Antibody-Drug Conjugates in Non-Small Cell Lung Cancer: Emergence of a Novel Therapeutic Class.

PURPOSE OF REVIEW: Antibody-drug conjugates (ADCs) are a class of therapeutics that combine target-specific monoclonal antibodies with cytotoxic chemotherapy. Here, we describe the components of ADCs and review their promising activity, safety, and applicability in non-small cell lung cancer (NSCLC). RECENT FINDINGS: Technological advancements have reinvigorated ADCs as a viable treatment strategy in advanced solid tumors. Several target-specific ADCs have shown promise in treatment-refractory NSCLC, including agents targeting HER2, HER3, TROP2, CEACAM5, and MET, among others, with multiple confirmatory phase 3 trials ongoing. Critically, ADCs have demonstrated efficacy signals in both driver mutation-positive and mutation-negative advanced NSCLC, reinforcing their potential as an efficacious treatment strategy that transcends diverse tumor biology in advanced NSCLC. ADCs are a promising class of anti-cancer therapeutics that have significant potential in advanced NSCLC. Beyond confirmatory phase 3 trials, several questions remain including optimal agent sequencing, combinatorial methods, and unique toxicity management.

Transplant Eligible and Ineligible Elderly Patients with AML-A Genomic Approach and Next Generation Questions.

The management of elderly patients diagnosed with acute myelogenous leukemia (AML) is complicated by high relapse risk and comorbidities that often preclude access to allogeneic hematopoietic cellular transplantation (allo-HCT). In recent years, fast-paced FDA drug approval has reshaped the therapeutic landscape, with modest, albeit promising improvement in survival. Still, AML outcomes in elderly patients remain unacceptably unfavorable highlighting the need for better understanding of disease biology and tailored strategies. In this review, we discuss recent modifications suggested by European Leukemia Network 2022 (ELN-2022) risk stratification and review recent aging cell biology advances with the discussion of four AML cases. While an older age, >60 years, does not constitute an absolute contraindication for allo-HCT, the careful patient selection based on a detailed and multidisciplinary risk stratification cannot be overemphasized.

Molecular profiling METex14+ non-small cell lung cancer (NSCLC): Impact of histology.

OBJECTIVES: MET exon 14 skipping alterations (METex14+) represent a heterogeneous subgroup of non-small cell lung cancer (NSCLC) with distinct biological and genomic features. We characterized this heterogeneity in a large cohort, integrating genomic and transcriptomic profiling with clinical outcomes, to elucidate the histologic and molecular traits and survival patterns of METex14+ NSCLC. MATERIALS AND METHODS: NSCLC tissue samples (n = 28,739) underwent DNA-based next-generation sequencing (592 genes, NextSeq) or whole-exome sequencing (NovaSeq), RNA-sequencing including whole transcriptome sequencing (WTS, NovaSeq), and PD-L1 IHC (Dako 22C3) at Caris Life Sciences. Immune cell fractions were estimated from bulk RNA sequencing (quanTIseq). Real-world survival data (mOS) was calculated from insurance claims. Statistical analyses employed Chi-square, Fisher's exact, or Mann-Whitney U and log-rank tests and were corrected for hypothesis testing where applicable. RESULTS: A total of 711 METex14+ cases were detected. Of 575 cases of defined histology, 77 (13.6 %) were squamous (Sq), 474 (82.3 %) were nSq (non-squamous), and 24 (4.1 %) were adenosquamous. Mutations in POT1 and BRCA2 were enriched, and amplifications in MDM2, HMGA2, CDK4, and MET were common in METex14+ tumors. TMB-high and TP53 mutated tumors were reduced in METex14+ independent of histology. KEAP1 (2.1 vs 14.7 %) and STK11 mutations (0.8 vs 17.1 %) were reduced only in METex14+ nSq (vs METex14+ Sq, q < 0.05). While the prevalence of PD-L1 high tumors was enriched in METex14+ independent of histology, T-cell inflamed tumors were enriched only in nSq METex14+. B-cells and CD8+ T-cells (1.07-1.43-fold) were enriched in nSq METex14+, and dendritic cells (0.32 fold) were reduced only in METex14+ Sq. METex14+ tumors had a modest improvement in mOS compared to METex14- tumors (mOS = 22.9 m vs 18.6 m, HR = 0.914, p = 0.04). Moreover, METex14+ tumors who received immunotherapy (IO) had a modest improvement in survival (mOS = 27.5 m vs 21.8 m; HR = 0.803, p = 0.03) compared to those who did not receive IO. METex14+ nSq tumors were associated with improved mOS compared to METex14+ Sq tumors (mOS = 27.7 vs 8.9 m, HR = 0.493, p < 0.0001). CONCLUSION: METex14+ alterations are a heterogeneous subgroup of NSCLC. Our analysis reveals that METex14+ nSq exhibit improved survival compared to METex14+ Sq. The distinct genomic and transcriptomic variations across histologies warrant clinical consideration.

NSCLC With Synchronous EGFR Mutations in Li Fraumeni Syndrome: A Case Report.

We report a case of a patient with Li Fraumeni Syndrome (LFS) who developed synchronous EGFR exon deletion 19 and EGFR exon 20 insertion NSCLC and characterize the diagnostic and therapeutic challenges in managing her care. Osimertinib was effective in the EGFR deletion 19 population but did not garner a response in the EGFR exon 20 insertion population, which was treated definitively with surgical resection. At the time of oligoprogression, she underwent surgical resection, and radiation therapy was minimized. The biologic link between LFS and EGFR mutation remains unclear, and using larger, real-world cohorts could help to clarify the relationship between LFS and EGFR-mutant NSCLC.

TP53 in AML and MDS: The new (old) kid on the block.

MDS and AML are clonal hematopoietic stem cell disorders of increasing incidence, having a variable prognosis based, among others, on co-occurring molecular abnormalities. TP53 mutations are frequently detected in these myeloid neoplasms and portend a poor prognosis with known therapeutic resistance. This article provides a timely review of the complexity of TP53 alterations, providing updates in diagnosis and prognosis based on new 2022 International Consensus Classification (ICC) and World Health Organization (WHO) guidelines. The article addresses optimal testing strategies and reviews current and arising therapeutic approaches. While the treatment landscape for this molecular subgroup is under active development, further exploration is needed to optimize the care of this group of patients with unmet needs.

Remarkable Intracranial Response to Sotorasib in a Patient With KRAS G12C-Mutated Lung Adenocarcinoma and Untreated Brain Metastases: A Case Report.

Sotorasib is a KRAS G12C inhibitor that recently received approval for use in locally advanced or metastatic KRAS G12C-mutated NSCLC. CodeBreaK100, the phase 2 clinical trial leading to the approval of sotorasib, excluded patients with untreated brain metastases; there have been no reports describing efficacy of sotorasib on untreated brain metastases. We present a case of a patient with active untreated brain metastases with resulting disorientation and weakness who has radiographic response and complete resolution of neurologic symptoms with sotorasib. Our case illustrates the intracranial activity of sotorasib, but additional studies are needed to characterize the intracranial response rate and duration of response in these patients.

T-Cell Receptor Gene Rearrangement Clonality, Flow Cytometry Status, and Associated Outcomes in Early-Stage Cutaneous T-Cell Lymphoma.

IMPORTANCE: The prognostic significance of clonal T-cell receptor (TCR) rearrangement or low-level blood involvement as assessed by flow cytometry for patients with early-stage cutaneous T-cell lymphoma (CTCL) is not clear. OBJECTIVE: To assess the association of low-level blood involvement by TCR clonality and flow cytometry with outcomes for patients with early-stage CTCL. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort analysis was conducted from September 1, 2019, to February 29, 2020, of 322 patients with early-stage (I-IIA) CTCL seen at the Winship Cancer Institute of Emory University and Grady Memorial Hospital. T-cell receptor gene rearrangement and flow cytometry records from the peripheral blood were documented at initial assessment. EXPOSURES: T-cell receptor clonality and peripheral blood flow cytometry. MAIN OUTCOMES AND MEASURES: Univariate and multivariable models and Kaplan-Meier assessments were analyzed for overall survival (OS) and time to next treatment. The primary outcome was OS from diagnosis and time to next treatment, and the hypotheses were formulated prior to data collection. RESULTS: A total of 322 patients (166 female patients [51.6%]; median age at diagnosis, 53.8 years [range, 8.6-87.4 years]) with early-stage CTCL diagnosed from 1990 to 2018 were identified; of these, 258 had data available for both flow cytometry and TCR. Positive results for both TCR clonality and flow cytometry were associated with inferior OS in early-stage CTCL compared with both having negative results (hazard ratio [HR], 2.86; 95% CI, 1.02-8.06; P = .046). Positive results for only TCR clonality or only flow cytometry were not associated with OS (TCR clonality: HR, 1.31; 95% CI, 0.70-2.47; P = .40; flow cytometry: HR, 1.21; 95% CI, 0.58-2.52; P = .61) or time to next treatment (TCR clonality: HR, 1.05; 95% CI, 0.77-1.43; P = .76; flow cytometry: HR, 0.74; 95% CI, 0.47-1.16; P = .12). However, positive flow cytometry results were associated with reduced OS in the stage IIA subgroup (n = 94; HR, 1.17; 95% CI, 1.18-8.74; P = .02). Covariates associated with reduced survival included advanced age at diagnosis, male sex, and higher disease stage. CONCLUSIONS AND RELEVANCE: This cohort study of patients with early-stage CTCL suggests that low-level blood involvement as indicated by positive results for both TCR gene rearrangement and flow cytometry was associated with inferior OS, whereas positive results for either flow cytometry or TCR clonality was not. More precise measurements of blood involvement in CTCL and larger multi-institutional cohorts are needed to validate the prognostic significance of low-level blood involvement in early-stage CTCL.

Socioeconomic Factors Influence the Impact of Tumor HPV Status on Outcome of Patients With Oropharyngeal Squamous Cell Carcinoma.

PURPOSE: Human papilloma virus (HPV) association remains one of the most important predictors of clinical outcome in oropharyngeal squamous cell carcinoma (OPSCC). We aimed to determine whether the relationship between HPV status and overall survival was influenced by socioeconomic factors. MATERIALS AND METHODS: Using the National Cancer Database, we examined the relationship between socioeconomic status and overall survival, controlling for demographics and socioeconomic variables (age at diagnosis, race, sex, clinical stage, facility type, facility location, insurance status, median-income quartiles, percent of no high-school education quartiles, rural-urban dwelling, Charlson-Deyo score, primary site, and treatment type). RESULTS: HPV-positive patients with private insurance have improved overall survival compared with HPV-positive patients who are uninsured (hazard ratio [HR], 0.51, 95% CI, 0.41 to 0.63, P < .001). HPV-negative patients with private insurance have improved overall survival compared with HPV-negative patients who were uninsured (HR, 0.62, 95% CI, 0.53 to 0.73, P < .001). HPV-positive patients living in the south had improved overall survival compared with HPV-positive patients living in the west (HR, 0.83, 95% CI, 0.72 to 0.96, P = .013). As assessed through interaction, relationships between survival and insurance (P = .004), rural-urban status (P = .009), and facility location (P = .021) statistically differed between HPV-positive and HPV-negative patients. CONCLUSION: HPV status impact on overall survival for patients with OPSCC is influenced by socioeconomic factors including insurance status and treatment facility. A deeper understanding of these interactions is needed to improve equity of care for patients with OPSCC.

Ability of the borreliacidal antibody test to confirm lyme disease in clinical practice.

Highly specific borreliacidal antibodies are induced by infection with Borrelia burgdorferi, and a borreliacidal antibody test (BAT) may be an accurate laboratory procedure for confirming Lyme disease in clinical practice. To investigate this, 34 Lyme disease sera and 34 sera from patients with other illnesses who had presented to a primary-care facility located in an area of borreliosis endemicity were tested by the BAT and Western blotting (WB). The BAT was more sensitive (79% versus 65%; P = 0.090), especially in cases in which patients had a single erythema migrans lesion (P = 0.021). In addition, the potentially cross-reactive sera were negative by the BAT but WB yielded three (9%) false-positive results. The results from 104 sera from possible Lyme disease patients demonstrated the clinical usefulness of the more sensitive and specific BAT. The BAT was positive for 40 (38%) sera from patients with Lyme disease-related symptoms and appropriate clinical and epidemiological findings. WB confirmed Lyme disease in 30 (75%) of the 40 BAT-positive patients but failed to detect B. burgdorferi infection in 10 BAT-positive patients. WB was also positive for 11 BAT-negative sera, but six (55%) patients had case histories which suggested that the results were false positives. Collectively, the results confirm that the BAT is a sensitive and highly specific test and suggest that widespread use would increase the accuracy of serodiagnostic confirmation of Lyme disease.