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Treatment options for patients with biliary tract cancer are limited, and the prognosis is poor. CTX-009, a novel bispecific antibody targeting both DLL4 and VEGF-A, has demonstrated antitumor activity in patients with advanced cancers as both a monotherapy and in combination with chemotherapy. In a phase II study of patients with advanced biliary tract cancer who had received one or two prior therapies, CTX-009 with paclitaxel demonstrated a 37.5% overall response rate (ORR). Described here is the design of and rationale for COMPANION-002, a randomized phase II/III study, which will evaluate the safety and efficacy of CTX-009 in combination with paclitaxel versus paclitaxel alone as second-line treatment for patients with advanced biliary tract cancer. The primary end point is ORR, and crossover is allowed.Clinical Trial Registration: NCT05506943 (ClinicalTrials.gov).
Looking for new options for patients with advanced biliary tract cancer? Explore COMPANION-002, Compass Therapeutics' phase II/III study of CTX-009 + paclitaxel as a second line treatment.#CMPX #biotech #healthcare #rarecancer.
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Intravascular lymphoma (IVL) is a rare extranodal non-Hodgkin lymphoma. We performed a retrospective analysis of 55 IVL patients who were treated at our institution 2003-2018. Median age at diagnosis was 68 years, and 64% were males. The most frequent presenting symptoms were skin rash 43% and weight loss 30%. MRI brain on IVL patients with CNS involvement (CNS-IVL) showed multifocal involvement in 76% (13/17). 89% (17/19) of non-CNS-IVL patients with abnormal FDG-PET had biopsy of an avid lesion resulting in definitive diagnosis. The top diagnostic biopsy site was the bone marrow (45%). 56% had multiorgan involvement. Based on CNS involvement, 36.5% (20/55) had CNS-IVL and 63.5% (35/55) had non-CNS-IVL. CNS-IVL group consists of clinically isolated CNS involvement (CNS-only IVL) (22%;12/55) and mixed clinical CNS and peripheral site involvement (M-IVL) (14.5%; 8/55). Non-CNS-IVL group consists of clinically isolated skin involvement (skin-only IVL) (9%; 5/55) and peripheral IVL with or without skin involvement (P-IVL); (54.5%; 30/55). Skin involvement was predominantly in the lower extremities. Pathologically, 89% (48/54) were B-cell IVL. Rituximab + high-dose methotrexate-based regimen were used in 75% (12/16) of CNS-IVL patients and RCHOP in 60% (17/28) of non-CNS-IVL patients. Estimated 5-year progression free survival (PFS) and overall survival (OS) for the entire cohort were 38.6% and 52%, respectively. Skin-only IVL was associated with excellent survival. Platelet count <150x109 /L, age > 60Y, and treatment without Rituximab were poor prognostic factors. Further research is necessary to identify novel therapies.
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Neoplasias del Sistema Nervioso Central , Linfoma de Células B , Linfoma de Células B Grandes Difuso , Linfoma no Hodgkin , Linfoma , Neoplasias Cutáneas , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Femenino , Humanos , Linfoma/patología , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Masculino , Pronóstico , Estudios Retrospectivos , Rituximab/uso terapéutico , Neoplasias Cutáneas/patologíaRESUMEN
Distress causes psychophysiological alterations that affect autonomic function. The current study explores psychophysiological modulation in diabetic distress in response to Surah Al-Rehman recitation. A single-group experimental study with before and after intervention assessments was conducted during April 2018 to February 2019 in which participants (n = 10) listened to Surah Al-Rehman recitation. Blood pressure, blood glucose, cortisol, ECG and EEG were recorded before and after recitation. Significant reduction in systolic blood pressure, increase in low frequency and absolute alpha power at Fp2 were observed. Heartbeat evoked potentials (HEP) were also significantly modulated at Fp1, Fp2 and F4. These findings suggest that Surah Al-Rehman modulated baroreflex activity thereby reducing sympathetic activity and improved heart brain coherence as reflected by HEP.
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Diabetes Mellitus , Hidrocortisona , Presión Sanguínea , Encéfalo , Glucosa , Frecuencia Cardíaca/fisiología , Humanos , PakistánRESUMEN
Immunoglobulin light-chain (AL) amyloidosis is a clonal plasma cell disorder characterised by production and deposition of misfolded monoclonal light chains in vital organs with potential to cause irreversible organ damage. The treatment of AL amyloidosis has evolved along the lines of multiple myeloma (MM) owing to clonal plasma cells being at the root of both disease processes. Treatment with melphalan and autologous haematopoietic cell transplantation, as well as proteasome inhibitors and immunomodulatory agents, are the standard of care for AL amyloidosis. While these treatment modalities are highly effective against the neoplastic plasma cells, patients often relapse and those with advanced disease may be unable to tolerate these treatments due to side-effects. Immunotherapy with monoclonal antibodies, bispecific antibodies, antibody-drug conjugates and chimeric antigen receptor T cells have revolutionised the treatment armamentarium for MM. These novel immunotherapy agents are in the early phases of evaluation and clinical development for patients with AL amyloidosis. The present review aims to discuss the role of novel immunotherapies currently in development and their potential for use in the treatment of AL amyloidosis.
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Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Inmunoconjugados/uso terapéutico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/terapia , Inmunoterapia Adoptiva , Humanos , Cadenas Ligeras de Inmunoglobulina/inmunología , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/inmunología , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/patologíaAsunto(s)
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Quinolinas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Compuestos de Fenilurea/efectos adversos , Quinolinas/uso terapéutico , Antineoplásicos/uso terapéutico , Receptor ErbB-2 , Receptores ErbB/genéticaRESUMEN
OBJECTIVE: Gastrointestinal bleeding (GIB) is a common cause of hospitalization in the older adult population. The aim of the study was to identify factors that are associated with the need for a therapeutic intervention in patients older than 65 years with nonvariceal GIB. METHODS: This is a retrospective cohort study of older adult patients admitted to a tertiary care center between 2009 and 2011 with nonvariceal GIB. The primary outcome was a composite endpoint of inpatient mortality or need for an endoscopic, surgical, or radiologic procedure to control the bleed or to treat the underlying source of the bleed. RESULTS: A total of 314 patients were included. In-hospital mortality was 1.3% (4 patients). An intervention to control the bleeding was performed in 15 patients (4.8%). Four patients (1.3%) needed a nonurgent intervention. Twenty-three patients (7.23%) had the primary combined outcome of in-hospital mortality or need for any therapeutic endoscopic, surgical, or radiologic intervention. Factors that were independently associated with the primary outcome were systolic blood pressure within the first 24 hours of <90 mm Hg (odds ratio 3.05, 95% confidence interval 1.08-8.59, P = 0.001), and initial hemoglobin of <7 g/dL (odds ratio 4.81, 95% confidence interval 1.56-14.74, P = 0.006). CONCLUSIONS: Nonvariceal GIB in older adult patients ceases spontaneously in most patients without an invasive intervention. Systolic blood pressure within the first 24 hours of <90 mm Hg and an initial hemoglobin level of <7 g/dL could be used to identify high-risk patients who may benefit from an urgent therapeutic intervention.
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Hemorragia Gastrointestinal , Manejo de Atención al Paciente/métodos , Anciano , Femenino , Florida/epidemiología , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/mortalidad , Hemorragia Gastrointestinal/terapia , Evaluación Geriátrica/métodos , Mortalidad Hospitalaria , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Remisión Espontánea , Estudios Retrospectivos , Medición de Riesgo , Factores de RiesgoRESUMEN
Despite improvements in overall cancer mortality, deaths related to pancreatic cancer continue to rise. Following first-line treatment, second-line options are significantly limited. Classically, first-line treatment consisted of either gemcitabine or 5-fluorouracil based systemic chemotherapy. Upon progression of disease or recurrence, subsequent second-line treatment is still gemcitabine or 5-fluorouracil based chemotherapy, depending on what was used in the first line and the timing of progression or recurrence. A better understanding of the molecular underpinnings of pancreatic adenocarcinoma (PDAC) has led to new treatment strategies including specifically targeting the desmoplastic stroma, cytokine signaling and actionable mutations. Furthermore, efforts are also directed to enhance the immunogenicity profile of PDAC's well-established immunologically "cold" tumor microenvironment. More recently, the outstanding response rates of chimeric antigen receptor T (CAR-T) cells in hematologic malignancies, have led to clinical trials to evaluate the treatment modality in PDAC. In this review, we summarize recently presented clinical trials for metastatic pancreatic adenocarcinoma with novel treatment approaches in the second line and beyond.
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INTRODUCTION: The Leukemia Inhibitory Factor (LIF) is a member of the interleukin-6 (IL-6) cytokine family. Known to induce differentiation of myeloid leukemia cells, evidence has accumulated supporting its role in cancer evolution through regulating cell differentiation, renewal, and survival. LIF has recently emerged as a biomarker and therapeutic target for pancreatic ductal adenocarcinoma (PDAC). The first in-human clinical trial has shown promising safety profile and has suggested a potential role for LIF inhibitor in combination regimen. AREAS COVERED: Herein, we summarize, discuss, and give an expert opinion on the role of LIF in PDAC promotion, and its potential role as a biomarker and target of anti-cancer therapy. We conducted an exhaustive PubMed search for English-language articles published from 1 January 1970, to 1 August 2022. EXPERT OPINION: PDAC carries a devastating prognosis for patients, highlighting the need for advancing drug development. The results of the phase 1 trial with MSC-1 demonstrated tolerability and safety but modest efficacy. Future research should focus on investigating LIF targets in combination with current standard-of-care chemotherapy, and immunotherapy can be a promising approach. Further, larger multicenter clinical trials are needed to define the use of LIF as a new biomarker in PDAC patients.
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Adenocarcinoma , Antineoplásicos , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Factor Inhibidor de Leucemia/uso terapéutico , Adenocarcinoma/tratamiento farmacológico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Antineoplásicos/farmacología , Biomarcadores , Estudios Multicéntricos como Asunto , Neoplasias PancreáticasRESUMEN
ALK-EML4 fusion-positive lung adenocarcinomas (LUADs) are effectively treated with ALK tyrosine kinase inhibitors, but most patients eventually develop resistance to these drugs owing to ALK-dependent or independent mechanisms. Endothelial to mesenchymal transformation with SCLC development is an ALK-independent mechanism of resistance that has not been previously reported with sequential ALK I1171T mutation while the patient is on treatment for the SCLC. Here, we report the first case of sequential SCLC transformation followed by ALK I1171T mutation in a patient with ALK-EML4 fusion-positive LUAD. After progression on multiple lines of therapy, we describe our experience of managing ALK-mutant LUAD and transformed SCLC with a novel combination of lorlatinib and temozolomide. We also briefly summarize cases of endothelial to mesenchymal transformation ALK-mutant LUAD from the literature.
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Recurrent hepatocellular carcinoma (HCC) poses a significant challenge after liver transplantation, affecting approximately 10-23% of patients with a median onset of 13 months post-transplantation. Extrahepatic involvement, such as lung, bone, adrenal glands, peritoneum, lymph nodes, and central nervous system (CNS), is commonly observed among transplant recipients with HCC recurrence. Notably, vascular invasion (VI), including microvascular invasion (MiVI) and macrovascular invasion (MVI), substantially increase the risk of recurrence by 2.42- and 7.82-fold, respectively. This article presents a unique case of a 72-year-old male patient with a history of HCV-related cirrhosis and HCC who underwent orthotopic liver transplantation (OLT). Six years later, he presented to the emergency department following a fall, which led to the discovery of a pathologic fracture of T7 and an incidental intracranial mass during imaging. Subsequent biopsy confirmed metastatic HCC in the T7 lesion, while magnetic resonance imaging revealed two enhancing brain masses. One mass measured 4.8 cm in the left occipitotemporal lobe, and the other measured 1.7 cm in the right frontal gyrus. Notably, the patient had exhibited MiVI and a mildly elevated alpha-fetoprotein level (AFP) of 7.6 ng/mL at the time of his OLT. This case underscores the predictive value of MiVI in HCC recurrence post-OLT. Accordingly, extended post-transplantation surveillance is crucial for patients with HCC and MiVI. Moreover, this report highlights the uncommon occurrence of delayed brain metastasis following OLT in a patient with HCC.
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Neoplasias Encefálicas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Trasplante de Hígado , Masculino , Humanos , Anciano , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Trasplante de Hígado/efectos adversos , Cirrosis Hepática/complicaciones , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/cirugía , Recurrencia Local de Neoplasia , Estudios RetrospectivosRESUMEN
Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC) occurs due to microsatellite instability (MSI) caused by mutations in one of the mismatch repair genes leading to deficient mismatch repair proteins (dMMR). Although lung cancer is very common there is no established association between LS and lung cancer. In this manuscript we describe a case of lung cancer in a LS patient and then summarize available literature on this topic. Sixty seven y/o female patient with history of stage I colon and urothelial cancer, meeting the Amsterdam criteria, was diagnosed with LS on genetic testing. Sixteen years after the diagnosis of colon cancer, she was found to have adenocarcinoma of the lung with Next-generation sequencing (NGS) testing revealing the presence of germline mutation in MSH2 in the tumor cells indicating the possibility of LS driven lung cancer. However, subsequent immunohistochemistry (IHC) on tumor cells indicated proficient mismatch repair genes confirming the sporadic nature of lung cancer. On review of literature, we found that the coincidental presence of lung cancer in patients with LS can sometimes be mistaken for causation and may lead to confusion. Lynch syndrome associated tumors which are microsatellite instable (MSI) can be treated effectively with immunotherapy with durable responses, however, not all tumors in patient with LS are MSI impacting the choice of therapy.
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Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Pulmonares , Femenino , Humanos , Neoplasias Colorrectales Hereditarias sin Poliposis/complicaciones , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Mutación de Línea Germinal , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/genética , Inestabilidad de Microsatélites , Mutación , AncianoRESUMEN
Purpose: To compare the outcomes of radiation segmentectomy for early-stage hepatocellular carcinoma (HCC) in patients with non-alcoholic fatty liver disease (NAFLD) versus hepatitis C virus (HCV). Materials and Methods: A retrospective analysis of consecutive patients with NAFLD- or HCV-related HCC treated with radiation segmentectomy from 01/2017-06/2022 was performed. Eligibility criteria included solitary tumor ≤8 cm or up to 3 HCC ≤3 cm, ECOG 0-1, and absence of vascular invasion or extrahepatic spread. Imaging best response was assessed per modified Response Evaluation Criteria in Solid Tumors. Target tumor and overall progression, time-to-progression (TTP), and overall survival (OS) were calculated. All outcomes were censored for liver transplantation (LT). Complete pathologic response (CPN) was assessed in patients who underwent LT. Results: Of 142 patients included (NAFLD: 61; HCV: 81), most had cirrhosis (NAFLD: 87%; HCV: 86%) and small tumors (median size NAFLD: 2.3 cm; HCV: 2.5 cm). Patients with NAFLD had higher BMI (p<0.001) and worse ALBI scores (p=0.003). Patients with HCV were younger (p<0.001) and had higher AFP levels (p=0.034). Median radiation dose (NAFLD: 508 Gy; HCV: 452 Gy) and specific activity (NAFLD: 700 Bq; HCV: 698 Bq) were similar between cohorts. Objective response was 100% and 97% in the NAFLD and HCV cohorts, respectively. Target tumor progression occurred in 1 (2%) NAFLD and 8 (10%) HCV patients. Target tumor TTP was not met for either cohort. Overall progression occurred in 23 (38%) NAFLD and 39 (48%) HCV patients. Overall TTP was 17.4 months (95% CI 13.5-22.2) in NAFLD and 13.5 months (95% CI 0.4-26.6) in HCV patients (p=0.86). LT was performed in 27 (44%) NAFLD and 33 (41%) HCV patients, with a CPN rate of 63% and 54%, respectively. OS was not met in the NAFLD cohort and was 53.9 months (95% CI 32.1-75.7) in the HCV cohort (p=0.15). Conclusion: Although NAFLD and HCV are associated with different mechanisms of liver injury, patients with early-stage HCC treated with radiation segmentectomy achieve comparable outcomes.
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Pancreatic cancer (PC) remains one of the most challenging diseases, with a very poor 5-year overall survival of around 11.5%. Kirsten rat sarcoma virus (KRAS) mutation is seen in 90%-95% of PC patients and plays an important role in cancer cell proliferation, differentiation, metabolism, and survival, making it an essential mutation for targeted therapy. Despite extensive efforts in studying this oncogene, there has been little success in finding a drug to target this pathway, labelling it for decades as "undruggable". In this article we summarize some of the efforts made to target the KRAS pathway in PC, discuss the challenges, and shed light on promising clinical trials.
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OBJECTIVES: The incidence and predictors of pneumonitis for patients with unresectable, locally advanced non-small cell lung cancer (NSCLC) in the era of consolidation durvalumab have yet to be fully elucidated. In this large single institution analysis, we report the incidence of and factors associated with grade 2 + pneumonitis in NSCLC patients treated with the PACIFIC regimen. MATERIALS AND METHODS: We identified all patients treated at our institution with definitive CRT followed by durvalumab from 2018 to 2021. Clinical documentation and imaging studies were reviewed to determine grade 2 + pneumonitis events, which required the following: 1) pulmonary symptoms warranting prolonged steroid taper, oxygen dependence, and/or hospital admission and 2) radiographic findings consistent with pneumonitis. RESULTS: One-hundred ninety patients were included. The majority received 60 Gray (Gy) in 30 fractions with concurrent carboplatin and paclitaxel. Median number of durvalumab cycles received was 12 (IQR: 4-22). At a median follow-up of 14.8 months, 50 (26.3%) patients experienced grade 2 + pneumonitis with a 1-year cumulative incidence of 27.8% (95% CI: 21.9-35.4). Seventeen (8.9%) patients experienced grade 3 + pneumonitis and 4 grade 5 (2.1%). Dosimetric predictors of pneumonitis included ipsilateral and total lung volume receiving 5 Gy or greater (V5Gy), V10Gy, V20Gy, V40Gy, and mean dose and contralateral V40Gy. Heart V5Gy, V10Gy, and mean dose were also significant variables. Overall survival estimates at 1 and 3 years were 87.4% (95% CI: 82.4-92.8) and 60.3% (95% CI: 47.9-74.4), respectively. CONCLUSION: We report a risk of pneumonitis higher than that seen on RTOG 0617 and comparable to the PACIFIC study. Multiple lung and heart dosimetric factors were predictive of pneumonitis.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neumonía , Neumonitis por Radiación , Anticuerpos Monoclonales , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Quimioradioterapia/efectos adversos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neumonía/complicaciones , Neumonía/etiología , Neumonitis por Radiación/diagnóstico , Neumonitis por Radiación/epidemiología , Neumonitis por Radiación/etiología , Dosificación RadioterapéuticaRESUMEN
PURPOSE: This investigation sought to evaluate the prognostic value of pretreatment of circulating tumor DNA (ctDNA) in metastatic biliary tract cancers (BTCs) treated with platinum-based first-line chemotherapy treatment. MATERIALS AND METHODS: We performed a retrospective analysis of 67 patients who underwent ctDNA testing before platinum-based chemotherapy for first-line treatment for metastatic BTC. For analysis, we considered the detected gene with highest variant allele frequency as the dominant clone allele frequency (DCAF). Results of ctDNA analysis were correlated with patients' demographics, progression-free survival (PFS), and overall survival (OS). RESULTS: The median age of patients was 67 (27-90) years. Fifty-four (80.6%) of 67 patients evaluated had intrahepatic cholangiocarcinoma; seven had extrahepatic cholangiocarcinoma, and six gallbladder cancers. Forty-six (68.6%) of the patients were treated with cisplatin plus gemcitabine, and 16.4% of patients received gemcitabine and other platinum (carboplatin or oxaliplatin) combinations, whereas 15% of patients were treated on a clinical trial with gemcitabine and cisplatin plus additional agents (CX4945, PEGPH20, or nab-paclitaxel). TP53, KRAS, FGFR2, ARID1A, STK11, and IDH1 were the genes with highest frequency as DCAF. The median DCAF was 3% (0%-97%). DCAF > 3% was associated with worse OS (median OS: 10.8 v 18.8 months, P = .032). Stratifying DCAF in quartiles, DCAF > 10% was significantly related to worse PFS (median PFS: 3 months, P = .014) and worse OS (median OS: 7.0 months, P = .001). Each 1% increase in ctDNA was associated with a hazard ratio of 13.1 in OS when adjusting for subtypes, metastatic sites, size of largest tumor, age, sex, and CA19-9. CONCLUSION: DCAF at diagnosis of advanced BTC can stratify patients who have worse outcomes when treated with upfront platinum-based chemotherapy. Each increase in %ctDNA decreases survival probabilities.
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Neoplasias de los Conductos Biliares , Neoplasias del Sistema Biliar , Colangiocarcinoma , ADN Tumoral Circulante , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Conductos Biliares Intrahepáticos/patología , Neoplasias del Sistema Biliar/tratamiento farmacológico , Colangiocarcinoma/tratamiento farmacológico , Cisplatino , Células Clonales/patología , Frecuencia de los Genes , Humanos , Platino (Metal)/uso terapéutico , Estudios RetrospectivosRESUMEN
Lung cancer remains the leading cause of cancer-related mortality in both men and women in the US and worldwide. Non-small cell lung cancer is the most common variety accounting for 84% of the cases. For a subset of patients with actionable mutations, targeted therapy continues to provide durable responses. Advances in molecular and immunohistochemical techniques have made it possible to usher lung cancer into the era of personalized medicine, with the patient getting individualized treatment based on these markers. This review summarizes the recent advances in advanced NSCLC targeted therapy, focusing on first-in-human and early phase I/II clinical trials in patients with advanced disease. We have divided our discussion into different topics based on these agents' mechanisms of action. This article is aimed to be the most current review of available and upcoming targeted NSCLC treatment options. We will also summarize the currently available phase I/II clinical trial for NSCLC patients at the end of each section.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Animales , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Receptores ErbB/antagonistas & inhibidores , Humanos , Terapia Molecular Dirigida , Medicina de PrecisiónRESUMEN
While first line targeted therapies are the current standard of care treatment for non-small cell lung cancer (NSCLC) with actionable mutations, the cancer cells inevitably acquire resistance to these agents over time. Immune check-point inhibitors (ICIs) have improved the outcomes of metastatic NSCLC, however, its efficacy in those with targetable drivers is largely unknown. In this manuscript, we reviewed the published data on ICI therapies in NSCLC with ALK, ROS1, BRAF, c-MET, RET, NTRK, KRAS, and HER2 (ERBB2) alterations. We found that the objective response rates (ORRs) associated with ICI treatments in lung cancers harboring the BRAF (0-54%), c-MET (12-49%), and KRAS (18.7-66.7%) alterations were comparable to non-mutant NSCLC, whereas the ORRs in RET fusion NSCLC (less than10% in all studies but one) and ALK fusion NSCLC (0%) were relatively low. The ORRs reported in small numbers of patients and studies of ROS1 fusion, NTRK fusion, and HER 2 mutant NSCLC were 0-17%, 50% and 7-23%, respectively, making the efficacy of ICIs in these groups of patients less clear. In most studies, no significant correlation between treatment outcome and PD-L1 expression or tumor mutation burden (TMB) was identified, and how to select patients with NSCLC harboring actionable mutations who will likely benefit from ICI treatment remains unknown.
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Over the last decade, the treatment of advanced non-small cell lung cancer (NSCLC) has undergone rapid changes with innovations in oncogene-directed therapy and immune checkpoint inhibitors. In patients with epidermal growth factor receptor (EGFR) gene mutant (EGFRm) NSCLC, newer-generation tyrosine kinase inhibitors (TKIs) are providing unparalleled survival benefit and tolerability. Unfortunately, most patients will experience disease progression and thus an urgent need exists for improved subsequent lines of therapies. The concurrent revolution in immune checkpoint inhibitor (ICI) therapy is providing novel treatment options with improved clinical outcomes in wild-type EGFR (EGFRwt) NSCLC; however, the application of ICI therapy to advanced EGFRm NSCLC patients is controversial. Early studies demonstrated the inferiority of ICI monotherapy to EGFR TKI therapy in the first line setting and inferiority to chemotherapy in the second line setting. Additionally, combination ICI and EGFR TKI therapies have demonstrated increased toxicities, and EGFR TKI therapy given after first-line ICI therapy has been correlated with severe adverse events. Nonetheless, combination therapies including dual-ICI blockade and ICI, chemotherapy, and angiogenesis inhibitor combinations are areas of active study with some intriguing signals in preliminary studies. Here, we review previous and ongoing clinical studies of ICI therapy in advanced EGFRm NSCLC. We discuss advances in understanding the differences in the tumor biology and tumor microenvironment (TME) of EGFRm NSCLC tumors that may lead to novel approaches to enhance ICI efficacy. It is our goal to equip the reader with a knowledge of current therapies, past and current clinical trials, and active avenues of research that provide the promise of novel approaches and improved outcomes for patients with advanced EGFRm NSCLC.
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Macrophage activation leading to multi-organ dysfunction/failure has been described in various hematologic disorders like hemophagocytic lympho-histiocytosis (HLH), also known as macrophage activation syndrome (MAS) and macrophage activation like syndrome (MALS). Congestive heart failure (CHF) appears to be an uncommon manifestation of macrophage activation. This novel entity of macrophage activation-associated cytokine-mediated CHF has not been well reported in the medical literature. We report two young female patients with acute CHF secondary to macrophage activation-associated cytokine storm. An extensive diagnostic workup was negative for other etiologies, such as ischemia, myocarditis, or infections. Their clinical, laboratory, and pathologic findings did not meet the diagnostic criteria for hemophagocytic syndrome (HPS)/MAS. However, both had laboratory and pathologic findings which were consistent with macrophage activation and cytokine storm. One patient met criteria for MALS. Therapeutically, our patients were promptly treated with steroids with or without anti-cytokine therapy with rapid restoration of cardiac function. Macrophage activation-induced disease may not always fulfil the diagnostic criteria for the currently known macrophage activation disorders. We suggest that markers of macrophage activation and cytokine levels should be part of the diagnostic workup in patients with otherwise unexplained acute CHF. Additional research is warranted to further elucidate the underlying mechanism of this disorder.
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Alpelisib is a PIK3a inhibitor approved for the treatment of metastatic ER+ breast cancer in combination with fulvestrant. Although rash is a common side effect of this medication, we present the first case of drug reaction with eosinophilia and systemic symptoms (DRESS) upon initial exposure to alpelisib. Here we describe the clinical-pathological findings and management of our patient with alpelisib-induced life-threatening DRESS syndrome. The goal of this case report is to highlight association of alpelisib with DRESS syndrome, in clinical practice, so that alpelisib can be immediately stopped and treatment for this serious condition promptly initiated.