurrence events clustered in BRCA- patients and were driven predominantly by those without pCR, supporting further study of optimized postneoadjuvant escalation strategies for residual BRCA- disease.
A rapidly advancing class of engineered immunoglobulins, known as bispecific antibodies (bsAbs), that bind two distinct antigens offers new approaches for tumor targeting and immune modulation. BsAbs function as immune cell engagers, immune checkpoint modulators, or signaling pathway inhibitors. They differ in half-life, stability, and tissue penetration depending on whether they exist in crystallizable fragment (Fc)-based or fragment-based formats. Although bsAbs have shown strong efficacy in hematologic malignancies, their translation to solid tumors has been limited by antigen heterogeneity, off-tumor toxicity, and the immunosuppressive tumor microenvironment. Recent clinical advancements have led to eight approved bsAbs for solid tumors, including amivantamab for EGFR (epidermal growth factor receptor) exon 20 insertion-mutated non-small cell lung cancer (NSCLC), tebentafusp for uveal melanoma, cadonilimab for cervical cancer, tarlatamab for small cell lung cancer, ivonescimab for PD-L1 (programmed death-ligand 1)-positive NSCLC, zanidatamab for HER2 (human epidermal growth factor receptor 2)-amplified biliary tract cancer, zenocutuzumab for NRG1 (neuregulin 1) fusion-positive tumors, and catumaxomab for malignant ascites. These agents have demonstrated durable clinical benefit with manageable safety profiles. However, class-related toxicities such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and on-target off-tumor effects remain important challenges. Advances in Fc silencing, affinity tuning, and tumor-restricted activation have improved therapeutic selectivity and tolerability. Ongoing innovations include bsAb-drug conjugates, proteolysis-targeting chimeras (PROTACs), and multispecific antibody platforms designed to reprogram the tumor microenvironment and enhance immune infiltration. Biomarker-driven patient selection and rational combination strategies are expected to further improve outcomes. As engineering technologies mature, bsAbs are expected to become integral to precision oncology, expanding safe and effective immunotherapy options for patients with solid tumors. This review aims to provide a comprehensive overview of the mechanisms, clinical applications, challenges, and future directions of bsAbs in solid tumors.
SMARCA4 is an ATPase subunit in the switch/sucrose non-fermentable complex (SWI/SNF), a chromatin-remodeling complex. SMARCA4 provides energy for the SWI/SNF complex to regulate gene expression through chromatin structural rearrangement and transcription regulation. In SMARCA4-deficient cancers, its paralog SMARCA2 is sometimes upregulated and can serve as a pharmacological target. Of the 20-25% of cancers identified to have a mutation in a gene encoding a protein for the SWI/SNF complex, 15% of these alterations include SMARCA4 alterations. Therefore, SMARCA4-directed therapies are under investigation in clinical trials and are a promising new strategy for treating patients with a SMARCA4-mutated cancer. Currently, all published clinical trials of SMARCA4-directed therapies are for orally bioavailable small-molecule inhibitors. Clinical trials without results include small-molecule inhibitors, monoclonal antibodies, and a bifunctional MabPair product. The aim of this literature review was to summarize the current SMARCA4-directed therapies in oncology clinical trials.
Prostate cancer is the most common non-cutaneous malignancy affecting men in the United States, with the incidence of metastatic disease rising. Despite modern androgen deprivation therapy (ADT), nearly all cases of metastatic prostate cancer develop castration resistance. Informed by successes in the treatment of metastatic castration-resistant prostate cancer (mCRPC), novel treatment modalities have emerged as part of the armamentarium for metastatic hormone-sensitive prostate cancer (mHSPC). In this review, we detail treatments such as cytotoxic chemotherapy, androgen receptor pathway inhibitors (ARPIs), radiotherapy, radiopharmaceutical therapy, immunotherapy, and poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of mHSPC, synthesizing current evidence and guiding clinical decision-making. With technological advances and insight from molecular studies, we discuss emerging biomarkers as indicators to guide prognostication and therapeutic decisions. As a result of these developments, the treatment landscape for mHSPC is evolving toward a precision oncology paradigm incorporating combined systemic therapies.
Background: High-grade gliomas are associated with dismal outcomes and have devastating neurologic sequelae. Standard-of-care surgery, radiation, and temozolomide yield a median survival of 14-16 months in patients with glioblastoma (GBM). Methods: We report four patients with high-grade glioma (two with GBM; one initially diagnosed with GBM, now classified as World Health Organization grade 4 IDH1-mutant astrocytoma; and one with oligosarcoma [grade 4]). Tumor next-generation sequencing (NGS) was performed for all four patients, and they were treated based on their biomarkers. Results: NGS yielded actionable alterations targeted after conventional surgery/chemoradiation therapy: imatinib (for KIT and PDGRA amplification) and bevacizumab (for KDR [VEGFR2] amplification); everolimus (mTOR inhibitor for TSC2 and PTEN loss-of-function alterations); and ivosidenib (IDH1 inhibitor for IDH1 mutations in two cases, including the oligosarcoma). Three patients remain in radiographic and clinical remission at 39+, 48, and 52+ months; the patient with oligosarcoma showed clinical and imaging response lasting 8 months. Conclusions: Our exceptional responders with high-grade gliomas suggest that biomarker-matched targeted therapy can benefit select patients with high-grade glioma and warrants prospective clinical trials.
Introduction:Prognosis of metastatic pancreatic cancer remains poor. KRAS mutations are common in pancreatic cancer and are an attractive therapeutic target. Based on a next-generation mechanistic dynamic model, we hypothesized that a combination of type I½ RAF inhibitor (vemurafenib) and type II RAF inhibitor (sorafenib) would have clinical activity in KRAS-mutated advanced pancreatic cancer. Methods:We conducted an open-label pilot phase II trial of vemurafenib and sorafenib combination in advanced pancreatic cancer with KRAS mutations. Eligible patients had progressed on two or more prior treatment regimens, had adequate performance status, adequate organ function and measurable disease, and were able to swallow oral medication. The primary objective was disease control rate (partial or complete response or stable disease ≥ 16 weeks). Secondary objectives included safety, progression-free (PFS) and overall survival (OS), and changes in plasma phospho-ERK and phospho-AKT. Results:Nine patients with KRAS-mutated pancreatic cancer were enrolled. The median age was 62.8 years and the median prior lines of treatment was 3. Four of the initial five patients had treatment interruption due to adverse events, and the subsequent four patients were treated at a reduced dose. Three grade 3 adverse events were reported and included anemia (n = 1), hypophosphatemia (n = 1), and maculopapular rash (n = 1); rash and anemia were deemed treatment related. Disease control rate was 0%. Median PFS was 1.6 months (95% CI, 0.5-not available), and median OS was 2.9 months (95% CI, 0.6-5.4). Compared to baseline, the best response for relative plasma phospho-ERK levels were -39 to +11% and -32 to +49% for plasma phospho-AKT levels. Conclusion:The combination of vemurafenib and sorafenib in KRAS-mutated refractory pancreatic cancer did not yield disease control in this pilot phase II study. The lack of clinical efficacy may be due to inadequate inhibition of RAS-to-ERK signaling as toxicities necessitated dose reduction. Clinicaltrialsgov ID:NCT05068752.
The class II major histocompatibility complex transactivator (CIITA) is a non-DNA-binding master regulator of major histocompatibility complex class II (MHC-II) gene expression, essential for antigen presentation and adaptive immunity. Functioning as a scaffold, CIITA recruits chromatin remodelers and transcription coactivators to form the MHC-II enhanceosome, facilitating transcriptional activation. CIITA expression is tightly regulated through four promoters and is subject to both cytokine-induced and epigenetic control. Dysregulation of CIITA underpins several immune-related disorders. Its deficiency results in bare lymphocyte syndrome, a severe immunodeficiency. Variants in the CIITA gene have been implicated in autoimmune diseases, graft rejection, and immune dysregulation. Chromosomal translocations involving CIITA are among the most common genomic alterations in some B-cell lymphomas. Additionally, pathogens such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), and hepatitis B virus (HBV) exploit CIITA suppression to evade immune surveillance. In oncology, epigenetic silencing of CIITA contributes to MHC-II downregulation and tumor immune evasion. Restoration of CIITA expression enhances tumor immunogenicity, T cell infiltration, and responsiveness to immunotherapy. CIITA also modulates the tumor microenvironment, influences prognosis, and has therapeutic relevance in hematologic and solid tumors. Its multifunctional role positions CIITA as a critical immune regulator and a promising therapeutic target in cancer immunotherapy, antiviral strategies, and immune modulation.
The AXL receptor tyrosine kinase is a transmembrane protein commonly overexpressed in both solid and hematologic malignancies. AXL plays a role in malignant cell growth, survival, proliferation, and adaptive immunity. As such, AXL overexpression is correlated with a worse prognosis. Drugs impairing the function of AXL are currently in development as monotherapies and in combination with other agents and have displayed antitumor efficacy in preclinical models, including tumors with AXL overexpression. AXL inhibitors have demonstrated preliminary antitumor activity in clinical trials and have generally been well tolerated, with the most common side effects including neutropenia, diarrhea, fatigue, nausea, and anemia. This clinical review aims to provide a comprehensive summary of published information from clinical trials investigating AXL inhibitors as monotherapies or in combination regimens.
Introduction:Enadenotucirev (EnAd) and successor transgene-armed Tumor-Specific Immuno-Gene (T-SIGn) vectors are replication-competent, blood-stable viral vectors that traffic to tumor sites following intravenous (IV) administration. Following initial proof of mechanism for this immunotherapy modality, there is a need to identify a safe dosing approach, understand whether transgenes affect tolerability, and determine how to measure exposure and pharmacodynamic effects. Methods:Safety data from multiple phase 1 trials were aggregated to assess various dosing regimens and toxicities, including those that may be associated with transgene arming. Viral delivery to tumors, peripheral viral persistence, transgene expression, and cytokine responses were also assessed and compared between the unarmed EnAd and armed T-SIGn vectors. Results:IV administration of EnAd and the armed T-SIGn vectors led to virus detection in epithelial tumors and prolonged peripheral virus persistence. Despite the short half-life of the viruses and cell-free nucleic acids, viral DNA or transgene messenger RNA (mRNA) remained detectable in blood at higher dose levels for at least 56 days, indicating sustained release of these molecules likely driven by ongoing viral replication and concomitant transcription of the transgene in tumors. Safety, predominantly defined by the effects of IV administration and associated viremia, was managed by a well-tolerated dosing regimen. To date, no transgene-related or off-target toxicities have been observed. Transient monocyte chemoattractant protein 1 (MCP-1) and interleukin (IL)-6 elevations were associated with viremia. A second phase of elevations of proinflammatory cytokines such as IL-12p70, interferon (IFN) α2, IL-17A, and IFNγ without clinical symptoms started around day 12, suggesting that release of these cytokines was driven by localized pharmacodynamic effects within the tumor microenvironment (TME). Conclusion:Armed T-SIGn vectors exhibit the same high tumor selectivity and replicative activity as the unarmed parent EnAd and achieve consistent viral delivery to a broad range of epithelial tumor tissues. The aggregated safety analysis revealed that safety and tolerability are defined by systemic viremia but not off-target or transgene-related toxicities. Nucleic acid and cytokine release from tumors and changes in the TME (e.g., CD8+ T cells), indicative of the mechanism of action of replication-competent viral vectors, constitute potentially valuable data to support the definition of a recommended phase 2 dose and the assessment of the benefit of multicycle administration.
Introduction:This study aims to document patient characteristics, treatment modalities, and survival outcomes of patients with lung cancer in Vietnam from 2018 to 2024. Methods:This was a retrospective study of patients with lung cancer treated at Nghe An Oncology Hospital over a 6-year period (2018-2024). The primary endpoints included lung cancer treatment methods for non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) and overall survival (OS). Secondary endpoints involved factors related to survival duration. Results:A total of 3548 patients were included: 3087 with NSCLC (87%) and 419 with SCLC (11.8%) (median age 64 years, range 18-97 years; 3:1 male-to-female ratio). Adenocarcinoma (AC) was the predominant histologic subtype (67%), followed by squamous cell carcinoma (SCC) (13.4%). EGFR mutation was detected in 43.2% of cases. From 2018 to 2024, the proportion of early-stage lung cancer diagnoses (stages I and II) increased from 2.7% to 9%, and the detection rate of advanced or metastatic stages (stages III and IV) decreased. Surgery was the primary treatment for localized NSCLC (62.5%), and stage III cases predominantly received radiation and chemotherapy (40.8%), including 38.6% with concurrent chemoradiotherapy. In stage IV NSCLC, chemotherapy was the most common treatment (53.9%), followed by targeted therapy (25.2%) and immunotherapy (1.9%). SCLC was mostly diagnosed at the extensive stage (68.0%), with chemotherapy being the mainstay of treatment (73.0%), followed by chemoradiotherapy (12.9%) and palliative care (13.1%). Median OS was 15.3 months (95% CI, 14.5-16.1), with a 5-year survival rate of 14.2%. Median OS for NSCLC cases was 16.4 months (95% CI, 15.4-17.4), with 5-year survival rates of 55.2%, 47.6%, 20.2%, and 8.3% for stages I, II, III, and IV, respectively. Median OS for SCLC cases was 11.0 months (95% CI, 9.7-12.4), with a 5-year survival rate of 4.7%. Independent prognostic factors for mortality included male sex, poor performance status (PS ≥ 2), small cell histology, metastatic disease, brain metastases, and initial nonsurgical treatment. Conclusion:This study provides critical data on the epidemiology and prognosis of lung cancer in Vietnam, highlighting the role of personalized treatment approaches in improving clinical outcomes. These findings underscore the urgent need for integrated public health strategies to enhance early detection and access to advanced therapies, thereby reducing the lung cancer burden in Vietnam.
Over the past decade, the discovery of immunotherapy and targeted therapy has set new standards for the management of advanced non–small cell lung cancer (NSCLC). This study aims to investigate the prevalence of ALK, EGFR, KRAS, ROS1, MET, BRAF, and HER2 mutations in patients with NSCLC within the Middle East and North Africa (MENA) region and to assess the current state of molecular testing and targeted treatments in the Gulf Cooperation Council (GCC) region. The systematic literature review was performed using PubMed, Google Scholar, and Google searches to identify studies on the prevalence of ALK, EGFR, KRAS, ROS1, MET, BRAF, and HER2 mutations in patients with NSCLC in the MENA region. Additionally, 10 experts from the GCC region were interviewed to provide insights into molecular mutation testing, the challenges faced, and the current approaches to targeted therapies. The prevalence of ALK, EGFR, KRAS, ROS1, MET, and BRAF mutations was 7.9% (95% CI, 6.69–9.03%), 24% (95% CI, 22.05–25.41%), 19.7% (95% CI, 15.29–24.07%), 2.2% (95% CI, 0.77–3.57%), 4.7% (95% CI, 2.29–7.07%) and 3.7% (95% CI, 1.54–5.80%), respectively. HER2 mutation data were unavailable. Treatment generally adhered to international guidelines, with therapy selection based on tumor stage, molecular profile, and drug availability. Expert opinions highlighted significant advancements in molecular diagnostics and targeted therapies but also pointed out the challenges in standardizing and implementing these techniques across the GCC region. This review underscores the importance of personalized and region-specific approaches to NSCLC treatment, given the significant differences in mutation patterns in the MENA region. Further research is needed to gain a more comprehensive understanding of the prevalence and effect of driver mutations across broader MENA countries to inform future treatment strategies.
Introduction:Patients with advanced solid tumors may be considered for early phase clinical trials investigating the safety, tolerability, and dosing of experimental therapies. Optimizing participant selection is critical to maximize clinical benefit and meet trial endpoints with fewer participants. One in six participants does not meet routine life expectancy requirements (>3 months), highlighting the need for improved prognostication. Variant allele frequency (VAF) in circulating tumor DNA (ctDNA) correlates with overall survival (OS) in advanced solid tumors. We aimed to derive an optimal VAF threshold as a prognostic biomarker to enhance participant selection. Methods:ctDNA testing was performed as part of the TARGET (NIHR Clinical Research Network CPMS ID 39172) and TARGET National (NCT04723316) prospective cohort studies, in patients with advanced solid tumors referred for early phase clinical trials. Maximum (maxVAF) and mean VAF (meanVAF) were compared in their association with OS and ability to delineate favorable and poor outcomes at set threshold points using hazard ratios (HRs). Optimal thresholds of VAF were explored using receiver operating characteristic curve analysis to predict 3-month landmark OS. Univariable and multivariable analysis was performed to determine whether VAF was an independent prognostic marker. Results:Of 631 patients, 587 had evaluable ctDNA results. MeanVAF and maxVAF exhibited similar correlation with OS (rs = -0.32 vs -0.35, respectively) and similar prognostic utility at matched threshold points. A maxVAF value of 4% was selected as optimal for prognostic subgrouping (area under curve 0.77). OS was 5.9 versus 12.1 months (p < 0.0001) for patients with more than 4% and 4% or less maxVAF, respectively. Multivariable analysis confirmed more than 4% maxVAF as independently associated with reduced 3-month landmark OS (HR 2.17 [1.76-2.70], p < 0.001). Conclusion:VAF is an independent prognostic marker in patients with advanced solid tumors, with 4% maxVAF deemed optimal for delineating favorable and poorer prognostic subgroups in this patient cohort. Further validation and integration into existing prognostic scores are warranted.
Pulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive subtype of non-small cell lung cancer (NSCLC) with limited treatment options and poor prognosis. EGFR mutations generally respond to tyrosine kinase inhibitors (TKIs)-based targeted therapy but are typically associated with resistance to immunotherapy. We report a case of oligometastatic PSC harboring compound EGFR mutations (p.G719C and S768I). The patient exhibited disease progression despite sequential treatment with EGFR TKIs, including osimertinib, afatinib, and mobocertinib, in combination with chemotherapy. The treatment strategy was then shifted to immunotherapy with pembrolizumab alongside carboplatin and paclitaxel, leading to a remarkable response. Given the oligometastatic nature of the disease and the sustained response, bilateral adrenalectomy was performed, revealing a complete pathological response. The patient remains disease-free posttreatment, with no evidence of recurrence on follow-up imaging. This case challenges the conventional paradigm that EGFR-mutated NSCLC does not benefit from immunotherapy, highlighting the potential for an alternative treatment approach in rare subtypes such as PSC. Our findings emphasize the importance of comprehensive molecular profiling and a personalized treatment strategy to optimize outcomes in aggressive and refractory lung cancers.
The combination of targeted therapies and immunotherapies for advanced and metastatic sarcomas has been proposed owing to the enhanced effect of antiangiogenic therapies on the tumor microenvironment. We found eight studies published to date assessing the effectiveness of combined multitargeted vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitors with immune checkpoint inhibitors (ICIs) in sarcoma. It is difficult to draw conclusions owing to limited data and primarily single-arm studies, although initial literature appears promising and requires further study. It remains unknown which sarcoma subtypes may derive the most benefit owing to the limited literature. Benefit was seen primarily in angiosarcoma (AS) and alveolar soft part sarcoma (ASPS), as well as in other tumor subtypes, with few patients achieving complete response (CR). The patients who achieved CRs had desmoplastic small round cell tumor (DSRCT), AS, and chondrosarcoma (CS). Mixed results were found in patients with leiomyosarcoma (LMS), gastrointestinal stromal tumor (GIST), and bone sarcomas, although combination therapy appears to be less effective in these subtypes. Further studies are required to explore optimal treatment agents and dosing strategies to improve both efficacy and tolerability. Although initial results are promising in select patients, phase 3 randomized controlled trials are necessary to determine true treatment effect with combination therapy versus VEGF-inhibitor or ICI alone.
