BETA prime: a first-in-man phase 1 study of AdAPT-001, an armed oncolytic adenovirus for solid tumors.

AdAPT-001 is an oncolytic adenovirus (OAV) with a transforming growth factor beta (TGF-ß) trap, which neutralizes the immunosuppressive and profibrotic cytokine, TGF-ß. The aim or purpose of this phase 1 study was to assess the safety and tolerability and, secondarily, the efficacy of AdAPT-001 after single intratumoral injection (IT) (Part 1) and multidose IT injection (Part 2) in patients with superficially accessible, advanced refractory solid tumors. Part 1 enrolled 9 patients with a 3 + 3 single dose-escalation safety run-in involving 2.5 × 1011, 5.0 × 1011, 1.0 × 1012 viral particles (vps). No dose-limiting toxicities or treatment-related serious adverse events (SAEs) were seen. In Part 2, a dose-expansion phase, 19 patients received AdAPT-001 at 1.0 × 1012 vps until disease progression according to Response Evaluation Criteria in Solid Tumors or RECIST 1.1. The overall responses to treatment included confirmed partial responses (3), durable stable disease ≥ 6 months (5), and progressive disease (13). AdAPT-001 is well tolerated. Evidence of an anti-tumor effect was seen in both injected and uninjected lesions. The recommended Phase 2 dose was 1.0 × 1012 vp administered by intratumoral injection once every 2 weeks. Combination of AdAPT-001 with a checkpoint inhibition is enrolling.

Acquired resistance to KRAS G12C small-molecule inhibitors via genetic/nongenetic mechanisms in lung cancer.

Inherent or acquired resistance to sotorasib poses a substantialt challenge for NSCLC treatment. Here, we demonstrate that acquired resistance to sotorasib in isogenic cells correlated with increased expression of integrin ß4 (ITGB4), a component of the focal adhesion complex. Silencing ITGB4 in tolerant cells improved sotorasib sensitivity, while overexpressing ITGB4 enhanced tolerance to sotorasib by supporting AKT-mTOR bypass signaling. Chronic treatment with sotorasib induced WNT expression and activated the WNT/ß-catenin signaling pathway. Thus, silencing both ITGB4 and ß-catenin significantly improved sotorasib sensitivity in tolerant, acquired, and inherently resistant cells. In addition, the proteasome inhibitor carfilzomib (CFZ) exhibited synergism with sotorasib by down-regulating ITGB4 and ß-catenin expression. Furthermore, adagrasib phenocopies the combination effect of sotorasib and CFZ by suppressing KRAS activity and inhibiting cell cycle progression in inherently resistant cells. Overall, our findings unveil previously unrecognized nongenetic mechanisms underlying resistance to sotorasib and propose a promising treatment strategy to overcome resistance.

Stereotactic Body Radiation Therapy for Oligoprogressive and Oligorecurrent Non-Small-Cell Lung Cancer.

BACKGROUND AND PURPOSE: The role of stereotactic body radiation therapy (SBRT) in oligoprogressive non-small-cell lung cancer (NSCLC) is controversial. We evaluated whether SBRT in a subset of patients with oligoprogressive or oligorecurrent NSCLC offers a durable response, obviating the need to change systemic therapy. METHODS: A retrospective analysis of 168 NSCLC patients who underwent SBRT for oligoprogressive or oligorecurrent disease was performed. Oligoprogression was defined as progression in ≤5 lesions during or after systemic therapy following an initial complete or partial response. Oligorecurrence was defined as progression while off systemic therapy. Progression-free survival (PFS), overall survival (OS) and time to next treatment or death (TNT-D) were estimated. RESULTS: Median age was 68 years. Sixty-seven percent of patients were on systemic therapy at the time of progression. Progression at the primary site was present in 31% of the patients. The number of sites of metastatic progression was 0 to 2 in 76% and 3 to 5 in 24% of the patients. Two-year OS and PFS were 56% (95%CI 46%-64%) and 14% (95%CI 8%-21%), respectively. Median TNT-D was 9 months (95%CI 6-11). No grade 4 or 5 toxicity was seen. In multivariable analysis, patients with 3 to 5 sites of metastatic progression had worse OS (HR 2.6, 95%CI 1.5-4.3, P < .001) and shorter TNT-D (HR 1.7, 95%CI 1.1-2.5, P = .01) than those with 0 to 2 sites. CONCLUSION: SBRT is a safe and viable treatment option for oligoprogressive and oligorecurrent NSCLC. Patients with 0 to 2 sites had better OS and longer TNT-D compared to those with 3 to 5 lesions.

Targeted Therapies in Early-Stage Resectable Non-Small-Cell Lung Cancer: New Kids on the Block.

PURPOSE: With increased adoption of next-generation sequencing, tailored therapy on the basis of molecular status is being delivered for patients with early-stage resectable non-small-cell lung cancer (NSCLC). The purpose of this narrative review was to focus on recent developments of targeted therapies in the adjuvant and neoadjuvant/adjuvant setting for early-stage disease. METHODS: A systematic search of the MEDLINE/PubMed database was performed, focusing on studies published within the past 10 years. Our search queried "early-stage NSCLC (AND) tyrosine kinase inhibitor (TKI; OR) epidermal growth factor receptor (EGFR; OR) anaplastic lymphoma kinase (ALK)" and was limited only to prospective and ongoing studies. RESULTS: Most studies examining the benefit of targeted therapies in early-stage resectable NSCLC have been for EGFR-TKIs in the adjuvant setting. Currently, only one study, the ADAURA trial of adjuvant osimertinib, has demonstrated an overall survival benefit with the use of an EGFR-TKI in the adjuvant setting. Future work to build on the success of the ADAURA trial is focused on determining the optimal duration of targeted therapies and using biomarkers, such as circulating tumor DNA, to risk-stratify patients and guide maintenance targeted therapy duration. CONCLUSION: The results of several ongoing studies are eagerly awaited regarding the use of targeted therapies in the neoadjuvant/adjuvant setting and for more uncommon or rare mutations such as ALK, ROS proto-oncogene 1, rearranged during transfection, mesenchymal-epithelial transition factor, and B-Raf proto-oncogene V600E. The treatment landscape for early-stage NSCLC harboring actionable mutations is likely to shift dramatically in the upcoming decade.

Recurrent/Metastatic Nasopharyngeal Carcinoma Treatment from Present to Future: Where Are We and Where Are We Heading?

OPINION STATEMENT: Nasopharyngeal carcinoma (NPC) is distinct in its anatomic location and biology from other epithelial head and neck cancer (HNC). There are 3 WHO subtypes, which considers the presence of Epstein-Barr virus (EBV) and other histopathology features. Despite the survival benefit obtained from modern treatment modalities and techniques specifically in the local and locally advanced setting, a number of patients with this disease will recur and subsequently die of distant metastasis, locoregional relapse, or both. In the recurrent setting, the ideal therapy approach continues to be a topic of discussion and current recommendations are platinum-based combination chemotherapy. Phase III clinical trials which led to the approval of pembrolizumab or nivolumab for head and neck squamous cell carcinoma (HNSCC) specifically excluded NPC. No immune checkpoint inhibitor therapy, to date, has been approved by the FDA to treat NPC although the National Comprehensive Cancer Network (NCCN) recommendations do include use of these agents. Hence, this remains the major challenge for treatment options. Nasopharyngeal carcinoma is challenging as it is really 3 different diseases, and much research is required to determine best options and sequencing of those options. This article is going to address the data to date and discuss ongoing research in EBV + and EBV - inoperable recurrent/metastatic NPC patients.

Building Team Medicine in the Management of CNS Metastases.

CNS metastases are often terminal for cancer patients and occur at an approximately 10-fold higher rate than primary CNS tumors. The incidence of these tumors is approximately 70,000-400,000 cases annually in the US. Advances that have occurred over the past two decades have led to more personalized treatment approaches. Newer surgical and radiation techniques, as well as targeted and immune therapies, have enanled patient to live longer, thus increasing the risk for the development of CNS, brain, and leptomeningeal metastases (BM and LM). Patients who develop CNS metastases have often been heavily treated, and options for future treatment could best be addressed by multidisciplinary teams. Studies have indicated that patients with brain metastases have improved survival outcomes when cared for in high-volume academic institutions using multidisciplinary teams. This manuscript discusses a multidisciplinary approach for both parenchymal brain metastases as well as leptomeningeal metastases implemented in three academic institutions. Additionally, with the increasing development of healthcare systems, we discuss optimizing the management of CNS metastases across healthcare systems and integrating basic and translational science into our clinical care to further improve outcomes. This paper summarizes the existing therapeutic approaches to the treatment of BM and LM and discusses novel and emerging approaches to optimizing access to neuro-oncologic care while simultaneously integrating multidisciplinary teams in the care of patients with BM and LM.

Implications of updated staging system for p16+ oropharyngeal squamous cell carcinoma: Is valuable prognostic information being omitted?

BACKGROUND: This study characterized whether the updated AJCC 8th edition nodal staging system for p16+ oropharyngeal squamous cell carcinoma (OPSCC) resulted in the loss of prognostic value. METHODS: The NCDB was queried for patients with node-positive p16+ OPSCC. The prognostic impact of nodal size, nodal quantity, nodal laterality, and extracapsular extension (ECE) on overall survival (OS) was assessed. RESULTS: In the clinical cohort, inferior 5-year OS was observed in patients with more than one positive lymph node (p < 0.001; 82% vs. 86%), ECE (p < 0.001; 82% vs. 75%), or nodal size >6 cm (p < 0.001; 66% vs. 82%). In the pathologic cohort, inferior 5-year OS was observed in patients with > four positive lymph nodes (p < 0.001; 76% vs. 90%), ECE (p < 0.001; 83% vs. 92%), or largest nodal size >6 cm (p < 0.001; 81% vs. 89%). CONCLUSIONS: Simplifications in the current p16+ OPSCC staging system led to loss of prognostic information in nodal staging.

Tipifarnib Potentiates the Antitumor Effects of PI3Kα Inhibition in PIK3CA- and HRAS-Dysregulated HNSCC via Convergent Inhibition of mTOR Activity.

Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival (OS) ranging from 6 to 18 months. For those who progress on standard-of-care (chemo)immunotherapy, treatment options are limited, necessitating the development of rational therapeutic strategies. Toward this end, we targeted the key HNSCC drivers PI3K-mTOR and HRAS via the combination of tipifarnib, a farnesyltransferase (FTase) inhibitor, and alpelisib, a PI3Kα inhibitor, in multiple molecularly defined subsets of HNSCC. Tipifarnib synergized with alpelisib at the level of mTOR in PI3Kα- or HRAS-dependent HNSCCs, leading to marked cytotoxicity in vitro and tumor regression in vivo. On the basis of these findings, the KURRENT-HN trial was launched to evaluate the effectiveness of this combination in PIK3CA-mutant/amplified and/or HRAS-overexpressing R/M HNSCC. Preliminary evidence supports the clinical activity of this molecular biomarker-driven combination therapy. Combined alpelisib and tipifarnib has potential to benefit >45% of patients with R/M HNSCC. By blocking feedback reactivation of mTORC1, tipifarnib may prevent adaptive resistance to additional targeted therapies, enhancing their clinical utility. SIGNIFICANCE: The mechanistically designed, biomarker-matched strategy of combining alpelisib and tipifarnib is efficacious in PIK3CA- and HRAS-dysregulated head and neck squamous carcinoma and could improve outcomes for many patients with recurrent, metastatic disease. See related commentary by Lee et al., p. 3162.

Early Stage and Locally Advanced Nasopharyngeal Carcinoma Treatment from Present to Future: Where Are We and Where Are We Going?

OPINION STATEMENT: Nasopharyngeal carcinoma (NPC) is a rare malignancy, endemic in China, that is commonly diagnosed in locally advanced scenarios. Its pathogenesis is strongly associated with Epstein-Barr virus (EBV), an infection for which measuring EBV plasma DNA levels has helped as a prognostic factor guiding treatment options, including a stronger treatment in those with high titers. Additionally, tobacco and alcohol are often implicated in EBV-negative patients. The local disease is treated with radiotherapy alone, preferentially intensity modulated radiotherapy. For locally advanced disease, the backbone treatment is concurrent chemoradiotherapy with the ongoing research dilemma being adding adjuvant chemotherapy or induction chemotherapy. The ongoing research is focused not only on identifying patients that will benefit from adjuvant or induction chemotherapy, but also on identifying the best chemotherapeutic regimen, regimen alternatives to diminish toxicity, the role that immune checkpoint inhibitors play, and the use of molecularly guided treatment targeting patients with NPC whether driven by EBV or tobacco and alcohol. Knowing the precise oncogenesis of NPC not only offers a better understanding of the role that EBV plays in this tumor but also helps create targeted therapies that could potentially block important pathways such as the NF-κB pathway. Much is yet to be done, but the prognosis and management of NPC patients have changed drastically, offering precise treatment methods and excellent control of the disease, even in locally advanced scenarios.

Prognostic Role of Biologically Active Volume of Disease in Patients With Metastatic Lung Adenocarcinoma.

BACKGROUND: Number of metastatic sites can identify patient populations with non-small cell lung cancer (NSCLC) that benefit from aggressive therapy. Total volume of disease is also relevant. We evaluated the prognostic impact of biologically active volume of disease (BaVD) on patients with metastatic lung adenocarcinoma. MATERIALS AND METHODS: Positron emission tomography/computerized tomography (PET/CT) scans from patients with newly diagnosed lung adenocarcinoma prior to starting any therapy were identified. SUV thresholds of 3 and 4 were used to auto-contour all FDG avid areas. Kaplan-Meier analysis and Cox regression were performed to examine influence on OS. RESULTS: One hundred forty-eight patients were included in the analysis. The median BaVD when using an SUV threshold of 3 was 122.8 mL. The median BaVD when using an SUV threshold of 4 was 46.2 mL When stratified by median BaVD using an SUV of 3, median OS was higher for patients with <=122.8 mL (2.12 years) compared to patients with >122.8 mL (1.46 years) (log-rank P = .001). Similarly, when stratified by median BaVD using an SUV of 4, median OS was higher for patients with <=46.2 mL (1.91 years; 95% CI: 1.65-3.22 years) compared to patients with >46.2 mL (1.48 years; 95% CI: 1.07-1.80 years) (log-rank P = .007). On multivariable analysis, BaVD was significantly associated with OS when using an SUV threshold of 3 (HR: 20.169, P < .001) and 4 (HR: 4.117, P < .001). CONCLUSION: BaVD is an important prognostic factor in metastatic lung adenocarcinoma and may aid identification of patients with limited disease who may be candidates for more aggressive therapies.

Wolf in sheep's clothing - Oral proliferative verrucous leukoplakia: Progression with longitudinal molecular insights.

BACKGROUND: Oral proliferative verrucous leukoplakia (OPVL) is a chronic form of oral leukoplakia that progresses to a multifocal disease with confluent, exophytic and proliferative features. The clinical differential diagnosis for OPVL includes frictional keratosis, leukoplakia, chronic hyperplastic candidiasis, squamous papilloma, verrucous hyperplasia, verrucous carcinoma and squamous cell carcinoma. In this study, we aimed to delineate the dynamic changes in molecular signature during OPVL progression. We compare to a cohort of oral cavity keratinizing squamous cell carcinoma (OSCC) patients covering the spectrum of verrucous carcinoma to invasive squamous cell carcinoma including cytologically bland cuniculatum variant. METHODS: Samples from a large OPVL lesion that exhibited a histopathologic continuum of OPVL progression. RESULTS: Canonical hotspot TERT promoter mutations were identified in all patients. TERT C228T was dominant and mutually exclusive with TERT C250T. In patients with TERT C250T, there was concurrent PI3 point mutation. TP53 mutations were also consistently found (8/10). At the protein level, p53 was abnormal, with loss of function and gain of function. CONCLUSIONS: OPVL is a pathology that shows proximity to the gene expression profile of OSCC, highlighting signatures in common that can be important targets for drug treatment, as well as in the development of diagnostic and prognostic strategies for this disease.

Clinical and Molecular Features of KRAS-Mutated Lung Cancer Patients Treated with Immune Checkpoint Inhibitors.

Background: The molecular and clinical features of KRAS-mutated lung cancer patients treated with immunotherapy have yet to be characterized, which could guide the development of therapeutics targeting KRAS with potential immuno-oncology treatment combinations. Research Question: Do KRAS-mutated patients with different subtypes and comutations have different clinical responses and overall survival (OS) to checkpoint inhibitors? Study Design and Methods: 87 patients with NSCLC at the City of Hope who received immune checkpoint inhibitors were identified and analyzed retrospectively. Tumor genomic alterations were extracted from the clinical data with next-generation sequencing using various platforms. Demographic, clinical, molecular, and pathological information was collected with the approval of the institutional review board of the City of Hope. OS was calculated if it was available at the study time point, and responses were determined according to the RECIST v1.1. Results: Among 87 patients, 32 had a KRAS G12C mutation (36.8%), 19 had G12V (21.9%), 18 had G12D (20.7%), 6 had G12A (6.9%), 3 had G12R (3.45%), and 10 had amplification (11.49%) and other uncommon mutations. G12D had a statistically significant Odds Ratio (OR) between patients who had responses and progression of the disease (OR (95% CI) = 0.31 (0.09−0.95), p < 0.05), with 5 G12D-mutated patients having responses and 11 G12D-mutated patients having progression of the disease. In the univariate analysis with OS, there was a trend of better OS in the G12D-mutated patients, with no statistically significant difference in terms of OS between the patients who had G12D mutation and the patients who had other KRAS mutations (HR (95% CI) = 0.53 (0.21−1.36), p = 0.185). The median OS was significantly worse with KRAS comutation CDKN2A/B loss (4.2 vs. 16.9 months, HR = 3.07 (1.09−8.69), p < 0.05) and MET (3.4 vs. 17 months, HR = 3.80 (1.44−10.05), p < 0.01), which were included for the multivariate analysis. The OS with other KRAS comutations was not statistically significant, including STK11 and KEAP1. Conclusion: KRAS mutation subtypes such as G12D and comutations such as CDKN2/A and MET may modulate the immunotherapy responses and outcomes in lung cancer.

Ablative Radiotherapy as a Strategy to Overcome TKI Resistance in EGFR-Mutated NSCLC.

Tyrosine kinase inhibitor (TKI) therapy is the recommended first-line treatment for metastatic non-small-cell lung cancer (NSCLC) positive for epidermal growth factor receptor (EGFR) gene mutation. However, most individuals treated with TKI therapy for EGFR-mutant NSCLC will develop tumor resistance to TKI therapy. Therapeutic strategies to overcome TKI resistance are the topic of several ongoing clinical trials. One potential strategy, which has been explored in numerous trials, is the treatment of progressive sites of disease with stereotactic body radiation treatment (SBRT) or stereotactic radiosurgery (SRS). We sought to review the literature pertaining to the use of local ablative radiation therapy in the setting of acquired resistance to TKI therapy and to discuss stereotactic radiation therapy as a strategy to overcome TKI resistance.

BETA PRIME: Phase I study of AdAPT-001 as monotherapy and combined with a checkpoint inhibitor in superficially accessible, treatment-refractory solid tumors.

AdAPT-001 is an investigational therapy consisting of a replicative type 5 adenovirus armed with a TGF-ß receptor-immunoglobulin Fc fusion trap, designed to neutralize isoforms 1 and 3 of the profibrotic and immunosuppressive cytokine, TGF-ß. In preclinical studies with an immunocompetent mouse model, AdAPT-001 eradicated directly treated 'cold' tumors as well as distant untreated tumors, and, from its induction of systemic CD8+ T cell-mediated antitumor immunity, protected the mice from rechallenge with tumor cells. AdAPT-001 also sensitized resistant tumors to checkpoint blockade. This manuscript describes the rationale and design of the first-in-human phase I, dose-escalation and dose-expansion study of AdAPT-001 alone and in combination with a checkpoint inhibitor in adults with treatment-refractory superficially accessible solid tumors.

The purpose of this study is to find out more about the experimental oncolytic virus called AdAPT-001 that has been designed to selectively eliminate cancer cells. The virus is also designed to make a particular protein called a TGF-ß trap, which neutralizes TGF-ß, an overproduced chemical in cancer cells that puts the immune system into a comatose state. This article discusses a clinical trial called BETA PRIME for patients with no other standard treatment options. The trial will explore different doses of AdAPT-001 both alone and in combination with an approved checkpoint inhibitor or another immunotherapy, which blocks the 'off' signal on immune cells, to determine the safest and best dose. Clinical Trial Registration: NCT04673942 (ClinicalTrials.gov).

Phase I study of nab-paclitaxel-based induction followed by nab-paclitaxel-based concurrent chemotherapy and re-irradiation in previously treated head and neck squamous cell carcinoma.

BACKGROUND: Recurrent head and neck squamous cell carcinoma (HNSCC) is associated with poor overall survival (OS). Prior studies suggested incorporation of nab-paclitaxel (A) may improve outcomes in recurrent HNSCC. METHODS: This Phase I study evaluated induction with carboplatin and A followed by concomitant FHX (infusional 5-fluorouracil, hydroxyurea and twice-daily radiation therapy administered every other week) plus A with cohort dose escalation ranging from 10-100 mg/m2 in recurrent HNSCC. The primary endpoint was maximally tolerated dose (MTD) and dose-limiting toxicity (DLT) of A when given in combination with FHX (AFHX). RESULTS: Forty-eight eligible pts started induction; 28 pts started AFHX and were evaluable for toxicity. Two DLTs occurred (both Grade 4 mucositis) at a dose level 20 mg/m2. No further DLTs were observed with subsequent dose escalation. The MTD and recommended Phase II dose (RP2D) of A was 100 mg/m2. CONCLUSIONS: In this Phase I study, the RP2D of A with FHX is 100 mg/m2 (AFHX). The role of re-irradiation with immunotherapy warrants further investigation. CLINICAL TRIAL INFORMATION: This clinical trial was registered with ClinicalTrials.gov identifier: NCT01847326.

GITR agonistic stimulation enhances the anti-tumor immune response in a mouse model of ESCC.

Esophageal cancer is a significant health burden in the United States and worldwide and is the 8th leading cause of cancer-related death. Over 90% of esophageal cancers are squamous cell cancers (ESCC). Despite the development of new therapies, the overall 5-year survival rate remains lower than 20%. Recent clinical trials of immunotherapy approaches in ESCC have shown that blocking PD-1/PD-L1 interactions can reduce tumor burden and increase survival, but this only occurs in a fraction of patients. This emphasizes the need for additional therapeutic options to improve overall response rates, duration of response, and overall survival. Glucocorticoid-induced TNFR-related protein (GITR) stimulation has emerged as a promising immunotherapy target, as its stimulation appears to promote tumor regression. In this study, we evaluated the consequences of GITR agonistic stimulation with the DTA-1 antibody (anti-GITR agonist) on esophageal squamous cell carcinoma (ESCC) progression. Increased expression of GITR was observed in esophageal tumors from ESCC patients in comparison to normal adjacent tissue and in a mouse model of ESCC. 100% of mice treated with 4-NQO/IgG control antibody developed invasive squamous cell carcinoma. Less advanced esophageal tumors were seen in mice treated with 4-NQO/anti-GITR agonist compared to 4-NQO/IgG treatment. 4-NQO/anti-GITR agonist-treated mice demonstrated a significant increase in mucosal CTL/Treg ratios as well as decreased gene expression profiles of pathways related to esophageal squamous cell carcinogenesis. Thus, GITR agonism merits further study as a treatment strategy for ESCC patients.

Genomic Landscape of Advanced Solid Tumors in Circulating Tumor DNA and Correlation With Tissue Sequencing: A Single Institution's Experience.

PURPOSE: Circulating tumor DNA (ctDNA) has emerged as a promising noninvasive biomarker for baseline characterization and longitudinal monitoring of a tumor throughout disease management. The aim of this study was to evaluate the utility of ctDNA across a wide spectrum of tumor types. METHODS: We retrospectively identified 1,763 patients with advanced cancers who had next-generation sequencing of ctDNA or tumor tissue completed by a designated commercial assay at Northwestern University. RESULTS: ctDNA identified at least one gene alteration in 90% of patients. The number of detected alterations (NDA) and mutant allele frequency (MAF) of the most frequently mutated genes varied significantly across tumor types, with the highest MAF observed in gastric, colorectal, and breast cancers and the highest NDA observed in colorectal, lung squamous, and ovarian/endometrial cancers. TP53 was the most mutated gene in all tumor types. PIK3CA, ERBB2, BRCA1, and FGFR1 alterations were associated with breast cancer, and ESR1 mutations were exclusively detected in this tumor type. Colorectal cancer was characterized by alterations in KRAS and APC mutations, whereas KRAS, EGFR, PIK3CA, and BRAF mutations were common in lung adenocarcinoma. Concordance between blood and tissue sequencing was notably observed for truncal gene alterations (eg, APC and KRAS), whereas low concordance was often observed in genes associated with treatment resistance mechanisms (eg, RB1 and NF1). Tumor mutational burden (TMB) varied significantly across tumor types, and patients with high MAF or NDA had a significantly higher TMB score with one of the investigated platforms. CONCLUSION: The study provided new insights into the ctDNA mutational landscape across solid tumors, suggesting new hypotheses-generating data and caveats for future histotype-agnostic workflows integrated with tissue-based biomarkers such as TMB.

Prolonged response to checkpoint inhibitor therapy in two metastatic mucoepidermoid salivary gland carcinoma cases: a research report.

Salivary gland tumors (SGTs) are heterogeneous tumors that range from benign masses to aggressive high-grade carcinomas with distant metastatic potential and limited response to chemotherapy. Mucoepidermoid carcinoma (MEC) accounts for 10% of SGTs and has a poor prognosis. In this research report, we describe two cases of metastatic high-grade MECs with prolonged response to immune checkpoint inhibitor pembrolizumab. Case 1 presented with a left neck mass, and biopsy of the parotid mass revealed MEC. The patient underwent surgical resection and adjuvant chemoradiation therapy for stage IVB disease. Post-treatment, she was found to have brain and spinal metastases and was placed on pembrolizumab. Case 2 presented with a left neck mass, and biopsy of the right parotid gland revealed MEC. Further staging demonstrated metastatic disease in the lungs, and he was placed on pembrolizumab. Both cases of MEC demonstrated prolonged extracranial responses to pembrolizumab. Although both cases reported little to no PD-L1 expression, these results demonstrate immunotherapy efficacy in advanced/metastatic MEC.

Heterotopic SMARCB1-deficient high-grade transformed/dedifferentiated acinic cell carcinoma and sine-qua-non radiology- pathology with TNM challenge.

Heterotopic salivary tissue (HSGT) is found where salivary glands are not normally placed. HSGT manifests as accessory salivary glands, salivary tissue associated with branchial cleft anomalies, and true heterotopic salivary gland tissue. Benign and malignant salivary heterotopias have been described in the literature, with the most common reported neoplasm being Warthin tumor. In the malignant group, the most frequent tumors are mucoepidermoid carcinomas (MEC) and acinic cell carcinomas (AciCC). For the treating physician, this condition presents a diagnostic dilemma, whether these salivary heterotopias represent metastasis from orthotopic salivary origin or primary of heterotopic origin. We report a unique case of heterotopic high-grade/dedifferentiated SWI/SNF (SMARC-B1) deficient AciCC. A 48 yo male presented for evaluation of a persistently enlarged right sided lymph node for the past 6 months. A biopsy was performed, and initial interpretation was squamous cell carcinoma- p16 negative. Diffuse adenopathy and lack of an obvious primary source prompted a modified right neck dissection. Final pathological diagnosis was heterotopic SWI/SNF (SMARCB1)-deficient high-grade/dedifferentiated salivary AciCC. This case is an example of meticulous pathological investigation and multidisciplinary decision-making process of a heterotopic SMARCB1-deficient dedifferentiated AciCC. Heterotopic dedifferentiated AciCC are extremely rare (two cases reported so far), necessitating definitive surgery with neck dissection and adjuvant therapy. Long term outcomes are not known, and an adequate follow up is mandatory.

Patterns of Care in Maintenance Therapy in US Patients Undergoing Definitive Chemoradiation for Stage 3 Non-Small Cell Lung Cancer (NSCLC).

OBJECTIVE: The recommended treatment for patients with unresectable stage 3 non-small cell lung cancer (NSCLC) is definitive chemoradiation followed by 1 year of maintenance durvalumab. Our objective was to assess the rate of maintenance durvalumab use after chemoradiation. METHODS: Analyses were conducted in both open claims (IQVIA pharmacy and medical claims data) and adjudicated closed claims (IQVIA PharMetrics Plus Health Plan Claims Database). Patients with a lung cancer diagnosis between November 2017 and November 2020 who received definitive chemoradiation were included. RESULTS: Of the 5802 NSCLC patients included in the open claims source, 1794 (31%) received durvalumab, 1403 (24%) received maintenance chemotherapy, and 2605 (45%) did not receive any maintenance therapy. Of the 239 NSCLC patients included in the closed claims source, 127 (53%) received durvalumab, 40 (17%) received maintenance chemotherapy, and 72 (30%) did not receive any maintenance therapy. The most common maintenance chemotherapy agents patients received were carboplatin, pemetrexed, and paclitaxel. CONCLUSIONS: The rate of durvalumab utilization was overall low in both the open and closed claims data sources (31% and 53%, respectively). It remains unknown what percent of eligible patients end up receiving durvalumab, as our analysis was unable to filter out patients who were unfit for durvalumab or if they had progression after chemoradiation. Future efforts are needed to increase maintenance durvalumab utilization and to determine how best to manage patients who are unfit for durvalumab.